Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH3:21][C@@H:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[N+](C1C=CC=CC=1O)([O-])=O>>[CH3:21][C@H:22]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC[C@@H](C)O
Reactant: COC(=O)c1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1
Agent: O=[N+]([O-])c1ccccc1O
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]

Procedure:
Methyl 4'-hydroxy-3'-nitro-4-biphenylcarboxylate was coupled with (R)-2-octanol using the same procedure as that given for alkylation of phenol 9, Scheme I, to give (S)-methyl 4'-(1-methylheptyloxy)-3'-nitro-4-biphenylcarboxylate (Compound 30, Scheme V, R1 =(S)-OCH(CH3)C6H13) as a slightly yellow solid after flash chromatography with hexanes/ethyl acetate [93/7]. Recrystallization from hexanes gave material with mp 69° C.; Rf [hexanes/ethyl acetate 90/10]: 0.23; 1H-NMR (300 MHz, CDCl3): δ 0.85(t, 3H, J=6.8 Mz), 1.20-1.52(m, 8H), 1.36(d, 3H, J=6.1 Hz), 1.62(m, 1H), 1.80(m, 1H), 3.92(s, 3H), 4.53(m, 1H), 7.12(d, 1H, J=8.7 Hz), 7.59(d, 2H, J=8.4 Hz), 7.72(dd, 1H, J=2.4 Hz, J=8.7 Hz), 8.02(d, 1H, J=2.4 Hz), 8.08(d, 2H, J=8.4 Hz); 13C NMR (300 Mz, CDCl3): δ 13.99, 19.46, 22.50, 25.19, 29.09, 31.65, 36.13, 52.17, 76.58, 116.07, 124.04, 126.53, 129.31, 130.35, 131.90, 132.06, 141.11, 142.81, 151.49, 166.75; IR (CHCl3): 3020, 2920, 2850, 1725, 1625, 1620, 1540, 1490, 1360, 1280, 1180, 1120, 1020, 820 cm-1 ; Mass spectrum m/z(rel.intensity): 385(M+ 47), 354(27), 273(100), 242(34), 139(17), 71(10) 57(20), 43(45), 41(38).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:51]1([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:54]6[CH2:55][CH2:56][CH2:57][N:51]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH2:52][CH2:53]6)[CH:42]=5)[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
236(a) To a solution of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-5-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (130 mg, 0.19 mmol) in DCM (2 mL) was added tert-butyl 1-homopiperazine carboxylate (0.04 mL, 0.21 mmol), AcOH (0.01 mL, 0.23 mmol) followed by NaBH(OAc)3 (57.2 mg, 0.27 mmol). The reaction mixture was stirred at RT overnight. LC-MS showed minor amount of starting material remaining so 0.5 equiv. of tert-butyl 1-homopiperazine carboxylate and 1 equiv of NaBH(OAc)3 were added to the mixture. It was stirred for an additional 4 h. LC-MS showed no more starting material. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was purified with CombiFlash chromatography, eluting with 0 to 10% MeOH (2M NH3 in MeOH) in DCM. The product fractions were combined and concentrated under vacuum to give 1,1-dimethylethyl 4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-5′-(methyloxy)-3-biphenylyl]methyl}hexahydro-1H-1,4-diazepine-1-carboxylate (131 mg, 79%). LC-MS m/z 859 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:22][CH2:21][C:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[NH2:1][CH:4]1[CH2:22][CH2:21][C:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH2:5]1
Reactant: [N-]=[N+]=NC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Yield: 85 %

