Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][C:22]([C@@:24]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[CH3:25])=[CH:23][C:16]=3[N:15]=2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].C(N(CC)CC)C.[CH3:47][C:48]1[CH:65]=[CH:64][C:51]([C:52](OC2C=CC([N+]([O-])=O)=CC=2)=[O:53])=[CH:50][CH:49]=1>C(Cl)Cl>[CH3:47][C:48]1[CH:65]=[CH:64][C:51]([C:52]([NH:5][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][C:22]([C@@:24]([NH:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])([C:26]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:27])[CH3:25])=[CH:23][C:16]=4[N:15]=3)=[CH:8][CH:7]=2)=[NH:4])=[O:53])=[CH:50][CH:49]=1
Reactant: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Reactant: Cc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN[C@@](C)(C(=O)N1CCCC1)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccc(C)cc3)cc1)n2C
Temperature: 50 °C

Procedure:
A suspension of 0.7 g (1.2 mmol) of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-dihydrochloride in 25 ml of methylene chloride is combined with 4.0 ml (28 mmol) of triethylamine and 0.8 g (3.0 mmol) of 4-nitrophenyl 4-methyl-benzoate and heated to 50° C. for 3.5 hours, whereupon a clear solution is formed. After cooling, it is washed with sodium bicarbonate solution, saline solution and water, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified on silica gel, eluting with ethyl acetate/ethanol (50:1 and 9:1). The uniform fractions are combined, concentrated by evaporation, triturated with ether, suction filtered and dried.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11](C4C=CC=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[F:28][CH:29]([F:48])[O:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]=1[O:46][CH3:47]>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH:29]([F:28])[F:48])=[C:32]([O:46][CH3:47])[CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C[C@@H](Oc1cc(-c2ccccc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(F)F
Product: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)ccc1OC(F)F
Yield: 47.8 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-phenyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 2-(4-(difluoromethoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (123.6 mg, 0.412 mmol) as a starting material to afford 60.0 mg (47.8%) of (R)-4-((R)-1-((1-cyclopropyl-5-(4-(difluoromethoxy)-3-methoxyphenyl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (GS0697836). 1H NMR (300 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.58 (s, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.37 (d, J=1.8, 1H), 7.26-7.19 (m, 2H), 7.06 (t, J=8.4 Hz, 1H). 7.06 (t, J=75 Hz, 1H), 7.05 (s, 1H), 4.88-4.82 (m, 1H), 3.92 (s, 3H), 3.72-3.65 (m, 1H), 3.38 (t, J=9.3 Hz, 1H), 3.18 (dd, J=6.3, 6.9 Hz, 1H), 2.83-2.76 (m, 1H), 2.39-2.21 (m, 2H), 1.30 (d, J=6 Hz, 3H), 1.15-0.99 (m, 4H), LCMS-ESI+ (m/z): [M+H]+ calcd for C24H25F2N3O4:457.18; found 458.17.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:20](O)[CH2:21][CH2:22][OH:23]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:13]2[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[N:17]=2)=[C:9]([CH:10]2[O:23][CH2:22][CH2:21][CH2:20][O:11]2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C=O)=N1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2C2OCCCO2)=N1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
8.10 g (31.2 mmol) of 5-tert-butyl-2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-benzaldehyde was weighed into a 500 mL round bottom flask fitted with a stir bar and Dean-Stark trap. Added 300 mL of benzene and stirred to obtain a clear yellow solution. Added 383 mg (1.52 mmol) of pyridinium p-toluenesulfonate. Added 11.3 mL (156 mmol) of 1,3-propanediol. Heated the solution to reflux for 17 h. Cooled to room temperature Washed the reaction mixture with 200 mL of 50% saturated aqueous NaHCO3, 200 mL of water, and 200 mL brine. Dried over MgSO4 and removed the solvent on rotavap. Purified by silica gel flash chromatography using isocratic elution with 10% EtOAc/CH2Cl2 to obtain 4.93 g of the title compound as a clear yellow resin. MS (ESI) 318 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
The resultant compound from Example 98 (11.76 g, 33.2 mmol) in methylene chloride (25 ml) was treated with trifluoroacetic acid (25 ml). After stirring at room temperature for 90 min the solvent was evaporated to afford 9.91 g (100%) of the desired product as a solid, m.p. 48°-51° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:21][CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:22]2[NH:21][C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc(C(F)(F)F)cc1
Yield: 30.1 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-trifluoromethylphenyl)-3-oxopropionate (15.0 g) and 1-aminomethylnaphthalene (9.6 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(1-naphthyl)-5-(4-trifluoromethyl-phenyl)imidazole-4-carboxylate (6.4 g). 5.0 g therefrom was dissolved in ethyl alcohol (100 ml) and 1 M sodium hydroxide solution (30 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(1-naphthyl)-5-(4-trifluoromethylphenyl)imidazole-4-carboxyic acid (3.4 g), melting point 166° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([CH3:20])[CH3:19])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:20][C:18]([NH:21][C:22](=[O:25])[O:23][CH3:24])([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: COC(=O)NC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1ccc(S)cc1C
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(C)c1ccc(CSc2ccc(C)c(C)c2)cc1

