Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7].CN(C)C=O.Cl[CH2:34][C:35]#[CH:36].[H-].[Na+]>O>[F:27][CH:2]([F:1])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:36][C:35]#[CH:34])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)ccc1O
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)cc1OC
Yield: 13.4 %

Procedure:
477 mg (1.20 mmol) of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(4-chlorophenyl)acrylamide, 5 ml of anhydrous N,N-dimethylformamide, 180 mg (2.40 mmol) of 3-chloropropyne and 72 mg (1.80 mmol) of 60% sodium hydride were stirred at room temperature for 2 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 70 mg of 3-difluoromethoxy-N-[2-{3-methoxy-4-(2-propynyloxy)phenyl}ethyl]-2-(4-chlorophenyl)acrylamide (the present compound 1355).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4](I)[CH:3]=1.[Cu][C:12]#[N:13]>CC(N(C)C)=O>[NH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=1[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: Nc1cc(F)c(Cl)cc1I
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(Cl)c(F)cc1N
Yield: 78.4 %

Procedure:
A solution of 4-chloro-5-fluoro-2-iodo-phenylamine (2.5 g, 9.21 mmol) and copper (I) cyanide (1.65 g, 18.4 mmol) in DMA (45 ml) was heated to 130° C. overnight. Most of the DMA was removed under reduced pressure and the remaining residue was diluted with EtOAc and dichloromethane. The slurry was filtered and the filter cake was washed with dichloromethane and EtOAc. The filtrate was concentrated and the remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 98:2-85:15) to afford the title compound (1232 mg, 78%) as light red solid. MS (ESI): 169.2 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Br:27][CH:28]([CH2:32][CH3:33])[C:29](Br)=[O:30]>C(Cl)Cl>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=[C:11]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:30])[CH:28]([Br:27])[CH2:32][CH3:33])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(N)ccc1-c1cc2ccccc2s1
Reactant: CCC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Br)C(=O)Nc1ccc(-c2cc3ccccc3s2)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-(1-benzothien-2-yl)benzamide (Example 8A, 886 mg) and triethylamine (650 mg) are introduced into DCM (20 ml) at 0° C., and 2-bromobutyryl bromide (1000 mg) is slowly added. The reaction mixture is warmed to RT and then stirred overnight. The reaction mixture is subsequently diluted with DCM (100 ml) and washed with 5% strength potassium bisulfate solution (twice 50 ml), dried (sodium sulfate) and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (eluent cyclohexane-ethyl acetate 10:1 to 1:1). After concentration of the relevant fraction, 607 mg (47% of theory) of product are isolated.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[CH3:32][C:2]([O:1][C:34](=[O:36])[CH3:35])([CH3:33])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)(O)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC(C)(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 19, making variations only as required to use 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl)amide in place of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide to react with acetic anhydride, the title compound was obtained as a white powder (80% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 8.01, 7.75, 7.65, 7.57, 7.37, 6.99, 4.06, 3.88, 3.81-3.67, 3.58, 3.36, 2.06, 2.01, 1.52. MS (ES+) m/z 508 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:17]([O-])=O)[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[H][H].C([O-])(O)=O.[Na+]>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: [H][H]
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
6-chloro-7-methoxy-8-nitro-9H-β-carboline (510 mg, 1.84 mmol) was suspended in 50 ml of methanol and 100 mg of Pd/C (10%) was added. The flask was fitted with a balloon of hydrogen and the reaction mixture was stirred overnight at RT. Upon filtration through a pad of celite and evaporation of the methanol, a dark brown solid was obtained. This residue was suspended in methanol (15 ml) and added, with vigorous stirring, to a solution of saturated NaHCO3 (100 ml). The light brown solid that precipitated out was collected by filtration and dried thoroughly in vacuo to give the desired product (512 mg, quantitative yield).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH:15]=O)[C:13]=2[N:14]=1>>[CH3:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([N:14]=1)=[C:12]([CH2:15][NH:2][CH3:1])[CH:11]=[CH:10][CH:9]=2
Reactant: CN
Reactant: COc1cnc2cccc(C=O)c2n1
Product: CNCc1cccc2ncc(OC)nc12

