Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][OH:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CO)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1CO)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 72.1 %

Procedure:
Prepared in 72.1% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-(hydroxymethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.97 (s, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.22 (dd, J=9.4, 2.6 Hz, 1H), 7.19-7.13 (m, 2H), 5.58 (br. s., 1H), 5.03 (br. s., 1H), 5.00-4.93 (m, 1H), 4.90-4.82 (m, 1H), 4.63 (br. s., 1H), 3.91-3.75 (m, 2H), 3.57-3.43 (m, 3H), 2.63 (d, J=10.0 Hz, 1H), 2.42 (s, 3H), 1.96-1.52 (m, 10H), 1.20 (s, 3H), 1.13 (s, 9H), 1.09 (d, J=5.8 Hz, 3H); LCMS (ESI, M+1): 674.6.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:28][N:29]1[CH:33]=[C:32]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:23][CH2:24][O:25][CH2:26][CH2:27]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCOCC4)cc3)cc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1cc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCOCC5)cc4)cc23)cn1
Temperature: 130 °C
Yield: 24.8 %

Procedure:
A degassed mixture of 6-bromo-3-(4-morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (245 mg, 0.58 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (241 mg, 1.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (47 mg, 0.06 mmol) in 2N aqueous sodium carbonate solution (7 mL) and acetonitrile (7 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 10 g column, Biotage, 0-10% methanol in DCM) to afford the title compound as a white solid (61 mg, 25%). 1H NMR (CDCl3, 300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (d, J=2.2 Hz, 1H), 8.31 (d, J=1.1 Hz, 1H), 8.07 (s, 1H), 8.05 (d, J=0.8 Hz, 1H), 7.73-7.67 (m, 2H), 7.54-7.48 (m, 2H), 4.01 (s, 3H), 3.80-3.73 (m, 4H), 3.63 (s, 2H), 2.60-2.52 (m, 4H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:16][C:17]1[O:21][C:20]([C:22]2[CH:30]=[C:29]([C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[CH:33]=[CH:34][NH:35]4)[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3S(C2C=CC=CC=2)(=O)=O)=[N:19][N:18]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+].[OH-].[Na+]>C(#N)C.C(O)(C)C>[NH:35]1[C:36]2[C:32](=[C:31]([C:29]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[C:22]([C:20]4[O:21][C:17]([CH2:16][N:4]5[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][N:9]6[CH2:10][CH2:11][O:12][CH2:13][CH2:14]6)[CH2:6][CH2:5]5)=[N:18][N:19]=4)[CH:30]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:34]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: C1CN(CCN2CCOCC2)CCN1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(-c2cc(-c3nnc(CN4CCN(CCN5CCOCC5)CC4)o3)c3cn[nH]c3c2)c2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
4-[2-(1-piperazinyl)ethyl]morpholine (14.1 mg, 0.11 mmol) and 4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.102 mmol) were dissolved in acetonitrile (0.5 ml) and N,N-diisopropylethylamine (0.026 ml, 0.15 mmol) was added, followed by sodium iodide (15.3 mg, 0.102 mmol). The solution was stirred at 70° C. for 18 h and blown to dryness under a stream of nitrogen. Isopropanol (0.3 ml) was added followed by 2M sodium hydroxide (0.3 ml) and stirred for 5 h when the mixture was neutralised and the solvent removed under a stream of nitrogen. The crude product was dissolved in dimethylsulphoxide (0.3 ml) and methanol (0.15 ml) with formic acid (0.05 ml) then purified by Mass Directed Automated Preparative HPLC (Method F) to give the title compound (26.4 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(#N)C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>CCOC(C)=O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:25]=[CH:24][C:23]([O:27][CH3:28])=[O:26])[N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccn(S(=O)(=O)c3ccccn3)c2c1
Reactant: C=CC(=O)OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1cc2ccc(C)cc2n1S(=O)(=O)c1ccccn1
Temperature: 110 °C
Yield: 30.8 %

