Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
To a solution of 40.0 g (0.42 mol, 1 eq.) of phenol in 250 mL of dichloromethane at 0° C. was added 250 mL (1.8 mol, 4.2 eq.) of triethylamine. After 5 min, 49.3 mL (0.64 mol, 1.5 eq.) of methanesulfonyl chloride was added dropwise over 20 min. The resulting cloudy yellow solution was warmed to RT and stirred for 14 h. The reaction was partitioned between ether (250 mL) and water (100 mL) and the resulting organic layer was washed with cold 6N hydrochloric acid (2×200 mL). The combined aqueous layers were extracted with ether (2×50 mL) and the combined organic layers were washed with water (100 mL), saturated sodium bicarbonate (200 mL), brine (200 mL), dried (MgSO4) and concentrated. Recrystallization of the orange solid from isopropanol afforded 44.94 g (61%) of the title compound as light yellow crystals; mp 58.0°-58.5° C.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[CH3:52][C:53]1[C:54]([NH2:61])=[C:55]([NH2:60])[CH:56]=[CH:57][C:58]=1[CH3:59]>>[CH3:52][C:53]1[C:54]2[N:61]=[C:44]([C:40]3[C:39]([NH:38][C:36](=[O:37])[C:35]4[C:34]([F:33])=[CH:50][CH:49]=[CH:48][C:47]=4[F:51])=[CH:43][NH:42][N:41]=3)[NH:60][C:55]=2[CH:56]=[CH:57][C:58]=1[CH3:59]
Reactant: Cc1ccc(N)c(N)c1C
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1C

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D) and 3,4-dimethyl-1,2-phenylene diamine to give N-[3-(4,5-dimethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (89 mg) as a pale orange solid. (LC/MS: Rt 2.98, [M+H]+ 368.15).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][NH:29][CH2:26][CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 92.3 %

Procedure:
0.94 g (2.5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was stirred at room temperature overnight with 1 g (17 mmol) of propylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there was obtained 0.92 g (92%) of (S)-8-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 237°-239°, which was converted into the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:13])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][C:8]2[N:11]([CH3:21])[C:12](=[O:13])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5](=[O:7])[C:4]=2[CH:3]=1
Reactant: COC(=O)CCNC(=O)Nc1cnc(Cl)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CCn1c(=O)c2cc(Cl)ncc2n(C)c1=O
Temperature: 40 °C
Yield: 4.8 %

Procedure:
To a solution of 2-chloro-5-(3-(3-methoxy-3-oxopropyl)ureido)isonicotinic acid (33.8 g, 112 mmol) in acetone (386 mL) was added K2CO3 (46.4 g, 336 mmol) followed by CH3I (95.4 g, 672 mmol). The reaction was heated in a sealed tube at 40° C. for 24 h, cooled to RT, concentrated then diluted with EA (200 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 2:1) to give methyl 3-(6-chloro-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (1.6 g, 11% yield) as a yellow solid. LCMS: MH+ 298 and TR=2.857 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][CH2:18][OH:19]>C(O)CCC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][CH2:17][CH2:18][OH:19])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NCCCO
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCO
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 100 parts of 1-chloro-2-nitro-4-(trifluoromethyl)benzene, 90 parts of 3-amino-1-propanol and 200 parts of butanol is stirred and heated till reflux. Stirring at reflux is continued overnight. The reaction mixture is cooled and evaporated. Water is added to the residue and the whole is acidified with a hydrochloric acid solution. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The solid residue is crystallized from petroleumether. The product is filtered off and dried, yielding 141 parts (100%) of 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[N:13]([CH3:14])[C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:19].Cl>C(Cl)Cl>[CH:1]1([C:7]([C:9]2[N:13]([CH3:14])[C:12]([S:15]([NH2:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(C(=O)C2CCCCC2)ccc1S(=O)(=O)Cl
Reactant: N
Agent: Cl
Solvent: ClCCl
Product: Cn1c(C(=O)C2CCCCC2)ccc1S(N)(=O)=O
Yield: 69 %

Procedure:
Through a solution of compound 25c (1.7 g, 5.88 mmol) in DCM (120 mL) was bubbled NH3 for 30 min at 0° C. with stirring and then was added HCl to adjusted pH to 4-5 and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give compound 25d (1.1 g, 69%) as a crude solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[S:6]1(=[O:16])=[O:15]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)cc1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (417 mg) was coupled to p-fluorophenylboronic acid to provide 3-(3-chloropropyl)-1-(4-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (67 mg):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=3)=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cn2cc(Cl)ccc2n1
Reactant: Fc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc2ccc(Cl)cn2c1-c1cccc(F)c1
Temperature: 150 °C
Yield: 104.6 %

