Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:9][OH:10]>CO.[Pt]>[CH2:1]([N:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCC=O
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: CCCCCCN(O)CCCCCC
Yield: 83.4 %

Procedure:
A solution of hexanal (5.0 g, 50 mmol) and hydroxylamine hydrochloride (3.8 g, 55 mmol) in 60 ml of methanol is shaken under hydrogen at 40-45 psi (2.8-3.15 Kg/cm2) for two hours at room temperature in the presence of a catalytic amount of 5% platinum on carbon (400 mg). The reaction mixture is then treated following the procedure given in Example 1 to give 4.2 g of crude N,N-di-n-hexylhydroxylamine product as a white solid. The product is identified by 90 MHz 1H NMR and is seen to be contaminated with no more than 5% of hexanal oxime.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]=[C:13]=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]>O1CCCC1>[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:13]([NH:12][C:4]3[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=3)=[O:14])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Reactant: O=C=Nc1cc(F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(F)cc(C(F)(F)F)c3)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.8 %

Procedure:
0.061 cm3 (0.426 mmol) of 3-fluoro-5-trifluoromethylphenyl isocyanate is added at room temperature to a suspension of 100 mg (0.387 mmol) of 2-acetylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide in 5 cm3 of anhydrous tetrahydrofuran. The reaction medium is stirred at room temperature for 24 hours, cooled in a water-ice bath and then filtered on sintered glass. The solid collected is washed with a small amount of dichloromethane and cyclohexane and then dried under vacuum. 75 mg of 2-acetylamino-4-{4-[3-(3-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide are obtained in the form of a beige solid.
Reaction SMILES: C1(CCCCCCCCNC([C:18]2[CH:19]=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37](C(F)(F)F)[CH:36]=3)[C:21]([OH:34])=[C:22](C3C=CC=C(C(F)(F)F)C=3)[CH:23]=2)=O)C=CC=CC=1.Br[C:46]1[CH:51]=[C:50](I)[C:49](O)=[C:48](I)[CH:47]=1>>[C:46]1([C:18]2[CH:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:21]([OH:34])=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:19]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: Oc1c(I)cc(Br)cc1I
Product: Oc1c(-c2ccccc2)cc(-c2ccccc2)cc1-c1ccccc1

Procedure:
The title compound was prepared as a solid (0.055 g, 28%, product 2: tris-arylation) from 4-bromo-2,6-diiodophenol using the procedure to step 2 of Example 40; 1H NMR (CDCl3) δ 5.45 (s, 1H), 7.27-7.57 (m, 1 1H), 7.62 (d, J=8.3 Hz, 6H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[CH:19].[CH3:20]OS(OC)(=O)=O.O>O1CCCC1>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH3:20]
Reactant: COS(=O)(=O)OC
Reactant: C#Cc1ccccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC#Cc1ccccc1Br
Reaction time: 0.5 h

Procedure:
1M Lithium hexamethyldisilazide solution (6 mL) was added to 1-bromo-2-ethynylbenzene (1 g) in 20 mL tetrahydrofuran at room temperature, and the reaction was stirred 30 minutes. (CH3)2SO4 (0.58 mL) was added and the reaction was stirred 30 minutes. The reaction was poured into 20 mL water, extracted with 2×50 mL ether, and the combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated.
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=[C:36]([Cl:45])[N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[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=[C:36]([Cl:45])[N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[CH:28][C:29]=2[C:30]2[CH:46]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]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)c2nc3c(Cl)n2c1N1CCC(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)c2n3c(Cl)c(nc3c1CO)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 17.4 %

Procedure:
Prepared in 17.4% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-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 (500 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.90 (d, J=7.7 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.25 (s, 2H), 7.20-7.13 (m, 3H), 7.05 (s, 1H), 5.96 (br. s., 1H), 5.01-4.95 (m, 1H), 4.93-4.88 (m, 1H), 4.61 (br. s., 1H), 4.05-3.90 (m, 2H), 3.52 (br. s., 1H), 3.38 (br. s., 2H), 2.46 (br. s., 3H), 2.35 (br. s., 1H), 2.02-1.59 (m, 8H), 1.21 (br. s., 3H), 1.19 (s, 9H), 1.04 (d, J=5.9 Hz, 3H); LCMS (ESI, M+1): 708.1.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:33][C:34]1([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)[CH2:35][CH2:36][CH:37]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([F:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:38][CH2:39]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2nccs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(1,2,2,2-tetrafluoro-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 65, Step B) and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH2:17][CH2:18][CH3:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31]([CH2:33][CH2:34][OH:35])[CH:32]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[OH:35][CH2:34][CH2:33][N:31]1[CH:32]=[C:28]([C:2]2[C:3]([O:16][CH2:17][CH2:18][CH3:19])=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]3)[CH:29]=[N:30]1
Reactant: CCCOc1c(Br)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1c(-c2cnn(CCO)c2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 100 °C
Yield: 85.9 %