Procedure:
A solution of 3,4-dimethylbenzenethiol (9.24 g) in DMF (30 ml) reacted with a solution of methyl N-(1-(4-bromomethylphenyl)-1-methylethyl]carbamate (19.15 g) in DMF (100 ml) by Method 6a) to give methyl N-{1-methyl-1-[4-(3,4-xylylthiomethyl)phenyl]ethyl}carbamate as a sticky solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:14][C:15](=[O:22])[CH:16]([OH:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:11](=O)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][CH:10]([NH:14][C:15]([CH:16]([O:21][C:29]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:30])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:22])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(O)C(=O)NC(COCc1ccccc1)C(N)=O
Reactant: O=C(Cl)N1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(OC(=O)N1CCOCC1)C(=O)NC(C#N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-hydroxy-4-methyl-pentanoic acid (2-benzyloxy-1-carbamoyl-ethyl)-amide (0.169 g, 0.55 mmol) in CH2Cl2 (5 mL) was added 4-morpholinecarbonyl chloride (0.082 g, 0.55 mmol), Et3N (0.15 mL, 1.1 mmol) and DMAP (0.034 g, 0.27 mmol). The resulting mixture was allowed to stir overnight (20 h) under argon at room temperature. When the reaction was complete the mixture was diluted with CH2Cl2 (10 mL), then washed with HCl (1.0 N, 10 mL), water and brine, dried over Na2SO4, and concentrated to give the desired product as an off-white oil in 0.20 g 86% yield of the crude product which was chromatographed (SiO2, 5% hexanes in EtOAc) to give desired product in (0.12 g, 52%). (e) Morpholine-4-carboxylic acid 1-[(benzyloxymethyl-cyano-methyl)-carbamoyl]-3-methyl-butyl Ester
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12]O)[CH:6]=[CH:5]2.P(Br)(Br)[Br:15]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][Br:15])[CH:8]=2)[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2cc(Br)ccc2c1
Solvent: ClC(Cl)Cl
Product: BrCc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
To a three-necked flask (2 L) was added (6-bromonaphthalen-2-yl)methanol (47.7 g, 0.201 mol) and chloroform (600 ml). The mixture was then cooled with an ethanol-liquid nitrogen bath to −35□. To the suspension was added phosphorus tribromide (28.6 ml, 0.603 mol) dropwise slowly over 25 minutes. The cooling bath was removed and the reaction mixture was kept under stirring for additional 2.5 hours at room temperature. The mixture was cooled again and to it was added methanol (250 mL) dropwise slowly and released quickly was hydrogen bromide, which was absorbed with a potassium hydrate solution. The mixture was warmed to room temperature and the resulting precipitate was collected by filtering under reduced pressure. The filter cake was washed with ethanol and dried to afford a white solid, 2-bromo-6-(bromomethyl)naphthalene (35 g).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].[C:12](=O)(OC1C=CC=CC=1)[O:13]C1C=CC=CC=1>CN(C)C1C=CN=CC=1.CO>[CH3:1][N:2]1[C:3](=[O:11])[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[NH:10][C:12]1=[O:13]
Reactant: CNC(=O)c1cccnc1N
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CO
Product: Cn1c(=O)[nH]c2ncccc2c1=O
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
10.0 g (66 mmol) of 2-aminonicotinic acid methyl amide, 21.4 g (100 mmol) diphenyl carbonate and 8.5 g (66 mmol) 4-dimethylaminopyridine were melted at 140 to 150° C. The reaction was allowed to continue for 20 minutes at that temperature. The mixture is allowed to cool down to 50 to 60° C. and 300 ml methanol was added while stirring. The mixture is allowed to cool down to room temperature. 3-methyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione crystallized from the medium, was isolated by filtration and washed with water, methanol and tert.-butyl methyl ether. 7.80 g (67%) of 3-methyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was isolated (m.p. 272-4° C.).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[S:15][C:14]2[C:16]3([O:29][CH2:30][CH2:31][C:13]=2[CH:12]=1)[CH2:21][CH2:20][N:19]([CH2:22][C:23]1[C:24]([CH3:28])=[N:25][NH:26][CH:27]=1)[CH2:18][CH2:17]3>>[F:10][C:11]1[S:15][C:14]2[C:16]3([O:29][CH2:30][CH2:31][C:13]=2[CH:12]=1)[CH2:21][CH2:20][N:19]([CH2:22][C:23]1[C:24]([CH3:28])=[N:25][N:26]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:27]=1)[CH2:18][CH2:17]3
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Reactant: O=Cc1cccnc1Br
Product: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCCc1cc(F)sc12
Yield: 83 %

