Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 4-Chloro-5-methyl-2-nitro-phenol (3.752 g, 20.0 mmol), 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.83 g, 24 mmol), and triphenylphosphine (6.23 g, 24 mmol) in 75 mL THF is added diisopropyl asodicarboxylate (4.73 mL, 245 mmol) in several portions at 22° C. for 1 h. The reaction is stirred at the same temperature for an additional 2 hrs. The reaction mixture is concentrated in vacuo. The residue is taken up in 50 mL ether, and let stand at 22° C. for 14 hrs. The resulting crystals are removed by filtration. The filtrate is concentrated in vacuo, and the residue is purified over a 330 g SiO2 column (ISCO) using a gradient of 20 to 40% ethyl acetate in hexanes as eluent, affording 4-(4-Chloro-5-methyl-2-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as dark yellow viscous oil. MS (ES+); 315.1 (MH+-C4H8), 393.1 (MNa+).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:50][CH2:51][C:52](=[O:54])[CH3:53].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:50][CH2:51][C:52](=[O:54])[CH3:53])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CCCl
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Temperature: 65 °C

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (4 mL) was added 4-chlorobutan-2-one (20 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxobutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide. The crude product was used in the next step without purification. MS: (M+H)+=713.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:20])[C:15](=[O:28])[N:14]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:9][CH:8]=1)(=O)=O.[N+:38]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)([O-:40])=[O:39].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:14]2[C@H:13]([C:10]3[CH:9]=[CH:8][C:7]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([N+:38]([O-:40])=[O:39])[CH:46]=4)=[CH:12][CH:11]=3)[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[OH:20])[C:15]2=[O:28])=[CH:34][CH:33]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc([N+](=O)[O-])c3)cc2)N1c1ccc(F)cc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (50.0 mg, 0.092 mmol) and 3-nitrophenylboronic acid (21.6 mg, 0.129 mmol) were dissolved in 1:1 toluene:ethanol (2 mL). 2.0 M aqueous potassium carbonate (0.092 mL) was added and the solution degassed. Tetrakis(triphenylphosphine)palladium(0) (5.7 mg, 0.005 mmol) was added and the reaction stirred vigorously for 2 h at refluxing temperature under a nitrogen atmosphere. The cooled reaction was diluted into dichloromethane (15 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (2×5 mL). The combined extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 5% to 50% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-nitrobiphenyl-4-yl)azetidin-2-one (45.0 mg, 95% yield) as a clear film; Rf 0.33 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ ?8.42 (m, 1H), 8.21 (ddd, J=8.1, 2.4, 1.2 Hz, 1H), 7.89 (ddd, J=7.9, 1.5, 1.2 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.33-7.22 (m, 4H), 7.04-6.92 (m, 4H), 4.76 (t, J=6.0 Hz, 1H), 4.71 (d, J=2.1 Hz, 1H), 3.14 (m, 1H), 1.91-2.11 (m, 4H) ppm; MS [M−OH] 497.5.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH2:28][C:29]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)([C:34]([O:36][CH3:37])=[O:35])[C:30]([O:32][CH3:33])=[O:31])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]>ClCCl>[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH2:28][C:29]([N:38]2[CH2:39][CH2:40][N:41]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:42][CH2:43]2)([C:30]([O:32][CH3:33])=[O:31])[C:34]([O:36][CH3:37])=[O:35])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
0.6 ml (4 mmol) of triethylamine and then 0.3 ml (4 mmol) of methanesulfonyl chloride are added to a solution of 1.6 g (4 mmol) of dimethyl 2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate diluted in 30 ml of dichloromethane. The reaction medium is then stirred at ambient temperature for 3 h and then evaporated to dryness. The crude residue is purified by chromatography on silica gel, elution being carried out with a 99/1 dichloromethane/methanol mixture. 1.1 g (58%) of dimethyl 2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiperazin-1-yl)malonate are obtained in the form of a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH:20]=[CH:19][NH:18][C:16]=3[N:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].BrC1C=CC([CH2:28][S:29](CC2C=CC(Br)=CC=2)(=[O:31])=[O:30])=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H:49]1[CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]1N>O1CCOCC1.[Cu]I>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH:20]=[CH:19][N:18]([C:53]4[CH:52]=[CH:51][C:50]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:49][CH:54]=4)[C:16]=3[N:17]=2)=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(C)Oc1ccc(Nc2ncc3cc[nH]c3n2)cc1
Reactant: O=S(=O)(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(Nc2ncc3ccn(-c4ccc(S(C)(=O)=O)cc4)c3n2)cc1
Temperature: 110 °C