Procedure:
A mixture of (S)-1-(6-bromo-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.050 g, 0.153 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.055 g, 0.230 mmol), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl) palladium(II) (XPhos 2nd generation precatalyst) (0.012 g, 0.015 mmol), and cesium carbonate (0.150 g, 0.460 mmol) in 1,4-dioxane (2.0 mL) and water (0.40 mL) was heated in the microwave at 100° C. for 2.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane followed by 10% methanol-ethyl acetate) to afford (S)-1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.047 g, 86%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.97 (t, J=7.48 Hz, 3H), 1.03 (d, J=6.45 Hz, 3H), 1.23 (m, 1H), 1.64-1.80 (m, 2H), 2.07 (s, 3H), 2.18-2.38 (m, 2H), 2.75-2.90 (m, 1H), 3.50-3.65 (m, 2H), 3.68-3.80 (m, 2H), 4.17 (t, J=5.57 Hz, 2H), 4.62 (m, 1H), 4.84-4.94 (m, 1H), 7.12 (br d, J=8.21 Hz, 1H), 7.38 (d, J=8.50 Hz, 1H), 7.85 (s, 1H), 8.09 (s, 1H). MS (ESI, pos. ion) m/z 358 [M+H]+. The following examples were made according to the procedure outlined for Example 24:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].Br[C:37]1[CH:38]=[N:39][CH:40]=[N:41][CH:42]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:37]2[CH:38]=[N:39][CH:40]=[N:41][CH:42]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH3:35])[C:18]([C:24]1[CH:25]=[CH:26][C:27]2[O:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]=2[CH:34]=1)([OH:23])[C:19]([F:20])([F:22])[F:21]
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: Brc1cncnc1
Product: CC(c1ccc(-c2cncnc2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 186, step 2 from 5-{2-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-hydroxy-1-trifluoromethyl-propyl}-3-methyl-3H-benzooxazol-2-one (obtained in Example 186, step 1) with 5-bromopyrimidine [CAS Reg. No. 4595-59-9]. MS (m/e)=464.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:13]=1>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[CH:13]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(Nc1c(F)ccc(O)c1F)c1cccc(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: Oc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Temperature: 60 °C
Yield: 86 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-3-(3-fluorophenyl)benzamide (310 mg, 0.9 mmol, 1.0 eq) in THF (5 mL) was added BH3 (5.4 mL, 1M in THF, 5.4 mmol, 6.0 eq) and the reaction heated at 60° C. overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1) to give the title compound as an oil (255 mg, 86%).
Reaction SMILES: Cl.[CH:2]1([N:8]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:15][N:16]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([S:45]([N:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:14]3[S:13][C:12]([NH:11][C:9](=[O:10])[N:8]([CH:2]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[N:16][CH:15]=3)[CH2:19][CH2:20]2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Nc1ncc(CN2CCNCC2)s1)N(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc(CN2CCN(S(=O)(=O)c3ccccc3)CC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 84.7 %

Procedure:
Prepared as described in general procedure (Q) using 1,1-dicyclohexyl-3-(5-piperazin-1-ylmethyl-thiazol-2-yl)-urea hydrochloride (36 mg, 0.08 mmol), DIEA (42 μL, 0.24 mmol) and benzenesulfonyl chloride (20 μL, 0.16 mmol) to afford 37 mg (68%) of the desired product after purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:13]([CH2:12][CH2:11][CH2:10][OH:15])=[CH:14][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: C#CCCCO
Product: OCCCc1cc2cc(Br)ccc2o1

