Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17])=[CH:7][CH:8]=1.[NH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][N:33]([CH3:35])[CH3:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:34][N:33]([CH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][CH2:24][CH2:23][CH2:22][NH:21][C:14]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:6]1[O:5][C:4]([CH2:3][NH:2][CH3:1])=[CH:8][CH:7]=1)=[CH:15][N+:16]([O-:18])=[O:17])[CH3:35]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCOc2cccc(CN(C)C)c2)o1

Procedure:
A mixture of N-methyl-5-[[[2-[(1-methylthio-2-nitroethenyl)amino]ethyl]thio]methyl]-2-furanmethanamine (1.6 g) (prepared from the oxalate salt) and 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (1.15 g) was heated at 98°-100° for 3 hours. The oily product was chromatographed (silica/methanol-0.88 ammonia 79:1) and the appropriate eluate evaporated to dryness to give the title compound as a hydrate as an amber oil (2.12 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:19](=[O:21])[CH3:20]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-trifluoromethylphenol (20.00 g) was dissolved in chloroform (160 mL), and triethylamine (34.0 mL) and acetic anhydride (12.4 mL) were added to the solution, and then the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (23.76 g) as a pale yellow oily substance.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.ON1C(=O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:34][O:35][C:36](=[O:58])[C@H:37]([CH2:54][CH2:55][S:56][CH3:57])[NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][C:41]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:58])[C@H:37]([CH2:54][CH2:55][S:56][CH3:57])[NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:7]([CH:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])=[CH:42][C:41]=1[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)C2CCC(=O)N2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
To a solution of L-pyroglutamic acid (49 mg, 0.38 mmol) in 5 mL of DMF was added 3-hydroxy,1,2,3-benzotriazin-4(3H)-one (62 mg, 0.38 mmol), (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol) and [4-amino-2-phenylbenzoyl-L-methionine methyl ester (90 mg, 0.38 mmol), prepared as in Example 192B, and the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with 10 mL 1N HCl, 5 mL satd aqueous NaHCO3 and brine (3×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. Purification by radial chromatography (2-5% methanol-ethyl acetate gradient) to give [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester (92 mg, 79%) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][C:21]4[CH:22]=[C:23]([CH2:27][NH:28]C(=O)OC(C)(C)C)[CH:24]=[CH:25][CH:26]=4)[C:14]3=[O:36])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[NH2:28][CH2:27][C:23]1[CH:22]=[C:21]([CH2:20][NH:19][C:15]2[C:14](=[O:36])[N:13]([C:11]3[CH:12]=[C:7]([CH:8]=[CH:9][C:10]=3[CH3:37])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[CH:18]=[CH:17][N:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NCc2cccc(CNC(=O)OC(C)(C)C)c2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NCc2cccc(CN)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A mixture of [[3-[[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]methyl]phenyl]methyl]-carbamic acid, 1,1-dimethylethyl ester (Example 51,90 mg), dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 30 min. The mixture was concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (22 mg).
Reaction SMILES: Cl.N[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].F[P-](F)(F)(F)(F)F.N1C2C=CC=C(O[P+](N3CCCC3)(N3CCCC3)N3CCCC3)C=2N=N1.CCN(C(C)C)C(C)C>O1CCCC1>[C:33]([O:37][C:38](=[O:39])[NH:40][CH:41]([C:46]([C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1)=[O:47])[CH2:42][CH:43]([CH3:44])[CH3:45])([CH3:34])([CH3:36])[CH3:35]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cc(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)c2nn[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
In 15 ml of tetrahydrofuran, 300 mg (0.620 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride was dissolved, and 771 mg (3.10 mmol) of tert-butoxycarbonyl-L-leucine, 1.60 g (3.10 mmol) of (benzotriazolyloxy)tripyrrolidino-phosphonium hexa-fluorophosphate (PyBOP) and 0.54 mL (3.10 mmol) of Hunig's base were added thereto and the mixture solution was stirred at room temperature for three days. The reaction solution was concentrated under reduced pressure, and then the residue was partitioned between ethyl acetate and water. The organic phase was washed with a saturated sodium chloride solution, dried, and then concentrated under reduced pressure. The residue was purified by Megabond Elute Silica Gel (10 g, ethyl acetate), to obtain 320 mg (78%) of [1-(9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-ylcarbonyl)-3-methyl-butyl]carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:8][C:7]1=[O:21])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:23]([O:26][NH3+:27])[CH:24]=[CH2:25]>C(O)C.C([O-])(=O)C.[Na+]>[CH2:23]([O:26][NH:27][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:8][C:7]1=[O:21])[CH2:2][CH2:3][CH3:4])[CH:24]=[CH2:25]
Reactant: CCCC(=O)C1C(=O)CC(CCC2OCCCO2)CC1=O
Reactant: C=CCO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CCC2OCCCO2)CC1=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
10.0 parts by weight of 2-butyryl-5-[2-(1,3-dioxan-2-yl)-ethyl]-cyclohexane-1,3-dione were dissolved in 150 parts by volume of ethanol, 3.72 parts by weight of allyloxyammonium chloride and 3.03 parts by weight of anhydrous sodium acetate were added, and the mixture was stirred at 20° C. for 20 hours. The suspension was then stirred into ice-water and extracted with methylene chloride. The organic phase was concentrated to give 11.5 parts by weight of 2-(1-allyloxyaminobutylidene)-5-[2-(1,3-dioxan-2-yl)-ethyl]-cyclohexane-1,3-dione (compound No. 2) as a solid having the following structure (melting point: 50°-52° C.): ##STR8##
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:7](=[O:13])[C:8]([O:10]CC)=[O:9])=[CH:4][S:3]1.[OH-].[Na+]>>[O:1]=[C:2]1[NH:6][C:5]([C:7](=[O:13])[C:8]([OH:10])=[O:9])=[CH:4][S:3]1
Reactant: CCOC(=O)C(=O)c1csc(=O)[nH]1
Agent: CCOC(=O)C(=O)c1csc(O)n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)c1csc(=O)[nH]1
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylate, (1.45 g.) and 1N sodium hydroxide aqueous solution (21 ml.) was allowed to stand for 30 minutes at room temperature. After the reaction, the reaction mixture was washed with diethyl ether and then adjusted to pH 1 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and diethyl ether and dried to give powder of 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)glyoxylic acid, which can be represented as 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylic acid, (0.30 g.). On the other hand, the filtration was extracted with ethyl acetate, and the ethyl acetate was distilled off from the extract to give the same object compound (0.40 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1cccc(F)c1
Product: N#CC1(c2cccc(F)c2)CCCCC1
Yield: 98.2 %

