Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[Br:15])[CH:2]=[CH2:3].C[Sn](C)(C)[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=2)=[N:11][C:10]=1[Br:15])[CH:2]=[CH2:3]
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: C=CCn1ccnc1-c1sc(Br)nc1Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Temperature: 115 °C
Yield: 54.1 %

Procedure:
To a solution of 5-(1-allyl-1H-imidazol-2-yl)-2,4-dibromo-1,3-thiazole (5.00 g, 14.3 mmol) in 1,4-dioxane (133 mL) was added N-[4-(trimethylstannyl)pyridine-2-yl]acetamide (5.14 g, 17.2 mmol), lithium chloride (1.82 g, 43.0 mmol), copper (I) iodide (0.818 g, 4.30 mmol) and tetrakis (triphenylphosphine)palladium(0) (1.24 g, 1.07 mmol). The flask was purged with argon and then the mixture was heated at 115° C. for 4 hours. The reaction was allowed to cool to room temperature, and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (3.13 g, 54%). LCMS: (FA) ES+, 406. 1H NMR (400 MHz, d6-DMSO) δ: 10.77 (s, 1H), 8.66-8.61 (m, 1H), 8.49-8.44 (m, 1H), 7.61-7.56 (m, 1H), 7.49-7.45 (m, 1H), 5.98-5.87 (m, 1H), 5.19-5.12 (m, 1H), 4.95-4.88 (m, 1H), 4.70-4.64 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(c2cccnc2O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cccnc3O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(2-hydroxy-pyridin-3-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]3[CH2:30][NH:31][CH3:32])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].C=O.[C:36]([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:32][N:31]([CH2:30][C:22]1[N:21]([CH2:20][C:18]2[CH:17]=[CH:16][C:10]3/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:33][C:6]=4[O:7][CH2:8][C:9]=3[CH:19]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:36]
Reactant: [BH3-]C#N
Reactant: CNCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: C/C(C#N)=C1/c2ccc(Cn3c(CN(C)C)nc4ccccc43)cc2COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.1 %

Procedure:
[step 5] (E)-2-[3-fluoro-8-({2-[(methylamino)methyl]-1H-benzo[d]imidazol-1-yl}methyl)dibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (215 mg, 0.49 mmol) obtained in step 4 was dissolved in acetonitrile (9.8 mL), formaldehyde (0.26 mL, 3.43 mmol) and sodium cyanoborohydride (62 mg, 0.98 mmol) were added, and the mixture was stirred at room temperature for 6 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-0/100 v/v) to quantitatively give the title compound (222 mg).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][NH2:20].S1(CCCC1)(=O)=O>CO>[CH3:19][NH:20][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: CNc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
11 g of 4-chloro-3-nitro-benzophenone, 20 g of methylamine, 153.4 g of methanol and 27.5 g of sulpholane are warmed to 125° for 15 hours in a closed vessel. The reaction solution is evaporated to dryness, the residue is boiled thoroughly with 400 ml of 2 N hydrochloric acid for 20 minutes and the precipitate is filtered off, washed with water and dissolved in methylene chloride. After drying over sodium sulphate and evaporating, 4-methylamino-3-nitro-benzophenone with a melting point of 198°-201° is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([CH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1)[C:6]([N:8]1[CH2:12][C:11](F)(F)[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7].[CH2:67](OC(N1CC(F)(F)CC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)[C:68]1C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([CH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1)[C:6]([N:8]1[CH:9]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:36]6[NH:37][C:38]([CH:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:39][CH:40]=6)[CH:32]=5)[CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:10][C:11]2([CH2:68][CH2:67]2)[CH2:12]1)=[O:7]
Reactant: CC1(C)OB(c2ccc(-c3cnc(C4CC(F)(F)CN4C(=O)OCc4ccccc4)[nH]3)cc2)OC1(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(F)(F)CN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Yield: 44 %

Procedure:
[2-(6-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]hept-5-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester (0.10 g, 44%) was prepared following the procedure for [2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester, substituting 6-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester for 4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid benzyl ester. LCMS-ESI+: calc'd for C51H54N8O7: 890.41 (M+); Found: 891.99 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=[O:12]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]([NH:18][C:22]2[CH:21]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(N)cc1Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)Nc2ccc(C#N)c(Cl)c2)cc1Cl
Temperature: 60 °C
Yield: 73 %