Procedure:
In a sealed tube, 44 (9.60 g, 35.2 mmol), copper (II) acetate monohydrate (14.05 g, 70.4 mmol), and PdCl2(CH3CN)2 (0.91 g, 3.5 mmol) were placed under a nitrogen atmosphere. Acetonitrile (60 mL) was added followed by methyl acrylate (9.52 mL, 105.6 mmol). The mixture was heated at 110° C. for 20 h, allowed to reach rt, diluted with EtOAc, and washed with water and brine. The combined organic layers were dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 20% EtOAc-hexanes to provide 3.86 g (30%) of product 45 as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 3.81 (s, 3H), 6.39 (d, J=16 Hz, 1H), 6.97 (s, 1H), 7.06-7.08 (m, 1H), 7.39 (d, J=8 Hz, 1H), 7.40-7.45 (m, 1H), 7.84-7.90 (m, 1H), 7.94-7.96 (m, 1H), 8.06 (dt, J=1, 8 Hz, 1H), 8.42 (d, J=16 Hz, 1H), 8.52-8.54 (m, 1H). LC-MS (CI): m/z 357.1 [(M+H)+ C18H16N2O4S requires 356.08].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[F:41][C:42]1[CH:43]=[C:44]([CH:61]=[CH:62][CH:63]=1)[CH2:45][N:46]1[CH:50]=[C:49](C2OC(C)(C)C(C)(C)O2)[C:48]([CH3:60])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[F:41][C:42]1[CH:43]=[C:44]([CH:61]=[CH:62][CH:63]=1)[CH2:45][N:46]1[CH:50]=[C:49]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:7]=[CH:2][C:3]([CH:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:32][CH2:33]5)=[CH:4][CH:5]=4)[CH:9]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=2)[C:48]([CH3:60])=[N:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1C1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 76.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (120 mg, 0.182 mmol) was coupled with 1-(3-fluorobenzyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 12) (64 mg, 0.200 mmol) using Pd(PPh3)2Cl2 (6 mg, 0.009 mol) and sodium carbonate (58 mg, 0.547 mmol) in acetonitrile/water (3/2 ml) to afford 100 mg (76% yield) of the titled compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=S)[CH3:2].[N:17]#[C:18][NH2:19].[Pb]>>[C:18]([NH:19][C:4]([NH:3][CH2:1][CH3:2])=[N:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)#[N:17]
Reactant: N#CN
Reactant: CCNC(=S)NCCNCc1cnccn1
Agent: [Pb]
Product: CCNC(=NCCNCc1cnccn1)NC#N

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3 and chromatographing gives N-ethyl-N'-[2-(2-pyrazinylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3 gives N-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylamino)ethyl]-guanidine.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].C(O)(=O)C.[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19]>C(C(C)=O)C>[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@H]1CC(=O)OC1=O
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
14.3 g of N-formyl-L-aspartic anhydride (0.1 mole) was added to a mixture of 100 ml of methyl ethyl ketone and 24.0 g of acetic acid (0.4 mole). The solution was stirred at room temperature for 15 minutes. A solution of 17.9 g of L-phenylalanine methyl ester (0.1 mole) dissolved in 200 ml of methyl ethyl ketone was added to the above solution and stirred at room temperature for 6 hours to produce N-formyl-α-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:27]=1[CH:28]=O.CO[Si](OC)(OC)OC>CN(C)C=O.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:19])([CH3:20])[C:13](=[CH:28][C:27]1[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:26]=1[O:25][CH3:24])[C:12]2=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Agent: CO[Si](OC)(OC)OC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1C=C1C(=O)c2cc(OCc3ccccc3)ccc2OC1(C)C
Temperature: 80 °C
Yield: 79 %

Procedure:
A mixture of 5.0 g (17.7 mmole) of the product of Example 100, 1.1 g (19 mmol) potassium fluoride, 3.5 g (19.5 mmole) 2-methoxy-5-nitrobenzaldehyde and 2.9 mL (2.97 g, 19.5 mmole) tetramethylortho-silicate in 15 mL dimethylformamide was heated at 80° C. for 7 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was and washed successively with 1N HCl, 5% NaHCO3, water and brine and then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel eluting with 30% ethyl acetate in hexanes gave 6.23 g (79%) of a foam. Recrystallization from ethyl acetate in hexanes yielded the title product as a solid m.p. 110°-112° C. NMR (CDCl3): δ1.70 (s, 6H); 3.82 (s, 3H); 5.02 (s, 2H). Analysis calculated for C20H23NO6 : C, 70.10; H, 5.20; N, 3.14. Found: C, 70.19; H, 5.21; N, 3.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH:16]=[CH:17][CH:18]=1)[C:5]2=O.O.[NH2:31][NH2:32]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:7][NH:32][N:31]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: COc1ccc(-c2cccc(-c3coc4cc(O)c(Cl)cc4c3=O)c2)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cccc(-c3c[nH]nc3-c3cc(Cl)c(O)cc3O)c2)cc1OC