Procedure:
The compound of Preparation 13 is essentially prepared as described in Preparation 12 by using 2-bromopyridine-3-carbaldehyde and 2-fluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[4,5-dihydrothieno[2,3-c]pyran-7,4′-piperidine]. Residue is purified by normal phase Isco chromatography to yield 83% of the title compound. MS (m/z): 427 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>CN(C=O)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([O:1][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: Cc1cc(C)nc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(OCCOc2ccc([N+](=O)[O-])cc2)c1
Temperature: 120 °C
Yield: 13.3 %

Procedure:
A mixture of 2-hydroxy-4,6-dimethylpyridine (1.7 g, 13.8 mmol), potassium carbonate (3.82 g, 27.6 mmol) and 1-(2-bromo-ethoxy)-4-nitro-benzene (4.0 g, 16.6 mmol) in DMF (30 mL) was heated to 120° C. and maintained for 15 h. The mixture was cooled to ambient temperature, filtered and concentrated to give a residue which was purified by column chromatography using 4% ethyl acetate/petroleum ether as eluent to afford 2,4-dimethyl-6-[2-(4-nitro-phenoxy)-ethoxy]-pyridine as yellow solid (530 mg, 11%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.S(C1C=CC(C)=CC=1)(O[CH2:30][CH:31]1[O:33][CH2:32]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:30][C@H:31]4[CH2:32][O:33]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
4-(4-Fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (339 mg, 1 mmol), (prepared as described for the starting material in Example 7), was dissolved in dimethylacetamide (5 ml) under nitrogen. (2R) Glycidyl tosylate (285 mg, 1.25 mmol) and potassium carbonate (345 mg, 2.5 mmol) were added and the reaction stirred at ambient temperature for 2.5 hours, then warmed to 40° C. and left overnight. The solvent was removed under vacuum and the residue partitioned between water and dichloromethane. The organic phase was washed with brine and dried (Na2SO4). The residue was purified by column chromatography, eluting with methylene chloride/methanol (97/3) to give 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2R)-oxiran-2-ylmethoxy]quinazoline (339 mg, 85%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:16])[CH3:15]>>[CH2:14]([NH:16][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: CCN
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Product: CCNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
In a manner similar to Example 31, 4-fluoro-3-nitrobenzoic acid was treated with ethylamine to give 4-ethylamino-3-nitrobenzoic acid, which was then esterified with anhydrous hydrogen chloride in methanol to give the title compound. 1H-NMR (CDCl3): δ 8.89 (1H, d), 8.28 (1H, br s), 8.06 (1H, dd), 6.87 (1H, d), 3.90 (3H, s), 3.42 (2H, m), 1.40 (3H, t).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([O:31][CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:38]([N:37]([CH3:36])[C:33]([CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:24]2[CH2:23][CH2:22][CH2:21][CH:20]([N:8]([CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:26][C:25]=2[CH:27]=1)=[O:34])[CH2:39][CH2:40][CH3:41]
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Reactant: CCCCNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCN(C)C(=O)COc1ccc2c(c1)CC(N(C[C@H](O)COc1ccccc1)C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under nitrogen, a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2yloxy]acetic acid (100 mg) in dichloromethane (3 ml) were added N-methylbutylamine (29 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47 mg) in the presence of catalytic amounts of 4-dimethylaminopyridine at 5° C., and the mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give N-[3-[(butylmethylcarbamoyl)methoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-N-tert-butoxycarbonyl-[(2S)-2-hydroxy-3-phenoxypropyl]amine (96 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=2)[C:13]#[N:14])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=3)[C:13]#[N:14])[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Product: CCCc1c(OCc2cccc(Sc3cc(C#N)ccn3)c2)ccc(C(C)=O)c1O
Yield: 81.2 %

