Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][P:8]([OH:10])[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11](N(CC)CC)[CH3:12].ClC(OCC)=O>O1CCCC1>[CH:1]1([CH2:7][PH:8](=[O:10])[O:9][CH2:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OP(O)CC1CCCCC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCO[PH](=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A tetrahydrofuran solution of 19.3 g of cyclohexylmethylphosphonous acid is cooled to 5°, at which temperature a suspension forms, and treated with 12.14 g of triethylamine. An exothermia ensues and the suspension is re-cooled to 5° before slow addition of 13.02 g ethyl chloroformate in 20 ml of anhydrous tetrahydrofuran. An exothermic reaction occurs with gas evolution. The white suspension is stirred overnight at room temperature and subsequently filtered. The filtrate is concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic phase is removed, dried and concentrated in vacuo to give a yellow oil. Distillation in high vacuum affords ethyl (cyclohexylmethyl)phosphinate; b.p. 120°-130° (2×10-2 mbar); 1H-NMR (CDCl3): δ (ppm)=7.17 (1H, d, J=527 Hz, P--H), 4.13 (2H, m, CH2OP), 1.95-1.58 (7H, m, 3×CH2 +CH), 1.38-0.75 (9H, m, 3×CH2 +CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:37][NH2:38]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3=[N:37][NH:38][C:19](=[O:21])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[CH:25]=[CH:26][C:27]([CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:28][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(Cl)cc1)C(c1ccc(CN(CC)CC)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(Cl)cc2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of ethyl 3-(4-chlorophenyl)-2-(4-((diethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (268 mg) in 85% hydrazine monohydrate (0.5 mL) and methanol (2 mL) was stirred at 23° C. for overnight. Methanol was removed under reduced pressure. The crude was purified by prep-HPLC to give the title compound (93 mg, yield 37%). LC-MS (ESI) m/z: 459 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.93 (t, 6H), 2.38 (q, 4H), 3.44 (s, 2H), 4.35 (d, 1H), 4.73 (d, 1H), 7.13-7.19 (m, 5H), 7.22-7.25 (m, 4H), 7.38 (d, 2H), 7.41 (s, 1H), 7.56-7.59 (m, 1H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][O:14][C:27](=[O:28])[NH:26][CH2:24][CH3:25])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCN=C=O
Reactant: OCCOc1ccc(Cn2cccn2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)OCCOc1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a mixture of 2-[4-(1-pyrazolyl)methylphenoxy]ethanol (produced in Reference Production Example 3 described below) (500 mg), triethylamine (255 mg) and dry toluene (20 ml) was added dropwise an anhydrous toluene solution (1 ml) of ethyl isocyanate (179 mg). This mixture was then stirred at room temperature overnight, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 87 mg of ethylcarbamic acid 2-[4-(1-pyrazolyl)methylphenoxy]-ethyl ester (compound 37). Yield, 13%.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].[CH3:16][O:17][CH2:18]Cl>CC(N(C)C)=O>[CH3:16][O:17][CH2:18][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
11.2 g of potassium t-butoxide were added, whilst ice-cooling and stirring, to a solution of 12.0 g of 3-hydroxybenzaldehyde in 100 ml of dimethylacetamide, and, about ten minutes later, 8.05 g of methoxymethyl chloride were added dropwise to the resulting mixture. The reaction mixture was then stirred at room temperature for 1 hour, after which it was partitioned between ethyl acetate and water. The organic layer was concentrated by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 11.1 g (yield 68%) of 3-methoxymethoxybenzaldehyde as a colorless oil. 10 g of this colorless oil were dissolved in 100 ml of acetonitrile, and 18.3 g of (triphenylphosphoranyldene)acetaldehyde were added to the solution. The resulting mixture was then heated under reflux for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with a mixture of ethyl acetate and hexane in a proportion of about 2:1 by volume. The mixture was stirred and the resulting precipitates were filtered off. The filtrate was concentrated by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 7.16 g (yield 62%) of 3-(3-methoxymethoxyphenyl)-2-propenal as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Cl[CH2:21][CH2:22][S:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][S:23][CH2:24][CH3:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CCSCCCl