Procedure:
2-Chloro-4-aminobenzonitrile (305.2 mg, 2 mmol) and carbonyldiimidazole (324 mg, 2 mmol) were combined in a reaction vial, and THF (3 mL) was added. The resulting mixture was heated overnight at 60° C., and the product, 1,3-bis-(3-chloro-4-cyano-phenyl)-urea was isolated by filtration and washed with several portions of 1N HCl to provide 220 mg (73% yield). This intermediate (200 mg, 0.6 mmol) was dispersed in DMF (2 mL) in a microwave vial, and a solution of 3-aminomethyl-N-(3-dimethylaminomethyl-benzyl)-benzamide (200 mg, 0.7 mmol), prepared in a fashion analogous to 3-aminomethyl-N-(4-dimethylaminomethyl-phenyl)-benzamide (Example 3), in DMF (1 mL), was added. The vial was sealed and heated in a microwave at 150° C. for 70 min. The reaction mixture was purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient providing 76 mg of product which was contaminated with the aniline by-product. To remove the aniline, the mixture was dissolved in a solution of methanol/acetonitrile (20/80, 10 mL) and divided into 10 portions each of which were loaded directly onto a Varian 50 mg SCX cartridge. Each cartridge was washed with 2×2 mL acetonitrile and 2×2 mL methanol, then treated with NH3 in methanol (7N, 2 mL) to elute the pure title compound (60 mg, 18.4% yield), MS analysis electrospray, 462 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][NH:15][C:16]2=[O:19])=[CH:12][C:11]=1[C:20]([OH:22])=O.[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:23]([O:25][CH2:26][CH2:27][O:28][NH:29][C:20]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[C:16](=[O:19])[NH:15][CH2:14]2)=[O:22])=[CH2:24]
Reactant: C=COCCON
Reactant: O=C1NCc2cc(C(=O)O)c(Nc3ccc(I)cc3F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1cc2c(cc1Nc1ccc(I)cc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
6-(2-Fluoro-4-iodo-phenylamino)-1-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid (209 mg, 0.52 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (58 mg, 0.56 mmol), HOBt (77 mg, 0.56 mmol), EDCI hydrochloride (109 mg, 0.56 mmol) and DIPEA (96 μL, 0.56 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield the title compound as a brown solid (100 mg, 40%). LCMS (Method B): RT=3.32 min, 2M+H+=995.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[Cl:1][C:2]1[N:3]=[C:4]([I:15])[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Cl)nc1I
Yield: 54.8 %

Procedure:
To a solution of 2-chloro-5-hydroxypyridine (5 g, from step 11b) and 8.6 g of Na2CO3 in 100 mL of water was added 9.8 g of I2. The mixture was stirred until the iodine color disappeared. The reaction mixture was then adjusted to pH 5 and extracted with EtOAc. The extract was dried over MgSO4, and the solvent was removed. The residue was recrystallized from MeOH to afford 5.4 g of the title compound: 1H NMR (CD3OD, 300 MHz) δ 7.09 (d, 1H, J=8.5 Hz), 7.20 (d, 1H, J=8.5 Hz); MS m/z: 256 (M+H)+, 273 (M+NH4)+.
Reaction SMILES: [N:1]1([C:8]2[C:9]3[S:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3[F:22])[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](=[O:28])=[O:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[N:1]1([C:8]2[C:9]3[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3[F:22])[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C=O
Reactant: Fc1cc(-c2nc(N3CCCCCC3)c3sccc3n2)c(F)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cc2nc(-c3cc(F)c(Cl)cc3F)nc(N3CCCCCC3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14181.2 %