Procedure:
3.7 g of 2-azido-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a suspension of 3 g of lithiumaluminiumhydride in 100 ml of dry ether. The mixture is refluxed for 1 hour. After the mixture has been cooled down, 12 ml of water are added carefully after which the mixture is stirred for some time. The suspension is filtered and after that the filtrate is dried and evaporated to dryness. The residue is converted with maleic acid into the maleate. Melting point of the maleate: 198°-202° C. Yield 85%.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].Cl[CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].CN(C=O)C.O>CCOC(C)=O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:10][C:11]#[C:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[N:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCCl
Reactant: Nc1cc[nH]c(=S)n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccnc(SCC#CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
A mixture of thiocytosine (0.5 g.), N-(4-chlorobut-2-ynyl)phthalimide (1.03 g.), DMF (5 ml.) and 1,5-diazabicyclo[5,4,0 undec-5-ene (0.67 g.) was stirred for 2 hours. The solution was treated with water (20 ml.) and EtOAc (10 ml.) and the insoluble solid collected to give 4-amino-2-(4-phthalimidobut-2- ynylthio)pyrimidine (1.2 g.) m.p. 197°-202° (decomp.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CS(C)=O>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:8][CH2:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1
Reactant: OCCC1CCCO1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1OCCC1CCCO1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 2-(tetrahydrofuran-2-yl)ethanol (1.0 g, 8.61 mmol), prepared following the procedure as described in Synthesis, 594 (1996), in 15 mL of DMSO was added NaH (344 mg, 8.61 mmol, 60% in mineral oil) in portions. After the resulting suspension was stirred for 15 min., a solution of 1-chloro-2-methoxy-4-nitrobenzene in 5 mL of DMSO was added dropwise. The reaction mixture was stirred overnight, quenched with 15 mL of H2O, and extracted with EtOAc (3×30 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to yield a brown oil. The oil was purified by column chromatography (silica gel, 0%-35% gradient elution with EtOAc/hexanes) to yield 1.68 g (73%) of 2-(2-(2-methoxy-4-nitrophenoxy)ethyl)tetrahydrofuran as a yellow solid. MS (ESI) 268 (M+H)+. Subsequent conversion of the aryl nitro substituent to the title aryl amine was accomplished in 98% yield, following the procedure described in Example 6 step C. MS (ESI) 238 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:11]([NH2:12])[C:7]2([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9][CH2:10]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [Li]c1ccccc1
Reactant: N#CC1(N2CCCCC2)CCC1
Product: NC(c1ccccc1)C1(N2CCCCC2)CCC1

Procedure:
The title compound, light yellow liquid, MS: m/e=245.3 [(M+H)+], was prepared in accordance with the general method of intermediate B from 1-piperidin-1-yl-cyclobutanecarbonitrile (intermediate O) and phenyllithium.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:12]1([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:11])[CH2:9][CH3:10])[CH2:14][CH2:13]1
Reactant: CCC(=O)c1ccc(Cl)cc1
Reactant: Br[Mg]C1CC1
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(Cl)cc1)C1CC1

Procedure:
The title compound was prepared starting from 1.50 g (8.90 mmol) of 1-(4-chlorophenyl)propan-1-one and 35.6 ml (17.79 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.42 g (76% of theory) of the title compound were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)C1C=CC(C(C2C=CC=C3C=2N=CC=C3)=C2CCN(CC3N=CSC=3)CC2)=CC=1.CNCCO.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][C:52](=[C:55]([Br:65])[C:56]2[CH:64]=[CH:63][C:59]([C:60](O)=[O:61])=[CH:58][CH:57]=2)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>>[OH:1][CH2:2][CH2:3][N:4]([CH3:5])[C:60]([C:59]1[CH:63]=[CH:64][C:56]([C:55]([Br:65])=[C:52]2[CH2:51][CH2:50][N:49]([C:47]([O:46][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:48])[CH2:54][CH2:53]2)=[CH:57][CH:58]=1)=[O:61]
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCN(Cc3cscn3)CC2)c2cccc3cccnc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)O)cc2)CC1
Agent: CNCCO
Product: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
A still further embodiment is directed to a process for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide comprising reacting 2-(methylamino)ethanol with 4-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)bromomethyl)benzoic acid to form tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromomethylene)piperidine-1-carboxylate; reacting the tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromomethylene)piperidine-1-carboxylate with 8-quinolineboronic acid to form tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinolin-8-yl)methylene)piperidine-1-carboxylate; deprotecting the tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinolin-8-yl)methylene)piperidine-1-carboxylate to form N-(2-hydroxyethyl)-N-methyl-4-((piperidin-4-ylidene)(quinolin-8-yl)methyl)benzamide; and reacting the N-(2-hydroxyethyl)-N-methyl-4-((piperidin-4-ylidene)(quinolin-8-yl)methyl)benzamide with thiazole-4-carbaldehyde to form the N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CC(C)=O>[Cl:14][CH:15]([F:19])[C:16]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:11])=[O:12]
Reactant: FC(F)=C(F)Cl
Reactant: NS(=O)(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NS(=O)(=O)c1ccccc1OC(F)(F)C(F)Cl
Temperature: 30 °C
Yield: 60.6 %