Procedure:
Using the method of Preparation 166 using 2-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.25 g, 5.15 mmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (1.00 g, 5.15 mmol) affords the title compound (1.75 g, 81%). MS (APCI-neg) m/z (rel intensity): 417 (M−H, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[N+](C1C=CC=CC=1)([O-])=O>>[N+:32]([C:28]1[CH:27]=[C:26]([NH:1][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[C:9]([S:17][C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:10]=[CH:11][CH:12]=4)[C:7](=[O:24])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cccc(Cl)c1
Reactant: Nc1cccc2c1C(=O)c1cccc(Sc3ccccc3)c1C2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2cccc(Sc3ccccc3)c2C(=O)c2cccc(Nc3cccc([N+](=O)[O-])c3)c21
Reaction time: 18 h
Yield: 81 %

Procedure:
A mixture of 23.2 parts of 1-amino-5-phenylmercaptoanthraquinone, 14.35 parts of 1-chloro-3-nitrobenzene, 7 parts of sodium carbonate and 140 parts of nitrobenzene is dehydrated in the course of one hour, whilst stirring at the boiling point and whilst passing a stream of nitrogen through the mixture. After adding 0.42 part of copper-I chloride, the mixture is kept at 205°-210° for 18 hours, whilst a moderate stream of nitrogen is passed through. After cooling to 20°, the reaction product is filtered off, washed with nitrobenzene, ethanol and hot water and finally heated to the boil with 5% strength hydrochloric acid, filtered off, washed until acidfree and dried. This gives 25.7 parts (81% of theory) of 1-(3'-nitrophenylamino)-5-phenylmercaptoanthraquinone; melting point 246°. The colorant dyes polyester orange in bulk.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:3][CH2:2]1.[I:16]I.S(=O)(=O)(O)O>CC(O)=O>[CH:1]1([C:4]2[C:13]([I:16])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH2:14][CH3:15])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: II
Reactant: CCc1cc(C2CC2)ccc1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(C2CC2)c(I)cc1C(=O)OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a round-bottom flask was added a solution of methyl 4-cyclopropyl-2-ethylbenzoate (compound 226.3, 5.00 g, 24.5 mmol, 1.00 equiv) in AcOH (40 mL). I2 (6.80 g, 26.8 mmol, 1.10 equiv), NaIO4 (2.60 g, 12.2 mmol, 0.50 equiv), and sulfuric acid (400 mg, 4.08 mmol, 0.15 equiv) were added to the reaction. The resulting solution was stirred for 2 h at 50° C. After cooling to ambient temperature, the reaction was carefully quenched with Na2S2O3 (aq., sat.). The mixture was extracted with 2×100 mL of ethyl acetate, and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to furnish 4.00 g (49%) of methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate as a yellow oil.
Reaction SMILES: BrN1C(=[O:7])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[CH3:22]>C(Cl)(Cl)Cl>[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=[O:7])[CH:27]=1)[CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cccc(C=O)c1
Temperature: 100 °C

Procedure:
N-bromosuccinimide (1.78 g) and 2,2′-azobis(2-methylpropionitrile) (16 mg) were added to a solution of ethyl-3-methylphenylacetate (1.76 mL) in chloroform (18 mL) and heated to reflux for 3 hours. On cooling the mixture was diluted with chloroform (40 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (2×50 mL), brine (50 mL), dried (sodium sulfate) and concentrated. The residue was dissolved in nitrogen degassed dimethylsulfoxide (50 mL) and sodium bicarbonate (13.5 g) added. The mixture was heated at 100° C., under nitrogen for 30 min. The reaction was cooled in an ice-bath and poured into brine (300 mL). The aqueous phase was extracted with diethyl ether (3×300 mL). The combined organics were dried (sodium sulfate) and concentrated. Purification on silica, eluting with 10% diethyl ether in iso-hexane, to afford the subtitle compound as a yellow oil (1.23 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13][CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[N:17]=[C:16]1S(C)(=O)=O.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[N:15]([CH2:14][CH2:13][O:12][CH3:11])[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(Oc2ccc(Br)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a stirred solution of 4-bromophenol (149 mg) in DMF (4 mL) was added NaH (60% in oil, 36.0 mg) at room temperature. The mixture was stirred at room temperature for 30 min. To the mixture was added 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (200 mg). The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (243 mg).