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(3′,4′-dimethoxy-biphenyl-3-yl)-7-hydroxy-chromen-4-one (0.1 g, 0.24 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-[4-(3′,4′-dimethoxy-biphenyl-3-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as an off white solid (0.05 g, 49.3.3%); Rf 0.3 cf SM 0.6 ethyl acetate/hexane (70/30).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:31])[C:8]4[CH:20]=[C:19](Br)[C:18]([O:22][CH2:23][C@H:24]5[CH2:28][O:27]C(C)(C)[O:25]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:32]([Cu])#[N:33].C(OCC)(=O)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:31])[C:8]4[CH:20]=[C:19]([C:32]#[N:33])[C:18]([O:22][CH2:23][C@H:24]([OH:25])[CH2:28][OH:27])=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC1(C)c2cc(OC[C@H](O)CO)c(C#N)cc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Temperature: 220 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-2, 17 mg, 37 mmol) was dissolved in DMA, added with CuCN (17 mg, 5 eq.), and stirred at 220° C. for 2 hr under irradiation with microwave. After cooling, the reaction solution was added with ethyl acetate, and the precipitated solid was filtered to remove the solvent. The resulting residues were purified by HPLC to obtain the title compound (4 mg).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: O
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Reaction time: 0.33 h
Yield: 27.9 %

Procedure:
Cyanuric chloride (10.0 g, 54.2 mmol, 1.0 eq.) was dissolved in methylene chloride (60 ml) and morpholine (4.70 ml, 54.2 mmol, 1.0 eq.) was slowly added (drop by drop) to the reaction mixture at −50° C., stirred for 20 minutes at the same temperature and poured into water. After extraction with methylene chloride and ethyl acetate (2×), the organic layers were dried over MgSO4 and concentrated. Further purification was done by flash chromatography (1:1 hexane/ethyl acetate) to yield the title compound as a colorless solid (3.56 g, 28%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C@H:19]2[CH2:24][N:23]([CH:25]([CH3:27])[CH3:26])[CH2:22][CH2:21][N:20]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH:25]([N:23]1[CH2:22][CH2:21][N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C@@H:19]([C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[O:18])[CH2:24]1)([CH3:27])[CH3:26]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To tert-butyl (2R)-2-({4-[(benzyloxy)carbonyl]piperazin-1-yl}carbonyl)-4-isopropylpiperazine-1-carboxylate (660 mg) in ethyl acetate (20 mL, degassed) was added Pd/C (10%) (200 mg) and the mixture was degassed again. The reaction was placed under an H2 atmosphere and stirred vigorously for 16 h. The reaction was filtered and 500 mg of 10% Pd/C added and place under hydrogen atmosphere and stirred for an additional 5 h. The reaction was filtered through a PTFE filter and evaporated to give the title compound (462 mg) as a solid on further drying.
Reaction SMILES: [CH:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([NH:20][CH2:21][C:22]#[C:23][CH2:24]Cl)[CH3:19]>>[CH:12]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:11])[C:8]([O:10][CH2:24][C:23]#[C:22][CH2:21][NH:20][CH2:18][CH3:19])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCNCC#CCCl
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Product: CCNCC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
by standard esterification technique, reacting cyclohexylphenyl glycolic acid with 4-ethylamino-2-butynyl chloride to produce 4-ethylamino-2-butynyl cyclohexylphenyl-glycolate (DEO).
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[C:12]([CH3:20])([CH2:16][CH2:17][CH2:18]O)[C:13]([NH2:15])=[O:14].O>C1(C)C(C)=CC=CC=1>[O:1]=[S:2]1(=[O:21])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1([CH3:20])[CH2:16][CH2:17][CH2:18][NH:15][C:13]1=[O:14]
Reactant: CC(CCCO)(C(N)=O)N1C(=O)c2ccccc2S1(=O)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1(N2C(=O)c3ccccc3S2(=O)=O)CCCNC1=O
Yield: 37 %

Procedure:
5 g 2-(2,3-Dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-5-hydroxy-2-methyl-valeramid are dissolved in 150 ml of xylene and the resulting solution is boiled under reflux for several hours, using a water separator. After the theoretical quantity of water has been separated off, the mixture is allowed to cool and concentrated in vacuo to a small volume. The precipitate is filtered off and recrystallized from n-butanol to give 3-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-3-methyl-2-oxo-piperidine in the form of white crystals melting at 211° to 215° C., identical with the product obtained in example 1. The yield is 37% of the theoretical.
Reaction SMILES: ClC1C=CC(O)=C(C2C=NN3C=CC=NC=23)C=1.C(C1C2C([N:31]([C:35]3[C:39]4[C:40](C(C)(C)C)=[C:41]([C:44]5[CH:49]=[C:48]([Cl:50])[CH:47]=[CH:46][C:45]=5[O:51][C:52]5[CH:57]=[C:56]([F:58])[C:55]([S:59]([N:62]6[CH:66]=[CH:65][CH:64]=[N:63]6)(=[O:61])=[O:60])=[CH:54][C:53]=5[F:67])[CH:42]=[CH:43][C:38]=4[O:37][N:36]=3)C(=O)[O-])=NOC=2C=CC=1C1C=C(Cl)C=CC=1OC1C=C(F)C(S(N2C=CC=N2)(=O)=O)=CC=1F)(C)(C)C>>[N:62]1([S:59]([C:55]2[C:56]([F:58])=[CH:57][C:52]([O:51][C:45]3[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:44]=3[C:41]3[CH:42]=[CH:43][C:38]4[O:37][N:36]=[C:35]([NH2:31])[C:39]=4[CH:40]=3)=[C:53]([F:67])[CH:54]=2)(=[O:60])=[O:61])[CH:66]=[CH:65][CH:64]=[N:63]1
Reactant: CC(C)(C)c1c(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)n3cccn3)cc2F)ccc2onc(N(C(=O)[O-])c3noc4ccc(-c5cc(Cl)ccc5Oc5cc(F)c(S(=O)(=O)n6cccn6)cc5F)c(C(C)(C)C)c34)c12
Agent: Oc1ccc(Cl)cc1-c1cnn2cccnc12
Product: Nc1noc2ccc(-c3cc(Cl)ccc3Oc3cc(F)c(S(=O)(=O)n4cccn4)cc3F)cc12
Yield: 2 %