Procedure:
Methylamine (2M in THF, 5 mL) and 3-methoxy-quinoxaline-5-carbaldehyde (0.94 g, 5 mmol, prepared according to WO 2006/021448) were coupled according to method K. The title amine was isolated as a yellowish solid (0.52 g, 51% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[N+:17]([O-])([OH:19])=[O:18].C([O-])(O)=O.[Na+]>CC(O)=O.O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])O
Reactant: CNc1nccc(Oc2ccc(O)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1nccc(Oc2ccc(O)c([N+](=O)[O-])c2)n1
Reaction time: 18 h

Procedure:
4-(2-Methylamino-pyrimidin-4-yloxy)-phenol (Step C, 0.20 g, 0.92 mmol) was dissolved in 5 mL AcOH at RT. Fuming HNO3 (0.064 g, 0.92 mmol) was diluted with about 0.012 mL water, then added dropwise over 1 min to the reaction. The reaction was stirred for 18 h, after which it was added slowly to 40 mL saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using hexanes/EtOAc gradient to yield the title compound. MS (MH+)=263.1; Calc'd 262.23 for C11H10N4O4.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH:6]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:29])(=[O:28])[N:25]([CH3:27])[CH3:26])[NH:13][C:12]=2[CH:11]=1)([CH3:8])[CH3:7]>>[CH:6]([O:9][C:10]1[CH:23]=[CH:22][C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[S:24](=[O:28])(=[O:29])[N:25]([CH3:27])[CH3:26])[N:13]([CH2:2][CH2:3][CH2:4][Cl:5])[C:12]=2[CH:11]=1)([CH3:8])[CH3:7]
Reactant: ClCCCBr
Reactant: CC(C)Oc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Product: CC(C)Oc1ccc2c(c1)N(CCCCl)c1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 96.6 %

Procedure:
Crude 2-isopropoxy-6-dimethylsulphamoyl-10-(3-chloropropyl)phenothiazine (60.8 g.) is prepared by reacting 1-bromo-3-chloropropane (80.8 g.) with 2-isopropoxy-6-dimethylsulphamoylphenothiazine (m.p. 187°-189°C.; 52.0 g.).
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[CH:9]([CH3:12])[CH2:10][O:11][C:7]=2[C:6]([O:13][CH3:14])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:14][O:13][C:6]1[C:7]2[O:11][CH2:10][CH:9]([CH3:12])[C:8]=2[C:3]([CH2:2][NH:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(CO)c2c1OCC2C
Product: COc1ccc(CNc2ccncc2)c2c1OCC2C
Yield: 26.5 %

Procedure:
Substantially the same procedure as in Step B of Example 48 was repeated using Compound 59a obtained in Step A of Example 59 and using 4-aminopyridine instead of 4-mercaptopyridine to give Compound 61 (26.5%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(Cl)Cl>[CH:24]([NH:27][C:4](=[O:6])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: O=C(O)c1c(F)cccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)NC(=O)c1c(F)cccc1F

Procedure:
A solution of 2,6-difluorobenzoic acid (10 g, 63 mmol) and carbonyldiimidazole (10.26 g, 63.5 mmol) in 300 mL methylene chloride was stirred for 1 hour at ambient temperature. Isopropyl amine (5.39 mL, 63.25 mmol) was added and stirring was continued over night. An equivalent volume of methylene chloride was added, and the reaction mixture was washed with water, 1M NaOH, 1M HCl, and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo to give a near quantitative yield of the amide as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:13])=[O:12]
Reactant: COC(=O)CCCN
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: COC(=O)CCCNS(=O)(=O)c1ccc2ccccc2c1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-naphthylsulphonyl chloride was reacted with methyl 4-aminobutyrate to give methyl 4-(2-naphthalenesulphonamido)butyrate in 94% yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.I[CH:26]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29]4)[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Product: CC(C)(C)OC(=O)N1CC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Yield: 100.7 %