Procedure:
A solution of ethyl 6-chloroimidazo[1,2-a]pyridine-2-carboxylate (0.8 g, 3.6 mmol), cesium carbonate (1.3 g, 3.9 mmol), palladium acetate (64 mg, 0.29 mmol), and triphenylphosphine (0.15 g, 0.57 mmol) in 1,4-dioxane (43 mL) was treated with 1-bromo-3-fluorobenzene (0.54 mL, 4.8 mmol), degassed with nitrogen, and heated in the microwave at 150° C. for 30 min. The reaction mixture was filtered over celite and the filtrate was concentrated to give a crude residue. This material was purified by flash column chromatography to give the desired product (1.2 g, 94%). LCMS for C16H13ClFN2O2 (M+H)+: m/z=319.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH:41]1([NH2:45])[CH2:44][CH2:43][CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([NH:45][CH:41]4[CH2:44][CH2:43][CH2:42]4)=[O:40])=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC4CCC4)c3)ccc2n1CC1CCOCC1
Reaction time: 0.33 h

Procedure:
DIPEA (0.1 mL, 74 mg, 0.57 mmol) was added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.078 mmol) (see following step B for preparation) and cyclobutylamine (0.1 mL, 83 mg, 1.17 mmol) in DMF (5 mL) at 0° C. Stirring for 20 min, HATU (100 mg, 0.31 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature, diluted with H2O (50 mL) and extracted with EtOAc (3×25 mL). The combined organic phases were washed with H2O (2×10 mL), NaCl (10 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to 30 mg (78%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.41-1.57 (m, 4 H), 1.60 (s, 9 H), 1.66-1.78 (m, 2 H), 1.95-2.09 (m, 2 H), 2.20-2.35 (m, 3 H), 3.25-3.34 (m, 2 H), 3.85-3.93 (m, 2 H), 4.33-4.41 (m, 1 H), 4.43 (d, J=7.62 Hz, 2 H), 6.67 (dd, J=3.32, 1.56 Hz, 1 H), 7.28 (dd, J=3.32, 2.34 Hz, 1 H), 7.81-7.84 (m, 1 H), 7.91-7.95 (m, 1 H), 7.95-7.99 (m, 1 H), 8.26 (dd, J=1.66, 0.68 Hz, 1 H); MS (ESI) (M+H)+=498.8; Anal. Calcd for C26H34N4O4S+0.90 TFA+0.80H2O (615.68): C, 54.23; H, 5.98; N, 9.10. Found: C, 54.25; H, 6.02; N, 9.12.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:29][CH2:30][CH2:31][CH3:32])[N:9]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]#[N:28])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])[CH3:2].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:29][CH2:30][CH2:31][CH3:32])[N:9]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:39][N:38]=[N:37][N:28]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])[CH3:2]
Reactant: CCCCc1nc(C(=O)OCC)c(Cl)n1C1CCc2cc(-c3ccccc3C#N)ccc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCc1nc(C(=O)OCC)c(Cl)n1C1CCc2cc(-c3ccccc3-c3nnn[nH]3)ccc21
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of 2-butyl-5-chloro-1-[5-(2-cyano-phenyl)-indan-1-yl]-1H-imidazole-4-carboxylic acid ethyl ester (177 mg, 0.41 mmol) and trimethyltin azide (108 mg, 0.5 mmol) was heated in toluene (1.0 mL)for 72 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was chromatographed on SiO2 -gel using a gradient of 2% MeOH/CH2Cl2 to 15% MeOH/CH2Cl2 to give 50 mg of a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][OH:16]>>[OH:16][CH2:15][CH2:14][NH:13][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: NCCO
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: O=C(NCCO)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and 2-aminoethanol; MS: 205 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[S:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)O1.Br[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:31]=[C:30]([CH:32]3[CH2:34][CH2:33]3)[NH:29][N:28]=2)[C:23]([C:35]#[C:36][Si](C)(C)C)=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[CH:32]1([C:30]2[NH:29][N:28]=[C:27]([NH:26][C:24]3[C:23]([C:35]#[CH:36])=[CH:22][N:21]=[C:20]([C:9]4[S:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=4)[N:25]=3)[CH:31]=2)[CH2:34][CH2:33]1
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)s2)OC1(C)C
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C#Cc1cnc(-c2ccc(S(C)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Yield: 49.9 %