Procedure:
The product from Example 112A and 4-pentyn-1-ol is processed as described in Example 112B to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:15]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113.2 %

Procedure:
To a solution of 3-tert-butylphenol (5.0 g; 33.28 mmol) in N,N-dimethylformamide (166 mL) at room temperature under nitrogen was added sodium hydride (2.0 g; 49.92 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then iodomethane (6.2 mL; 99.84 mmol) was added. After stirring at room temperature overnight, the reaction mixture was quenched with water and aqueous hydrochloric acid (2N) and extracted with ethyl acetate. The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 400 mL gradient elution) to yield the title product as a clear oil (6.19 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[CH2:33]([NH2:35])[CH3:34]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH2:33]([NH:35][C:28]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:8]([F:7])([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:15])[CH3:16])(=[O:13])=[O:12])=[CH:23][CH:22]=2)=[CH:32][CH:31]=1)=[O:30])[CH3:34]
Reactant: CCN
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-c2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringe wise to 4-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoic acid (140 mg, 0.37 mmol, prepared in example 4) in CH2Cl2 (10 mL) while stirring under nitrogen at room temperature. Immediately, 1 drop of DMF was added by pipette initiating a foaming of the mixture. The reaction was stirred one hour at this temperature and then concentrated under reduced vacuum to yield a white semi-solid. This material was placed into THF (10 mL) and added dropwise to a stirring solution of 2.0 M ethylamine in THF (0.5 mL) at room temperature and the mixture was stirred overnight. In the morning, the solution was concentrated under reduced vacuum and the resulting oil was taken into CH2Cl2 and the organic layer was washed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 151 mg as an oil. This material was purified via silica gel chromatography employing the Chromatotron and using a 2000 micron rotor while eluting with a solvent of methylene chloride/ethyl acetate 1:1 to yield the title compound (127 mg, 85%) as a viscous oil. Ion spray M.S. 407.4 (M*+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[F:11].N(C1C2CCCCC=2C(C#N)=CC=1)=[C:13]=[O:14]>>[N:1]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[C:3]=1[F:11])=[C:13]=[O:14]
Reactant: N#Cc1ccc(N=C=O)c2c1CCCC2
Reactant: N#Cc1ccc(N)c(F)c1Cl
Product: N#Cc1ccc(N=C=O)c(F)c1Cl

Procedure:
4-Isocyanato-3-fluoro-2-chlorobenzonitrile was prepared from 4-amino-3-fluoro-2-chlorobenzonitrile (73B) in a manner similar to that described in Example 2 for the preparation of 2E.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[C:16]1([NH:22][C:23]2[N:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CO>[C:16]1([NH:22][C:23]2[C:24]([CH:25]=[CH:1][C:2]([C:4]3[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=3)=[O:3])=[CH:27][CH:28]=[CH:29][N:30]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cccnc1Nc1ccccc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)C=Cc2cccnc2Nc2ccccc2)cc(OC)c1OC
Temperature: 30 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To a stirred solution of 3,4,5-trimethoxyacetophenone (213 mg, 1.01 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 mL) after 5 minutes to the reaction mixture 2-(phenylamino)nicotinaldehyde (200 mg, 1.01 mmol) was added, stirred for 6 h at 30° C. The progress of the reaction was monitored by TLC for completion. After completion of the reaction, the reaction mixture was acidified with 2N HCl, the resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The resulting product was purified by by recrystallization from ethanol to afford compound 6a as a pale yellow solid (365 mg, 92% yield).; mp 125-128° C. 1H NMR (CDCl3): δ 8.26 (d, 1H, J=4.1 Hz), 8.01 (d, 2H, J=8.3 Hz), 7.95 (d, 1H, J=15.8 Hz), 7.81 (d, 1H, J=8.3 Hz), 7.55 (d, 1H, J=16.1 Hz), 7.48 (q, 2H), 7.01-7.09 (m, 3H), 6.83 (q, 1H), 6.62 (s, 1H), 3.91 (s, 3H) 3.84 (s, 6H); ESI MS: 391 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([N:40]2[CH2:44][CH2:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[C:41]2=[O:52])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]([CH2:27][CH2:28][O:29][CH3:30])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([N:40]2[CH2:44][CH2:43][N:42]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[C:41]2=[O:52])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][NH:19][CH2:27][CH2:28][O:29][CH3:30])=[CH:31][CH:32]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)cc1
Yield: 135.6 %