Procedure:
Following the general method as outlined in Intermediate 16, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 812 mg; 2.38 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (674 mg; 2.38 mmol), 1.19 g (100%) of the title compound was obtained as a yellow solid, which was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[N:28]([CH3:30])[CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([S:24](=[O:26])(=[O:27])[NH2:25])=[CH:20][CH:19]=3)[C:9]=2[N:28]([CH3:30])[CH3:29])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(N(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1c(-c2ccc(Cl)cc2)sc(C(=O)O)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 34e, 2.00 g, 4.30 mmol) was suspended in ethanol (30 ml) and solution of NaOH (0.86 g, 21.5 mmol) in water (4 ml) was added to it at 25° C. The reaction mixture was then heated at 75° C. under stirring for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was diluted with water (10 ml) and cooled using ice bath. To the cooled mixture was added aqueous 10% HCl to bring the pH of the solution to about 6. The mixture so obtained was extracted with ethyl acetate (3×30 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain the title compound (1.60 g, 85.1%)
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:17]([CH:29]=[CH2:30])=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.O>C(Cl)Cl>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:18]3[C:17]([CH:29]=[CH2:30])=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:19]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: C=Cc1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C=Cc1cnc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 0.5 h
Yield: 106 %

Procedure:
A mixture of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-vinylpyrimidin-2-yl)thiophene-2-sulfonamide (80 mg, 0.17 mmol) and BCl3 (3 mL) in DCM (10 mL) was stirred for 0.5 h, Water was added and extracted with EA. The combined organic layers were dried (NaHSO4), filtered. The filtrate was concentrated to afford the compound 5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-vinylpyrimidin-2-yl)thiophene-2-sulfonamide (Compound 209) (70 mg, 90%). LC-MS (m/z)=389 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.80-0.81 (m, 2H), 1.01-1.04 (m, 2H), 1.96-2.02 (m, 1H), 5.50 (d, J=11.6 Hz, 1H), 5.96 (d, J=17.2 Hz, 1H), 6.43 (s, 1H), 7.08-7.15 (m, 1H), 7.63 (d, J=4 Hz, 1H), 7.87 (bs, 2H), 8.00 (bs, 1H), 8.56 (s, 1H), 10.13 (bs, 1H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=2)O1>>[CH:12]1([NH:11][C:10]2[C:5]3[N:6]([C:2]([C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=4)=[CH:3][N:4]=3)[CH:7]=[CH:8][N:9]=2)[CH2:14][CH2:13]1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1cnc2c(NC3CC3)nccn12
Product: CC(=O)Nc1ccc(-c2cnc3c(NC4CC4)nccn23)cc1
Yield: 12 %

Procedure:
Using Method 2, the title compound was prepared in 12% yield from 3-bromo-imidazo[1,2-a]pyrazin-8-yl)-cyclopropyl-amine (Example 6) and N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetamide (from Aldrich).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH3:23])[N:20]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)[N:19]=4)[O:16][CH:17]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:14]=[C:15]([C:18]4[CH:22]=[C:21]([CH3:23])[N:20]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=5)[N:19]=4)[O:16][CH:17]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(C5=CCCCC5)cc4)co3)cc2C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(C5CCCCC5)cc4)co3)cc2C)cc1
Yield: 43.3 %