Procedure:
Following the procedure as described in EXAMPLE 44, making non-critical variations to replace 4-chloro-2-(pyrazolo[1,5-a]pyrimidin-3-yl)phenol with bis(tert-butyl (5-(2-(4-((1H-pyrazol-1-yl)sulfonyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-yl))carbamate (0.36 g, 0.52 mmol), 5-(2-(4-((1H-pyrazol-1-yl)sulfonyl)-2,5-difluorophenoxy)-5-chlorophenyl)benzo[d]isoxazol-3-amine was obtained as a colorless solid in 2% yield (0.005 g): 1H NMR (300 MHz, CDCl3) δ 8.11-8.10 (m, 1H), 7.78 (dd, J=6.4, 9.3 Hz, 1H), 7.72 (s, 1H), 7.62-7.59 (m, 2H), 7.50 (d, J=2.4 Hz, 1H), 7.41-7.37 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.40-6.35 (m, 2H) (NH not observed); MS (ES+) m/z 502.7 (M+1), 504.7 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[CH:2]1[CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C.[Cl-].[Na+].O>[Si:18]([O:8][CH2:1][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][CH2:7]1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CC=CCC1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CC=CCC1
Reaction time: 20 h
Yield: 99.8 %

Procedure:
To a stirred solution of 1,2,3,6-tetrahydrobenzylalcohol (1) (1.12 g, 10 mmol) and imidazole (1.36 g, 20 mmol) in DMF (10 mL) was added TBDMSCl (1.81 g, 12 mmol). After 20 hours, the mixture was treated with brine (100 mL) and the product was extracted with hexanes (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4 and evaporated in vacuo to give compound (2) (2.26 g, 100%) as colorless liquid. Rf0.29 (hexanes). 1H NMR (CDCl3) δ 5.65-5.64 (m, 2H), 3.48 (d, J=2.3 Hz, 1H), 3.45 (d, J=2.3 Hz, 1H), 2.08-2.00 (m, 3H), 1.82-1.66 (m, 3H), 1.32-1.19 (m, 1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) δ 127.04, 126.23, 67.95, 36.34, 28.23, 25.97, 25.70, 25.33, 24.78, 18.38, −5.32.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][CH2:12][C:13]1[O:17][C:16]([C:18]2[N:19]=[C:20]([N:23]=[C:24]([NH2:26])[NH2:25])[S:21][CH:22]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.O.C(OCC)(=O)C>[NH2:25][C:24](=[N:23][C:20]1[S:21][CH:22]=[C:18]([C:16]2[O:17][C:13]([CH2:12][NH:11][CH:8]=[O:10])=[CH:14][CH:15]=2)[N:19]=1)[NH2:26]
Reactant: O=CO
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: NC(N)=Nc1nc(-c2ccc(CNC=O)o2)cs1
Reaction time: 0.5 h

Procedure:
A mixture of acetic anhydride (2.4 ml) and formic acid (1.0 ml) was stirred for 30 minutes at 50° to 60° C. The above mixture was added to a mixture of 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (1.5 g) in tetrahydrofuran (15 ml) and N,N-dimethylformamide (15 ml) at ambient temperature and the mixture was stirred for 2.5 hours at ambient temperature. To the reaction mixture was added a mixture of ethyl acetate, tetrahydrofuran and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with a brine and dried over magnesium sulfate. The solvent was removed by concentratoin in vacuo and the residue was recrystallized from a mixture of methanol, dioxane and tetrahydrofuran to give 2-(diaminomethyleneamino)-4-(5-formamidomethylfuran-2-yl)thiazole (0.80 g).