Procedure:
The title compound was prepared from 2-(3-fluorophenyl)acetonitrile (2.58 ml, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J to yield 1-(3-fluorophenyl)cyclohexanecarbonitrile (4.43 g, 97%) as a clear oil. 1H NMR (CDCl3) δ 1.26-1.39 (m, 1H), 1.76-1.88 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 6.93-6.98 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.30-7.35 (m, 1H). 13C NMR (CDCl3) δ 23.7, 25.0, 37.5, 44.6, 122.5, 125.0, 125.1, 126.0, 129.5, 130.0, 142.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:24]=1.[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][C:9]1[S:8][C:7]2[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Oc2c(Br)sc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.1 g, 6.17 mmol) in THF 201 mL) at room temperature was added N-bromosuccinimide (1.208 g, 6.79 mmol). The resulting solution was stirred vigorously at room temperature for 2 h after which time the reaction was quenched by addition of sat. aq. Sodium Thiosulfate solution and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Heptane) to afford (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.4 g, 5.72 mmol, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (d, J=16.0 Hz, 1H), 7.46 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H), 6.91 (dd, J=8.8, 2.2 Hz, 1H), 6.31 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), LC/MS (m/z, MH+): 420.9.
Reaction SMILES: [NH2:1]C1C=NC2C(C=1NCC(C)(O)C)=CC=C(OCC1C=CC=CC=1)C=2.C(OCC)(OCC)OCC.C(OC)(OC)(OC)CCC.[CH2:46]([O:53][C:54]1[CH:55]=[CH:56][C:57]2[C:58]3[N:66]([CH2:67][C:68]([CH3:71])([OH:70])[CH3:69])[CH:65]=[N:64][C:59]=3[CH:60]=[N:61][C:62]=2[CH:63]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[NH2:1][C:60]1[C:59]2[N:64]=[CH:65][N:66]([CH2:67][C:68]([CH3:71])([OH:70])[CH3:69])[C:58]=2[C:57]2[CH:56]=[CH:55][C:54]([O:53][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:63][C:62]=2[N:61]=1
Reactant: CC(C)(O)Cn1cnc2cnc3cc(OCc4ccccc4)ccc3c21
Reactant: CC(C)(O)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: CCCC(OC)(OC)OC
Solvent: CCOC(OCC)OCC
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(OCc4ccccc4)ccc3c21