Procedure:
A solution of 4-(4-cyclohex-1-en-1-ylphenyl)-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,3-oxazole (Example 80, 30 mg, 0.073 mmol) in ethanol (1.5 ml) was hydrogenated in a continuous-flow reactor (H-cube, Thales Nano, Hungary) at an hydrogen pressure of 1 bar at rt with a flow rate of 1 ml/min using palladium (10% on charcoal) as a stationary phase. After evaporation of the solvent, the crude material was purified by preparative HPLC to afford the title compound as a white solid (13 mg, 43%): 1H NMR (400 MHz, DMSO-d6) 8.57 (s, 1H), 7.72 (d, 2H), 7.29 (d, 2H), 7.17 (d, 2H), 7.07 (d, 2H), 6.67 (s, 1H), 5.36 (s, 2H), 3.51-3.40 (m, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 1.82-1.69 (m, 4H), 1.48-1.22 (m, 6H); ES-MS m/z 412, HPLC RT (Method D) 3.52 min.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:14])=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([Cl:14])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 100 °C

Procedure:
A solution of 4-carboxybenzaldehyde (30.0 g, 0.200 mol) in toluene (300 mL) was treated with thionyl chloride (28.6 g, 0.240 mol) and DMF (1.0 mL). The reaction mixture was heated at 100° C. for 2 h, during which time the solids dissolved to yield a pale yellow colored solution. The reaction mixture was cooled to 0° C. to yield a solution of the title compound in toluene, which was used without further manipulation.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[N:16]=1.C(Cl)Cl>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1ccccc1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
To a suspension of 0.70 g (28.3 mmol) of sodium hydride in 40 mL of benzene was added 1.90 g (24.5 mmol) of methyl glycolate and 6.00 g (18.9 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine. The mixture was heated at 60° C. and monitored by TLC (silica, methylene chloride) for conversion to product. After 3 days, an additional 0.70 g (28.3 mmol) of sodium hydride and 1.90 g (24.5 mmol) of methyl glycolate was added to the reaction. After an additional 3 days, the reaction was cooled to ambient temperature and partitioned by the addition of 100 mL of 2 M sodium hydrogen sulfate and 200 mL of ethyl acetate. The aqueous phase was extracted twice with 50 mL portions of ethyl acetate. The-combined organic phases were dried with magnesium sulfate and concentrated to 7.85 g of yellow solid. The solid was purified by flash chromatography (500 g silica, step gradient from 1:1 heptane-methylene chloride to methylene chloride) to provide 6.35 g (90%) of [[2-(methylthio)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.25 (t, J=7.5 Hz, 3H), 2.54 (s, 3H), 2.58 (q, J=7.5 Hz, 2H), 3.79 (s, 3H), 5.05 (s, 2H), 5.40 (s, 2H), 6.30 (s, 1H), 7.07 (d, J=7.1 Hz, 2H), 7.24 (m, 3H)
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].Cl[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH3:20]>C(Cl)(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]([C:17]1[CH:16]=[CH:15][C:14]([S:19][CH3:20])=[C:13]([Cl:12])[CH:18]=1)=[O:11]
Reactant: COC(=O)C(=O)Cl
Reactant: CSc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)C(=O)c1ccc(SC)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A solution of aluminum trichloride (54.9 g, 412 mmol) in chloroform (180 mL) under argon was cooled to 0° C. and then treated dropwise with a solution of methyl chlorooxoacetate (24.3 mL, 264 mmol) in chloroform (180 mL). The reaction mixture was stirred at 0° C. for 30 min and then was treated dropwise with a solution of 2-chlorothioanisole (39.4 g, 247 mmol) in chloroform (180 mL). The reaction mixture turned red in color. The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 4 h. The reaction mixture was then slowly poured onto ice (700 mL). The resulting yellow mixture was stirred for 15 min and then was filtered through celite to remove the aluminum salts. The filtrate was then extracted with methylene chloride (3×50 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (1×50 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (3-chloro-4-methylsulfanyl-phenyl)-oxo-acetic acid methyl ester (36.4 g, 60%) as a light yellow oil: EI-HRMS m/e calcd for C10H9ClO3S (M+) 243.9961, found 243.9958.