Procedure:
3.32 ml of 1.59M n-butyllithium-hexane solution was added dropwise for 5 minutes at −78° C. into a mixture of 1.82 g of 4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine and 40 ml of THF and stirred for 15 minutes. Approximately 50 g of crushed dry ice was added to the reaction mixture and the temperature subsequently raised to room temperature. 50 ml of 10% citric acid solution was added to the reaction mixture and extracted with EtOAc. After the organic layer washed with a saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give a foam-like substance. The foam-like substance was recrystallized from THF-acetonitrile to give 288 g of 4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:26](=[O:28])(=[O:27])[N:25]([CH3:30])[CH3:24])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Product: CN(C)S(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 67.7 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and dimethylsulfamoyl chloride (144 mg, 1.01 mmol) affords 92 mg (68%) of the title compound as a yellow oil. MS (ES) 427 (M+Na), 403 (M−H); HPLC shows 93% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([OH:30])[C:23](=[CH:28][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25]>>[OH:30][C:22]1[CH:21]=[C:20]([NH:19][C:14]([C:8]2[S:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:9]=2[O:10][CH:11]([CH3:12])[CH3:13])=[O:16])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Reactant: COC(=O)c1ccc(N)cc1O
Product: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)cc1O
Yield: 59.1 %

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (200 mg, 0.75 mmol) and methyl 4-aminosalicylate (117 mg, 0.70 mmol) [obtained by esterification of 4-aminosalicylic acid, sodium salt (Sigma) with iodomethane] provides 172 mg (59%) of product; mp 158.5°-160° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:9])[CH2:10][NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc([C@H]2CO2)cc1
Solvent: O
Product: O[C@H](CNCc1ccccc1)c1ccc(F)cc1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
A mixture of (2S)-2-(4-fluorophenyl)oxirane (8.28 g) and benzylamine (19.3 g, 180 mmol) was heated at 80° C. for 4 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. After removal of the solvent, the precipitate was collected by filtration and washed with hexane to give (1S)-1-(4-fluorophenyl)-2-(benzylamino)ethanol (8.3 g) as white crystals (yield 57% for 3 steps).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:7]1[CH2:11][CH:8]1[CH:9]=[CH2:10]>C1COCC1.[Pd]>[OH:7][CH2:11][CH:8]=[CH:9][CH2:10][N:1]1[CH2:6][CH2:5][N:4]([CH2:10][CH:9]=[CH:8][CH2:11][OH:7])[CH2:3][CH2:2]1
Reactant: C=CC1CO1
Reactant: C1CNCCN1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCC=CCN1CCN(CC=CCO)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
1.23 g (14.3 mmol) of piperazine was dissolved in 20 ml of THF. 0.8 g of the polymer-bound palladium catalyst of Example 2 and 2.3 ml (28.6 mmol) 3,4-epoxy-1-butene was then added to the reaction mixture. The reaction mixture was stirred for 24 hours at room temperature. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure, resulting in a 98% yield of N,N'-di-(4-hydroxy-2-butenyl)-piperazine (1,4 adduct). None of the isomeric 1,2 adduct was detected.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16].N1C=CN=C1>CN(C=O)C.O>[CH:1]([Si:4]([O:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[Br:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1ccccc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1ccccc1Br)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Triisopropylsilyl chloride (8.0 ml, 46.0 mmol) was added dropwise to a solution of 2-bromobenzyl alcohol (7.0 g, 39.6 mmol) and imidazole (5.1 g, 75.0 mmol) in DMF (25 ml) and the resulting solution stirred at 20° C for 18 hours. The reaction mixture was diluted with water (400 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts was washed with saturated brine (1×75 ml), dried (MgSO4) and concentrated to yield the title compound as a clear oil (10.2 g, 78%). 1H NMR (250 MHz, CDCl3) δ 1.05-1.24 (21 H, m), 4.82 (2 H, s), 7.11 (1 H, dt, J=7.5, 1.2), 7.34 (1 H, t, J=7.6), 7.48 (1 H, dd, J=7.9, 1.1), 7.63 (1 H, d, J=6.7).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1Cl)=[O:5])C.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:4](=[O:5])[C:6]3=[N:7][NH:8][C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[C:15]3=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: COc1ccc(-n2nc3c4c([nH]nc-3c2=O)CCCC4)cc1
Yield: 12.8 %