Procedure:
1-{[3-Amino-7-(benzyloxy)quinolin-4-yl]amino}-2-methylpropan-2-ol, prepared as described in Parts A and B of Example 54, was treated according to the general method of Part G of Example 1 with triethyl orthoformate used in lieu of trimethyl orthobutyrate. The product, (7-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol, was treated according to the general methods of Parts H and I of Example 1 to provide (4-amino-7-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white powder, mp 254-257° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42])([O-:34])=[O:33]>C(Cl)Cl>[F:24][C:4]([F:3])([F:23])[C:5]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH2:19][CH2:18]2)=[CH:15][CH:16]=1)([OH:10])[C:6]([F:9])([F:8])[F:7]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 0.33 h
Yield: 40.8 %

Procedure:
To a 15 mL round-bottomed flask was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.25 g, 0.62 mmol, Example 91), triethylamine (0.26 mL, 1.9 mmol) and CH2Cl2 (6 mL). To this solution at room temperature was added 2-nitrobenzenesulfonyl chloride (0.14 g, 0.62 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was stirred for 20 min and then was concentrated onto silica gel. Purification by silica gel chromatography (0 to 6% MeOH in CH2Cl2) afforded 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-nitrophenylsulfonyl)piperazin-1-yl)phenyl)-2-propanol (0.13 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Cu][C:11]#[N:12].[C-]#N.[Na+].CN(C)C=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[N:12])=[N:4][C:3]=1[CH3:9]
Reactant: Cc1nc(Br)ccc1Br
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1nc(C#N)ccc1Br
Temperature: 95 °C
Reaction time: 48 h
Yield: 66.4 %

Procedure:
A 1-L, three-neck, round-bottom flask equipped with a mechanical stirrer and a nitrogen inlet was charged with 3,6-dibromo-2-methylpyridine (150 g, 0.59 mol), copper (I) cyanide (42.8 g, 0.47 mol) and sodium cyanide (23 g, 0.47 mol). To the mixture was added N,N-dimethylformamide (300 mL). The mixture was heated to 95° C. and stirred for 48 h. The reaction mixture was cooled to ambient temperature and poured into ethanol (3 L) while stirring. The mixture was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure and partitioned between water (3 L) and ethyl acetate (3 L). The organic layer was separated and washed with brine (2×600 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel plug purification (0-5% ethyl acetate in hexanes) to afford the product (61.5 g, 45% yield) as a white solid. In addition, 19.32 g (14%) of the mixture of the starting material and the product was isolated.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:23]([C:22]4[CH:26]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:24])[CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)c1
Reactant: Cc1cnc(C)c(N2CC3CNCC3C2)n1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CC3CN(c4nc(C)cnc4C)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 34 and 5-methyl-2-pyrimidin-2-yl-benzoic acid. MS (ESI): mass calculated for C24H26N6O, 414.51; m/z found 415.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.77 (d, J=4.9, 2H), 8.22 (d, J=8.1, 1H), 7.73 (s, 1H), 7.34-7.29 (m, 1H), 7.21-7.16 (m, 1H), 7.11 (t, J=4.8, 1H), 3.96-3.89 (m, 1H), 3.86-3.79 (m, 1H), 3.74-3.61 (m, 2H), 3.57-3.51 (m, 1H), 3.49-3.38 (m, 2H), 3.18-3.12 (m, 1H), 3.08-2.98 (m, 1H), 2.96-2.86 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncccc1O
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Product: O=C(Nc1ncccc1O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 2-aminopyridin-3-ol (29 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-60% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-hydroxypyridin-2-yl)benzamide as an off-white solid. Yield: 23 mg (21%). 1H-NMR: 8.08 (d, J=8.5 Hz, 2H), 7.93 (dd, J=5.0, 1.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.0, 1.5 Hz, 1H), 7.23-7.18 (m, 2H), 7.12-7.08 (m, 2H), 3.84-3.79 (m, 2H), 2.44 (J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Br:11])[C:5]=2[S:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:12]([C:3]1[S:4][C:5]2[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])(=[O:14])[CH3:13]
Reactant: Cc1csc2c(Br)cccc12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1sc2c(Br)cccc2c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
7.6 g (39.46 mmol) of 3-methyl-7-bromobenzothiophene (dried beforehand under vacuum over phosphorus pentoxide) and 70 ml of dichloromethane are placed in a 250 ml three-necked flask equipped with a thermometer. The mixture is cooled to 0° C. by an ice bath, 2.89 g (36.8 mmol) of acetyl chloride are added and then the reaction mixture is stirred for 5 minutes at 0 °C. 5 g of aluminium chloride are then added in small portions, the temperature being controlled so that it does not exceed 70° C., and stirring is continued at 0° C. for 45 minutes. The reaction mixture is poured onto crushed ice and extraction is carried out with ethyl acetate (3×150 ml). The organic phases are combined, washed with a saturated sodium bicarbonate solution (200 ml) and water (200 ml), dried over magnesium sulphate and then concentrated. The residue is purified by chromatography on a silica column (elution solvent: 5% ethyl acetate in petroleum ether). 8.55 g (Yield: 95%) of 2-acetyl-3-methyl-7-bromobenzothiophene are obtained in the form of a white solid. M.p.=105-107° C.
Reaction SMILES: Br.[OH:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([C:9](=O)[CH2:10][Br:11])[N:8]=1.C(=O)(O)[O-].[Na+].[C:18]([NH:21][C:22]([NH2:24])=[S:23])(=[NH:20])[NH2:19]>O.CC(C)=O>[BrH:11].[NH:21]([C:22]1[S:23][CH:10]=[C:9]([C:7]2[N:8]=[C:4]([CH2:3][OH:2])[NH:5][CH:6]=2)[N:24]=1)[C:18]([NH2:20])=[NH:19]
Reactant: O=C(CBr)c1c[nH]c(CO)n1
Reactant: N=C(N)NC(N)=S
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N=C(N)Nc1nc(-c2c[nH]c(CO)n2)cs1
Yield: 87.6 %