Procedure:
At 25 bis 30° C. and while stirring, 5.9 g (0.093 mol) of 88% strength potassium hydroxide powder was added over a period of 5 minutes to a solution of 28.4 g (0.164 Mol) of 2-hydroxybenzenesulfonamide in 200 ml of acetone. At 40° to 50° C. and while stirring, 29.6 g (0.254 mol) of chlorotrifluoroethylene was gassed in over a period of 12 hours. The precipitate was filtered off under such and washed with acetone. The filtrate was evaporated down under reduced pressure, stirred into 700 ml of water, suction filtered, washed and dried. There was obtained 28.8 g (60.7%) of the title compound of m.p. 113° to 116° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[CH2:18][CH:17]([C:21]([OH:23])=[O:22])[CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.Cl[CH2:30]Cl>CO>[CH3:30][O:22][C:21]([CH:17]1[CH2:18][C:19](=[O:20])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16]1)=[O:23]
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Reactant: ClCCl
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccccc3)cc2)C1
Yield: 93 %

Procedure:
7.46 g (24 mmol) (RS)-1-(4-benzyloxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid is dissolved in a mixture of 40 ml dichloromethane and 7.5 ml methanol. 0.13 ml concentrated sulfuric acid is added and the reaction mixture hold under reflux over night. The solvent is evaporated and the residue triturated with diethyl ether to yield 7.26 g (93%) of a colorless solid (used in the next step without further purification).
Reaction SMILES: [C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(O)=[O:2].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:27]1([C:1]([CH:4]([CH3:26])[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:2])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNCC1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 126.4 %

Procedure:
To a stirring solution of 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.2 g, 3.2 mmol) in N,N-dimethylformamide (75 ml) were added sequentially piperidine (299 mg, 1.1 eq), 1-hydroxybenzotriazole (475 mg, 1.1 eq), and dicyclohexylcarbodiimide (726 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.78 grams of a tan foam.
Reaction SMILES: [CH2:1]([N:3]([CH3:21])[C:4]([C:6]1([CH3:20])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([OH:17])[C:12]=2[CH3:16])[O:7]1)=[O:5])[CH3:2].[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[CH2:1]([N:3]([CH3:21])[C:4](=[O:5])[C:6]([OH:22])([CH3:20])[CH2:15][CH2:14][C:13]1[C:8](=[O:7])[C:9]([CH3:19])=[C:10]([CH3:18])[C:11](=[O:17])[C:12]=1[CH3:16])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCN(C)C(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: [Ce+4]
Agent: [NH4+]
Product: CCN(C)C(=O)C(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Yield: 92.3 %

Procedure:
Oxidation as described in protocol B, using 78 mg (0.268 mmol) of N-ethyl-6-hydroxy-N,2,5,7,8-pentamethylchroman-2-carboxamide and 323 mg CAN (0.590 mmol) yielded 76 mg of N-ethyl-2-hydroxy-N,2-dimethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH:3]=[CH2:4].[Sn](Cl)(Cl)(Cl)[Cl:16]>>[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:16])[C:7]=1[NH2:12])[CH:3]=[CH2:4]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: C=CCNc1ccncc1[N+](=O)[O-]
Agent: Cl
Product: C=CCNc1ccnc(Cl)c1N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
55 ml of 35% hydrochloric acid was added to 3.02 g of allyl-(3-nitropyridin-4-yl)amine, and the mixture was heated to 90° C. 19.1 g of tin chloride was added to the solution, and the mixture was kept at 90° C. for 30 minutes. The reaction solution was cooled in an ice-water bath, and then 250 ml ice/water was added thereto. The reaction solution was concentrated under reduced pressure, and then 250 ml of ammonia-saturated methanol was added thereto. The mixture was stirred for 20 hours. 750 ml of ethyl acetate was added to the solution, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.88 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:1).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=O)[CH2:15][C:16](=O)/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.Cl.Cl.[NH2:40][NH2:41].CO.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:1][N:2]([CH3:37])[C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[NH:41][N:40]=[C:16](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[CH:15]=2)=[CH:8][CH:7]=1
Reactant: NN
Reactant: CN(C)C(=O)COc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(OCCN3CCOCC3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C(=O)COc1ccc(/C=C/c2cc(/C=C/c3ccc(OCCN4CCOCC4)cc3)n[nH]2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To 2.70 g of N,N-dimethyl-2-[4-[(1E,6E)-7-[4-(2-morpholinoethoxy)phenyl]-3,5-dioxo-hepta-1,6-dienyl]phenoxy]acetamide were added 2.80 g of hydrazine dihydrochloride and 54 mL of methanol, and the mixture was stirred at 40° C. overnight. The reaction mixture was allowed to stand to cool, and poured into 200 mL of a saturated aqueous NaHCO3 solution. To this, 600 mL of AcOEt was added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (CHCl3/methanol system) to give 1.76 g of the title compound (66% yield).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[C:11]([N+:20]([O-])=O)[C:12]([F:19])=[C:13]([F:18])[C:14]=3[O:16][CH3:17])[C:9](=[O:23])[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.CN(C=O)C.[Pd]>[CH:1]1([N:6]2[C:15]3[C:10](=[C:11]([NH2:20])[C:12]([F:19])=[C:13]([F:18])[C:14]=3[O:16][CH3:17])[C:9](=[O:23])[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cn(C2CCCC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CCCC2)c2c(OC)c(F)c(F)c(N)c2c1=O
Yield: 91 %