Procedure:
A solution of 223 (60 mg, 0.082 mmol) and TFA (1 mL) in toluene (2 mL) was stirred 30 min at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether, the solid was collected and dried to give the title compound 220 (70 mg, 99.5%) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.95 (s, broad, 2H), 8.52 (d, J=5.5 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.84 (dd, J=2.5 and 13.1 Hz, 1H), 7.65-7.61 (m, 4H), 7.49 (t, J=8.8 Hz, 1H), 7.44 (dd, J=2.4 and 8.8 Hz, 1H), 7.30-7.25 (m, 2H), 6.65 (d, J=5.5 Hz, 1H), 4.21 (t, 1H), 3.93 (m, 4H), 3.57 (t, 2H), 3.30 (s, 3H), 3.11 (m, 2H). MS (m/z): 630.3 (M+H).
Reaction SMILES: [OH-].[Na+].CN(C=O)C.[CH2:8]([SH:10])[CH3:9].Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1>O>[Br:18][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([S:10][CH2:8][CH3:9])[CH:17]=1
Reactant: CCS
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
Under a nitrogen atmosphere, NaOH (1.25 g, 31.3 mmol) was added to anhydrous DMF (40 mL). Ethanethiol (2.60 mL, 2.20 g, 35.5 mmol) was then added by syringe and the mixture was stirred for 6 h at 25° C. while the NaOH dissolved. The solution was cooled to 0° C., and 3,5-dibromopyridine (5.92 g, 25.0 mmol) was added. After stirring for 15 min at 0° C. and 45 min at 25° C., the mixture was poured into water (250 mL) and extracted with ether (2×100 mL). Drying (Na2SO4) and evaporation of the ether, followed by vacuum distillation of the crude product gave 4.39 g (80.6% yield) of colorless oil, bp 91-95° C. at 0.30 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[N:4]=[C:3]1[CH:23]=O.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(O)(=O)C.CO>[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=1[CH2:29]/[N:30]=[CH:23]/[C:3]1[N:2]([CH3:1])[C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[N:4]=1
Reactant: Cn1c(C=O)nc2c(-c3ccccc3)ccc(-c3ccccc3)c21
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C/N=C/c2nc3c(-c4ccccc4)ccc(-c4ccccc4)c3n2C)c(OC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 0.1 g (0.32 mmol) 1-methyl-4,7-diphenyl-1H-benzimidazole-2-carbaldehyde, 55 mg (0.32 mmol) 2,4-dimethoxybenzylamine and 1 drop glacial acetic acid in 8 ml methanol were stirred for 12 hour at room temperature. The reaction mixture was cooled to −20° C. and filtered while cold. The solid was washed with cold (−20° C.) methanol (2×1 ml) and dried at reduced pressure. Yield—0.12g (81.1%). %). 1H NMR (250 MHz, CDCl3), δ, ppm: 3.76 (s, 3H), 3.80 (s, 6H), 4.81 (s, 2H), 6.46 (m, 2H), 7.14 (d, JHH=8.8 Hz, 1H), 7.25 (d, JHH=7.6 Hz, 1H), 7.46 (m, 9H), 8.02 (d, JHH=7.0 Hz, 2H), 8.61 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Br[CH2:19][C:20]1[O:24][N:23]=[CH:22][CH:21]=1>CN(C)C=O>[O:24]1[C:20]([CH2:19][CH2:4][C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])=[CH:21][CH:22]=[N:23]1
Reactant: BrCc1ccno1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)CCc1ccno1)C(=O)OCC
Reaction time: 1 h
Yield: 33478.9 %

Procedure:
3.1 g (70.7 mmole) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added to a solution of 14.0 g (6,43 mmole) of diethyl acetamidomalonate dissolved in 150 ml of dimethylformamide, whilst ice-cooling, and the mixture was stirred for 1 hour. At the end of this time, 23.9 g (0.148 mmole) of 5-bromomethylisoxazole were added to the reaction mixture, which was then stirred at room temperature for 4.5 hours, The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was mixed with water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: a 1: 2 by volume mixture of ethyl acetate and hexane), to afford 14.78 g (77.1%) of the title compound, melting at 75°-76° C.