Procedure:
1.78 g (0.0059 mol) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobromide was dissolved in water and saturated sodium bicarbonate solution was added to precipitate the free base. This material was collected by filtration and dried and combined with 956 mg (0.0081 mol) of amidinothiourea in 60 ml acetone and heated to 70°. After 15 minutes heating a solid formed. The reaction mixture was cooled and the resultant solid was collected by filtration to give 1.65 g (87%) 2-guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazole hydrobromide, mp>310°. A sample was converted to the free base by dissolving in hot water and adding sodium bicarbonate solid to pH 10 to precipitate 2-guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazole free base. This material was dried over toluene at high vacuum to give a light tan solid, mp 208°-209° with decomposition. nmr (DMSO-d6) (δ): 7.16 (s, 1H); 6.83 (broad s, 4H) 6.68 (s, 1H); 4.45 (s, 2H); 3.46 (very broad s, 1H). High resolution mass spectrum, calcd for C8H10N6OS: 238.0638; found: 238.0654.
Reaction SMILES: P(Cl)(Cl)(Cl)=[O:2].Cl[C:7]1[C:12]2[CH:13]=[N:14][N:15]([CH2:16][CH3:17])[C:11]=2[N:10]=[C:9]2[C:18](=[O:27])[C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21][CH2:22][C:8]=12>C(O)C>[CH2:16]([N:15]1[C:11]2[N:10]=[C:9]3[C:18](=[O:27])[C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[CH2:21][CH2:22][C:8]3=[C:7]([OH:2])[C:12]=2[CH:13]=[N:14]1)[CH3:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Solvent: CCO
Product: CCn1ncc2c(O)c3c(nc21)C(=O)c1ccccc1CC3

Procedure:
41 g. of 1-ethyl-5,6-dihydro-4-hydroxybenzo[5,6-cyclophepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.14 mol.) and 350 ml. of phosphorus oxychloride are refluxed for 4.5 hours. After cooling, the solution is filtered, the excess phosphorus oxychloride is removed in vacuo and the residue treated with water and extracted with chloroform. The chloroform extract is washed with water, dried with Na2SO4, treated with charcoal and then evaporated in vacuo to give 38 g. (87%) of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one; m.p. 156°-159° (ethanol; refrigerator).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[C:22]([O-])([O-])=O.[K+].[K+].C=O>CO.C(Cl)Cl>[CH2:10]([C:9](=[CH2:22])[C:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:2]([F:1])[CH:7]=1)=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C=C(CCCC)C(=O)c1ccc(NC(=O)C(C)(C)C)c(F)c1
Temperature: 55 °C
Yield: 105.2 %

Procedure:
A solution of N-(2-fluoro-4-hexanoylphenyl)-2,2-dimethylpropanamide (17.8 g, 60.7 mmol) in methanol (75 mL) was treated successively with K2CO3 (8.4 g, 60.7 mmol) and formaldehyde (37 wt. % solution in water, 5.0 mL, 67 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 55° C. for 4 hours. After cooling to room temperature, the mixture was diluted with CH2Cl2 (300 mL), dried over MgSO4, and filtered through a pad of silica gel, using more CH2Cl2 (200 mL) to wash the pad. The filtrate and washings were concentrated under vacuum to provide a mixture (19.5 g) of N-[4-(2-butylacryloyl)-2-fluorophenyl]-2,2-dimethylpropanamide, N-{2-fluoro-4-[2-(hydroxymethyl)hexanoyl]phenyl]-2,2-dimethylpropanamide, and N-{2-fluoro-4-[2-(methoxymethyl)hexanoyl]phenyl]-2,2-dimethylpropanamide.