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(5-(methylsulfonyl)thiophen-2-yl)-1,3,2-dioxaborolane (550 mg, 1.92 mmol, 1.5 eq), 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (480 mg, 1.28 mmol, 1.0 eq), PdCl2(dppf)CH2Cl2 (106.1 mg, 0.13 mmol, 0.1 eq), K2CO3 (529.0 mg, 3.84 mmol, 3.0 equiv.), dioxane (20 mL) and water (2 mL) was heated for 1 h at 90° C. under nitrogen atmosphere. The solvent was removed and the residue was purified by silica gel chromatography (PE/EtOAc=4:12:1 as eluant) to yield N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-ethynyl-2-(5-(methyl sulfonyl) thiophen-2-yl)pyrimidin-4-amine (Compound 255) (246 mg, 50%). LC-MS (m/z)=386 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.73-0.77 (m, 2H), 0.96-1.01 (m, 2H), 1.93-1.99 (m, 1H), 3.41 (s, 3H), 4.91 (s, 1H), 6.42 (s, 1H), 7.87 (dd, J1=4.0 Hz, J2=7.2 Hz, 2H), 8.54 (s, 1H), 8.94 (s, 1H).
Reaction SMILES: [NH2:1][OH:2].Cl.CC(O[Na])=O.[C:9]12[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:15][C:14]1[C:13](=O)[CH2:12][CH2:11][C:10]2=1>CO>[C:9]12[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:15][C:14]1/[C:13](=[N:1]\[OH:2])/[CH2:12][CH2:11][C:10]2=1
Reactant: O=C1CCc2c1sc1ccccc21
Reactant: NO
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CO
Product: O/N=C1/CCc2c1sc1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of NH2OH.HCl (18.4 g, 266 mmol) in MeOH (600 mL) at 0° C. was slowly added CH3COONa (21.8 g, 266 mmol). After stirring at 0° C. for 30 min, 329d (10 g, 53 mmol) was added. The reaction solution was allowed to warm to room temperature and stirred for overnight. It was then evaporated in vacuo. 100 mL of water was added to the residue and the resulting mixture was extracted with ethyl acetate (500 mL×3). The organic layers were combined, washed with brine (50 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give 329e as a yellow solid (10 g, 92%). MS: [M+H]+ 203.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[CH:18]=[C:17]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[NH:21][CH:20]=3)[CH:16]=[C:15]([Cl:30])[N:14]=2)[CH2:8][CH2:7]1)=[O:4].[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C=O)C>[Cl:30][C:15]1[N:14]=[C:13]([NH:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:7][CH2:8]2)[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[NH:21][CH:20]=2)[CH:16]=1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](NC(=O)CCl)CC4)c3)c2c1
Reactant: NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](NC(=O)CNC5CCCCC5)CC4)c3)c2c1

Procedure:
A mixture of Example 251a (50.0 mg, 0.112 mmol), cyclohexanamine (0.038 mL, 0.335 mmol) and triethylamine (0.054 mL, 0.39 mmol) in DMF (1.0 mL) was stirred at 60° C. for 2.5 hours. The reaction mixture was concentrated and purified by reverse-phase HPLC as described in Example 56 to give the title compound (44.6 mg) as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 1.20-1.53 (m, 9H), 1.72 (m, 1H), 1.83-1.95 (m, 2H), 1.98-2.25 (m, 6H), 3.07 (m, 1H), 3.67-3.84 (m, 4H), 3.96 (s, 3H), 6.80 (d, J=1.53 Hz, 1H), 6.89 (d, J=1.22 Hz, 1H), 7.87-7.94 (m, 2H), 8.08 (d, J=2.44 Hz, 1H). MS (DCI+) m/z 511.3 (M+H)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:10]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:11]=2[S:12][C:13]=1[C:14]([NH2:16])=[O:15].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:11]2[S:12][C:13]([C:14]([NH2:16])=[O:15])=[C:9]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]=2[CH:20]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(Sc3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Thiophenol (116 μL, 1.13 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (250 mg, 1.03 mmol) in 2 mL of DMF. Diazabicycloundecene (DBU) (169 μL, 1.13 mmol) is added and the mixture is warmed to 80° C. After 2 hours, the reaction mixture is allowed to cool and is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate:hexane gives 5-methoxy-3-(phenylthio)benzo[b]thiophene-2-carboxamide in 84% yield; mp 194°-196° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=O)[CH2:32][CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>C1COCC1>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH2:32][CH2:31]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCc2cc(OCc3ccccc3)ccc21
Reactant: COC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C=C1CCc2cc(OCc3ccccc3)ccc21
Temperature: -78 °C
Yield: 70 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in THF) (30 mL, 30 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (5.0 mL, 30 mmol) in THF (20 mL). The reaction was maintained at −78° C. for 11 minutes and then 5-(benzyloxy)-2,3-dihydroinden-1-one (5.2) (4.0 g, 17 mmol) in 10 mL of THF was added in one portion. The resulting mixture was stirred at −78° C. and allowed to warm to room temperature overnight. EtOAc (400 mL) was added, and the mixture was washed with water and brine, and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by chromatography (silica gel, 1:4 EtOAc/hexane) to give 5.3 in 70% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]=[O:17]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:16][OH:17])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: C=O
Reactant: Cc1ccc(-n2ccnc2)cc1[N+](=O)[O-]
Solvent: O
Product: Cc1ccc(-n2ccnc2CO)cc1[N+](=O)[O-]
Reaction time: 9 h