Procedure:
In a sealed tube, (4-Isopropoxy-phenyl)-(7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amine (350 mg, 1.17 mmol), 4-bromophenylmethylsulfone (552 mg, 2.35 mmol), CuI (68.4 mg, 0.352 mmol), and K3PO4 (763 mg, 3.52 mmol) are suspended in 1,4-dioxane (10 mL). Then, trans-1,2-diaminocyclohexane (42.7 μL, 0.352 mmol) is added at rt. The reaction vial is flushed with Ar and the mixture is heated to 110° C. for 6 h. After cooling to rt, the reaction mixture is diluted with EtOAc and the organic layer is washed with saturated aqueous NaCl solution (3×). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by reverse phase prep-HPLC (Waters) to afford the title compound (3) as an off-white solid. HPLC: tR=1.67 min (Method A); MS-ES: (M+H)+=423.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1([CH3:44])[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:37]2[CH:36]=[C:35]([CH3:44])[CH:40]=[CH:39][CH:38]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 118.8 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (3.0 g, 6.04 mmol), m-tolylboronic acid (2.05 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.5 g, 0.71 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated in a microwave at ˜90° C. for 2 h. The reaction mixture was cooled to 25° C., diluted with ethyl acetate (300 mL), washed with a saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (300-400 mesh, 9% ethyl acetate/petroleum ether) afforded 1-benzenesulfonyl-2-(3-methyl-1-m-tolyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (2.99 g, crude) as a white solid, which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ ppm 8.49 (dd, 1H, J1=4.8 Hz, J2=0.9 Hz), 7.89 (dd, 1H, J1=7.8 Hz, J2=1.5 Hz), 7.61 (dd, 2H, J1=8.4 Hz, J2=1.5 Hz), 7.43-7.01 (m, 7H), 6.89 (s, 1H), 6.52 (s, 1H), 6.11 (d, 1H, J=10.2 Hz), 2.73-2.60 (m, 1H), 2.17 (s, 3H), 1.12 (dd, 6H, J1=9.3 Hz, J2=6.6 Hz).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(F)ccc1S(=O)(=O)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)ccc1S(=O)(=O)Nc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
(Step 2) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.26 g), 2-(aminomethyl)-4-fluoro-N-phenylbenzenesulfonamide hydrochloride obtained in Step 1 (0.37 g) and potassium carbonate (0.45 g) in ethanol (20 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.12 g).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:29]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3)[C:10]3([CH2:35][O:27][C:19]4[CH:20]=[C:21]5[C:22](=[CH:26][C:18]3=4)[CH2:23][CH2:24][O:25]5)[C:9]2=[O:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cc(F)ccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccc(F)cc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-5-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-5′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (71%) as a colorless solid: mp 228-229° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 7.39-7.25 (m, 10H), 7.06 (s, 1H), 6.90-6.87 (m, 1H), 6.72-6.65 (m, 1H), 6.42-6.38 (m, 3H), 4.83 (ABq, 2H), 4.53 (t, J=9.0 Hz, 2H), 3.02-2.97 (m, 2H); MS (ES+) m/z 464.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:21])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>C(OCC)(=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:2]2[N:3]=[C:4]([O:11][C:12]3[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[CH3:21])[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2ccsc12
Reactant: N#Cc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2ccsc12
Temperature: 90 °C
Reaction time: 15 h
Yield: 34 %

Procedure:
To a solution of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (187 mg, 0.6 mmol), TFA (0.37 mL, 4.8 mmol) in TFE (3 mL) was added 4-aminobenzonitrile (283 mg, 2.4 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate (5 mL) and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC afforded the product as a white solid (81 mg, 34%):
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]2[CH2:13][CH:12]([NH:14][NH2:15])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([OH:36])=[C:27]([C:29](=O)/[CH:30]=[CH:31]/N(C)C)[CH:28]=1>C(O)C.C(O)(=O)C.COC(C)(C)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([OH:36])=[C:27]([C:29]2[N:14]([CH:12]3[CH2:13][N:10]([CH:9]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11]3)[N:15]=[CH:31][CH:30]=2)[CH:28]=1
Reactant: CN(C)/C=C/C(=O)c1cc(Cl)ccc1O
Reactant: NNC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Solvent: CCO
Product: Oc1ccc(Cl)cc1-c1ccnn1C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 42 %