Procedure:
A solution of 16 (6.0 g, 15 mmol) in EtOH-DMF (4:1, v/v, 250 mL) was hydrogenated under atmospheric pressure over 10% Pd/C (600 mg) at room temperature overnight. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo to dryness to yield 17 (5.0 g, 90%) which was used crude in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:13][NH:14][CH2:15][CH2:16][C:17]=2[N:18]=1)=[NH:8].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][C:12]2[CH2:13][N:14]([S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[CH2:15][CH2:16][C:17]=2[N:18]=1)=[NH:8]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CNCC2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CN(S(=O)(=O)c1ccccc1)CC2
Yield: 34.2 %

Procedure:
Reaction of 30 mg N-(2,6-dimethoxybenzyl)-N′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-yl)guanidine (0.09 mmol, Example 221.3) with 18 mg phenylsulfonic acid chloride and 40 mg polymer-bound DMAP (Argonaut; 1.06 mmol/g) in 5 ml dichloromethane followed by chromatographic purification (dichloromethane/methanol 2-4%) yielded 15 mg of the target product; ESI-MS [M+H+]=488.15.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[CH3:17].CC1(C)C(C)(C)OBO1.CCN(CC)CC.[C:34]([O:38][C:39](=[O:60])[NH:40][C:41]([C:43]1[S:44][C:45]([S:58][CH3:59])=[C:46]([S:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53](Br)[CH:52]=2)(=[O:50])=[O:49])[CH:47]=1)=[NH:42])([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO.O1CCOCC1>[C:34]([O:38][C:39](=[O:60])[NH:40][C:41](=[NH:42])[C:43]1[S:44][C:45]([S:58][CH3:59])=[C:46]([S:48]([C:51]2[CH:56]=[C:55]([C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:4][C:3]=3[CH3:17])[CH:54]=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:47]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc(NCCN2CCOCC2)ccc1Br
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)OBOC1(C)C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(NCCN3CCOCC3)cc2C)c1
Yield: 85 %

Procedure:
Following the same procedure as in Example 220, step a, reaction of (4-bromo-3-methyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine (440 mg, 1.9 mmol, as prepared in Example 221, step a), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.3 mL, 92 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (2.2 gm, 3.1 mmol, Strem Chemicals Inc, Newburyport, Mass.), Et3N (1.6 mL, 11.4 mmol), and dioxane (5 nm) afforded 520 mg (79%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of a tan oil. ESI-MS (m/z): Calcd. for C19H31BN2O3: 347.3 (M+H); found: 347.2. The above boronate ester (520 mg, 1.5 mmol) was reacted according to the procedure used in Example 1, step c, with {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (368 mg, 0.75 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (217 mg, 0.19 mmol, Strem Chemicals Inc, Newburyport, Mass.), Na2CO3 (3 mL, 2M), and toluene/EtOH mixture (2:1, 9 mL) to afford 400 mg (85%) of (imino-{4-[2′-methyl-4′-(2-morpholin-4-yl-ethylamino)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester after purification (SiO2, flash elution: EtOAc in hexanes). ESI-MS (m/z): Calcd. for C30H38N4O5S3: 630.8; found: 630.9, 531.1 (M−Boc). Treatment of this intermediate with trifluoroacetic acid and purification using C18-HPLC (as in Example 220, step c) provided 312 mg (78%) of the title compound as a white solid. 1H-NMR (CD3OD, 400 MHz): δ 8.31 (s, 1H), 7.90–7.95 (m, 2H), 7.60–7.65 (m, 2H), 7.04 (d, 1H, J=8.1 Hz), 6.61–6.66 (m, 2H), 3.95 (br s, 4H), 3.61 (t, 2H, J=6.3 Hz), 3.41 (m, 6H), 2.71 (s, 3H), 2.19 (s, 3H). ESI-MS (m/z): Calcd. for C25H30N4O3S3: 531.2 (M+H); found: 531.1, 266.2 (M2+).