Procedure:
4-Chloro-5,6,7,8-tetrahydrocinnoline-3-carboxylic acid ethyl ester (0.5 g), 4-methoxyphenylhydrazine hydrochloride (0.37 g) and potassium carbonate (0.29 g) in xylene were heated under reflux for 3 h. The solid was collected by filtration, washed with hexane, then water. The residue was absorbed onto silica and purified by flash chromatography using a gradient elution: CH2Cl2 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 99:1 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 98:2 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 97:3 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 96:4 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 95:5 (250 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (79 mg, 13%). δH (360 MHz; DMSO) 1.83 (4H, m, CH2), 2.67 (2H, t, J=5.3 Hz, CH2), 2.72 (2H, d, J=5.3 Hz, CH2), 3.78 (3H, s, OCH3), 7.02 (2H, d, J=9 Hz, ArH), 8.06 (2H, d, J=9 Hz, CH2), m/z (ESP+) 297 (MH+).
Reaction SMILES: [C:1]1([Li])C=CC=CC=1.[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]([O:31][C:32](=[O:54])[C:33]([CH3:53])([CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][C:38](=O)[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:50])([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:30]>C1COCC1>[CH2:29]([O:31][C:32](=[O:54])[C:33]([CH3:53])([CH3:52])[CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[CH2:1])[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:50])([CH3:49])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:30]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Reactant: [Li]c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: C=C(CCCCC(C)(C)C(=O)OCC)CCCCC(C)(C)C(=O)OCC
Reaction time: 5 h
Yield: 46.7 %

Procedure:
Under nitrogen atmosphere, a solution of phenyllithium (in diethyl ether:cyclohexane=30:70, 7.06 mL, 1.8 M, 12.7 mmol) was added dropwise over 10 min to a solution of methyltriphenylphosphonium iodide (5.52 g, 13.3 mmol) in anhydrous THF (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, before 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (4.5 g, 12.2 mmol) was added and the reaction mixture was stirred for 5 h at 50 □C. The resulting light-orange mixture was quenched by adding methanol (0.3 mL), and most of the solvent was removed on a rotary evaporator. The residue was purified by chromatography on silica (hexanes:ethyl acetate=95:5) to furnish the product (2.1 g, 47%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.67 (s, 2H), 4.10 (q, 4H, J=7.3 Hz), 1.97 (t, 4H, J=7.6 Hz), 1.6-1.3 (m, 8H), 1.30-1.15 (m, 10H), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.0, 149.6, 108.6, 60.1, 42.1, 40.6, 35.8, 28.2, 25.1, 24.7, 14.2. HRMS (LSIMS, nba): Calcd. for C22H41O4 (MH+): 369.3004, found 369.3009.
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.[Cl:48][C:49]1[CH:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51][N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:48][C:49]1[N:50]=[CH:51][C:52]([CH2:55][NH:56][C:21]([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=[C:8]([C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:24])=[O:7])[CH:9]=2)=[O:22])=[CH:53][CH:54]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(Cl)nc3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (21 mg, 0.064 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (25 mg, 0.13 mmol), 1-hydroxybenzotriazole hydrate (9.9 mg, 0.064 mmol), and CH2Cl2 (3 mL) were added 2-chloro-5-aminomethylpyridine (14 mg, 0.097 mmol) and N,N-diisopropylethylamine (17 μL, 0.097 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-80% MeCN/water[10 mM Et2NH]) to yield a white foam.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[S:10][C:9]=2[CH:17]=1.[CH3:19][OH:20]>S(=O)(=O)(O)O>[CH3:19][O:20][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:15])(=[O:16])[NH2:14])[S:10][C:9]=2[CH:17]=1
Reactant: CO
Reactant: NS(=O)(=O)c1cc2ccc(OCC3CO3)cc2s1
Agent: O=S(=O)(O)O
Product: COCC(O)COc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 18 h

Procedure:
One drop of concentrated sulfuric acid was added to a solution of 6-[2,3-epoxypropoxy]-2-sulfamoylbenzo[b]thiophene (2.0 g, 7.0 mmol) in methanol (25 ml). After 18 hours, the methanol was removed under vacuum. The residue was dissolved in ethyl acetate (200 ml), washed with water (2×25 ml), brine (2×25 ml) and dried (Na2SO4). The ethyl acetate was removed under vacuum. The white solid remaining was recrystallized from boiling ethyl acetate, 1.5 g, m.p. 128°-129° C.