Procedure:
In a sealed tube, 12 g of 1-(4-methyl-3-nitrophenyl)-imidazole was reacted with 12 ml of 37% formalin at 140° C. for 12 hours, and 6 ml of 37% formalin was further added and reaction was conducted for 9 hours under the same conditions as described above. The reaction mixture was cooled and water was added thereto. The precipitated crystal was recovered by filtration, dried and recrystallized from dimethyl formamide to obtain 10.2 g of the intended compound having a melting point of 185° C. Elementary analysis values as C11H11N3O4 were as follows.
Reaction SMILES: C([N:3](CC)[C:4](Cl)=[O:5])C.C1(N(C2C=CC=CC=2)C(Cl)=O)C=CC=CC=1.C(NC(Cl)=O)C.C1(NC(Cl)=O)C=CC=CC=1.[OH:41][C:42]1[C:55]2[C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47](=[O:57])[C:46]=2[CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1>[C:4](=[O:5])([O:41][C:42]1[C:55]2[C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47](=[O:57])[C:46]=2[CH:45]=[CH:44][CH:43]=1)[NH2:3]
Reactant: O=C1c2ccccc2C(=O)c2c(O)cccc21
Reactant: CCN(CC)C(=O)Cl
Agent: CCNC(=O)Cl
Agent: O=C(Cl)N(c1ccccc1)c1ccccc1
Agent: O=C(Cl)Nc1ccccc1
Solvent: c1ccncc1
Product: NC(=O)Oc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
Employing the same procedure as described in Example 4, diethylcarbamyl chloride, diphenylcarbamyl chloride, ethylcarbamyl chloride and N-methyl, N-phenyl carbamyl chloride were respectively reacted with 1-hydroxyanthraquinone in pyridine to obtain the corresponding 1-anthraquinonyl carbamate derivatives.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC.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>[CH3:34][O:33][C:26]1[CH:25]=[C:24]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)[CH:29]=[CH:28][C:27]=1[N+:30]([O-:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
Into a 5 mL microwave tube was charged tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.247 g, 0.800 mmol), 4-chloro-2-methoxy-1-nitrobenzene (0.100 g, 0.533 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.019 g, 0.027 mmol), sodium carbonate (0.113 g, 1.066 mmol) in water (0.889 ml) and dimethoxyethane (2.3 ml). The reaction mixture was heated at 130° C. for 20 minutes in a Biotage microwave reactor. The solids were filtered off and the filtrate was purified by reverse phase HPLC using 0.1% ammonium hydroxide. MS (DCI(+)) m/e 335.2 (M+H)+.
Reaction SMILES: F[C:2]12[CH2:12][C:6]3(F)[CH2:7][C:8](F)([CH2:10][C:4]([CH2:14][OH:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.C12(CO)CC3CC(CC(C3)C1)C2.ClC1C(F)=CC(F)=C(C=1)C(O)=O.[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([Cl:51])[C:49]=1F)[C:44]([OH:46])=[O:45]>>[C:4]12([CH2:14][O:15][C:49]3[C:48]([Cl:51])=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[CH:42][C:41]=3[Cl:40])[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:12][CH:2]([CH2:9]3)[CH2:3]1)[CH2:5]2
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Reactant: OCC12CC3(F)CC(F)(CC(F)(C3)C1)C2
Agent: O=C(O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1

Procedure:
Following the procedure as described in Example 274 step 1 and making variations as required to replace (3,5,7-trifluoroadamantan-1-yl)methanol with adamantan-1-ylmethanol and to replace 5-chloro-2,4-difluorobenzoic acid with 3,5-dichloro-4-fluorobenzoic acid, the title compound was obtained as a colorless solid (1.73 g, quant.): 1H NMR (300 MHz, DMSO-d6) δ 13.44 (br s, 1H), 7.86 (s, 2H), 3.53 (s, 2H), 1.99-1.90 (m, 3H), 1.73-1.57 (m, 12H); MS (ES−) m/z 353.2, 355.2 (M−1).