Procedure:
1-(diphenylmethyl)-3-hydrazinoazetidine dihydrochloride (Preparation 690, 1.00 g, 3.06 mmol) was added to an ice cold, stirred suspension of (2E)-1-(5-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one (Preparation 759, 700 mg, 3.1 mmol) in ethanol (5 ml) and acetic acid (5 ml), stirred at 0° C. for 2 hours then allowed to warm up to room temperature over 2 hours. The solvents were removed in vacuo and the residue partitioned between ethyl acetate (80 ml) and saturated aqueous sodium hydrogencarbonate solution (50 ml). The organic layer was separated and dried over sodium sulphate, filtered and the solvents removed in vacuo to give a yellow gum. This was dissolved in warm methyl-t-butyl ether (20 ml) and allowed to crystallize to give the title compound as a pale yellow powder, 541 mg, yield 42%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1oc(-c2ccc(Cl)nc2)cc1C=O
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.3 g), 2-chloropyridine-5-boronic acid (1.3 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.1 g, 68%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH3:10][NH:11][CH2:12][CH2:13][CH2:14][NH2:15]>C1COCC1>[F:9][C:2]([F:1])([F:8])[C:3]([NH:15][CH2:14][CH2:13][CH2:12][NH:11][CH3:10])=[O:5]
Reactant: CNCCCN
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CNCCCNC(=O)C(F)(F)F
Reaction time: 17 h
Yield: 106.4 %

Procedure:
Ethyl trifluoroacetate [383-63-1] (7.5 mL, 62.9 mmol) was slowly added to an ambient temperature solution of N1-methylpropane-1,3-diamine [6291-84-5] (6.5 mL, 62.8 mmol) in anhydrous THF (100 mL) then allowed to stir, under N2 blanket for 17 h. The reaction solution was then evaporated to provide 12.3 g of clear colorless liquid. LRMS (ESI) m/z 185.1 [(M+H)]+, calc'd for C6H11F3N2O: 184.16.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27]>O1CCOCC1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl)OCC(Cl)(Cl)Cl
Yield: 39.9 %

Procedure:
To a mixture of 5-(3-amino-4-chlorophenyl)-3-(2-furanyl)-1,2,4-oxadiazole (0.75 g) and 0.58 g of potassium carbonate in 25 ml of dioxane is added 0.80 g of 2,2,2-trichloroethyl chloroformate. The resulting mixture is heated at reflux for 2 hours, and concentrated to dryness. 50 ml of water is added to the residue and the resulting mixture is extracted three times with chloroform. The extracts are dried over magnesium sulfate, filtered and concentrated to dryness. The residue is absorbed on an alumina column and eluted with benzene to give 0.50 g of the title compound, melting point 114°-116°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH3:11])=[O:4].C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])[N:7]=[C:8]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[NH:9][C:10]=1[CH2:11][Br:32])=[O:4]
Reactant: COC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.37 g, 1.0 mmol) in CCl4 (5 mL) was added NBS (0.20 g, 1.1 mmol) in portions. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo and the residue was purified by column chromatography to give 6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound C) as a yellow solid. MS: calc'd 429 (MH+), measured 429 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[OH:10][CH2:11][CH:12]1[NH:17][CH2:16][C:15]2[CH:18]=[CH:19][S:20][C:14]=2[CH2:13]1.C(O)(C)C.C(OC(C)C)(C)C>C(O)C>[OH:10][CH2:11][CH:12]1[N:17]([C:2](=[S:3])[NH:1][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][C:15]2[CH:18]=[CH:19][S:20][C:14]=2[CH2:13]1
Reactant: OCC1Cc2sccc2CN1
Reactant: S=C=Nc1cccnc1
Solvent: CCO
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: OCC1Cc2sccc2CN1C(=S)Nc1cccnc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A solution of 3-isothiocyanatopyridine (1.36 g) in absolute ethanol (40 cc) is added dropwise, at a temperature of about 0° C., to a solution of (RS)-6-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.69 g) in absolute ethanol (60 cc). The resulting solution is stirred for 20 hours at a temperature of about 20° C. and the solid formed is then filtered off. The filtrate is evaporated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. and a white solid is obtained which is combined with the solid isolated by filtration. These solids are dissolved in a mixture, heated under reflux, of isopropanol and diisopropyl ether (1:2 by volume; 130 cc) and the solution, after cooling, is kept at +5° C. for 20 hours. The resulting crystals are filtered off, washed with diisopropyl ether (50 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)- 6-Hydroxymethyl-5-[(pyrid-3-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (2.3 g) is thus obtained in the form of white crystals melting at 186° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].Br[CH:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:14][CH3:15])=[N:10][N:11]2[CH:17]([CH3:19])[CH3:18])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)Br
Reactant: CCc1n[nH]c2cc(C(=O)OC)ccc12
Product: CCc1nn(C(C)C)c2cc(C(=O)OC)ccc12
Yield: 39.7 %

Procedure:
This compound was prepared according to the method of Preparation 3, using 750 mg (3.67 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 0.38 mL (4.04 mmol, 1.1 equiv) 2-bromopropane as starting materials to give 359 mg (40%) of a clear oil: HRMS calcd for C14H18N2O2+H: 247.1448. Found: 247.14530.