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCSCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 55.3 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 1-chloro-2-ethylsulfanyl-ethane (0.5 ml; 3.83 mmol) and K2CO3 (0.54 g; 3.83 mmol) at 40° C. for 4 d. After aqueous work-up and purification by RP chromatography the pure material (0.77 g) is de-acetylated in MeOH (35 ml) using DBU (0.3 ml) at reflux. After aqueous work-up 5-amino-1-(2-ethylsulfanyl-ethyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.65 g) is obtained and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH2:25][CH3:26])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH2:24]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:36](=[O:37])[C:30]3[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=3)[C:39]2=[O:38])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH2:25][CH3:26]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-propylaminophenyl)-5-phenylbenzoxazole (161 mg, 0.47 mmol) and 1,2,4-benzenetricarboxylic anhydride (90 mg, 0.47 mmol) the title compound was obtained (174 mg, 72%). 1H NMR (DMSO) δ 8.51(t, 1H), 8.42(dd, 1H), 8.31(s, 1H), 8.15(d, 1H), 8.08(m, 2H), 7.77(m, 4H), 7.50(m, 3H), 7.39(t, 1H), 7.03(d, 1H), 3.40(q, 2H), 1.68(m, 2H), 1.34(t, 3H). MS 518 m/z (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[CH:19][C:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:9][C:8]=1[O:21][CH3:22].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1.CCCCCC>[Si:12]([O:11][C:10]1[CH:19]=[CH:20][C:7]([B:23]([OH:28])[OH:24])=[C:8]([O:21][CH3:22])[CH:9]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B(O)O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, n-butyl lithium (a hexane solution) was added at −75° C. to a THF solution of (4-bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane, followed by stirring at −75° C. for 1 hour. Triisopropyl borate was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was treated with hydrochloric acid to obtain (4-{[tert-butyl(dimethyl)silyl]oxy}-2-methoxyphenyl)boronic acid.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][S:6][C:5](=[S:8])[N:4]1[CH2:9][C:10]([OH:12])=O.[CH2:13]([C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:24][N:23]([C:10](=[O:12])[CH2:9][N:4]2[C:3](=[O:2])[CH2:7][S:6][C:5]2=[S:8])[C@H:22]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)=[O:26])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CN1C(=O)CSC1=S
Yield: 39.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 99, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(4-oxo-2-thioxothiazolidin-3-yl)acetyl)pyrrolidine-2-carboxamide (13.5 mg, 39.9%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.92 (s, 1H), 7.51 (d, 2H), 7.30-7.16 (m, 9H), 6.93 (m, 2H), 4.76 (m, 1H), 4.60 (m, 1H), 4.43 (m, 1H), 4.35 (m, 2H), 2.87 (s, 2H), 2.68 (m, 3H), 1.95 (m, 2H). MS (EI) for C29H26FN3O4S2. found 564.7 (MH+).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[F-].[C:14]([C:17](=[N:22][O:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19])(=[O:16])[NH2:15].C(N(CC)CC)C>C(Cl)Cl.O>[NH:15]=[C:14]([O:16][CH2:6][CH3:7])[C:17](=[N:22][O:23][CH2:24][CH3:25])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CC[O+](CC)CC
Reactant: CCON=C(C(N)=O)C(=O)OC
Agent: F[B-](F)(F)F
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCON=C(C(=N)OCC)C(=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Meerwein reagent (triethyloxonium tetrafluoroborate) {prepared from bron fluoride etherate (2.84 g) by a method of Org. Syn., 46, 113 (1966)} in methylene chloride (30 ml) was added methyl 2-carbamoyl-2-ethoxyiminoacetate (syn isomer, 2.6 g) and the mixture was stirred for 18 hours at room temperature. The reaction mixture was cooled in an ice-bath and triethylamine (3 g) was added thereto, followed by an addition of water (20 ml). The organic layer was separated out, dried over magnesium sulfate and evaporated to give crude methyl 3-imino-3-ethoxy-2-ethoxyiminopropionate (syn isomer) (5.0 g) as an oil. ##STR15##
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](N)=[O:6].S(=O)(=O)(O)[OH:15]>>[Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:15])=[O:6]
Reactant: NC(=O)c1cc(F)c(F)c(Br)c1F
Reactant: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(F)c(Br)c1F
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromo-2,4,5-trifluorobenzamide (8.7 g) and 18N-sulfuric acid (50 ml) was stirred at 100° C. for 4 hours, and then poured into ice water (200 ml). The resulting precipitate was collected by filtration and recrystallized from dichloro-methane-n-hexane to give the title compound (6.9 g), mp 125°-127° C.
Reaction SMILES: [Br:1]C1C=CC(CC(OCC)=O)=CC=1.Br[C:15]1[CH:24]=[C:23]2[C:18]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][C:22]2=[O:25])=[CH:17][CH:16]=1>>[Br:1][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:15]=1)[C:22](=[O:25])[CH2:21][CH2:20][C:19]2([CH3:27])[CH3:26]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Product: CC1(C)CCC(=O)c2ccc(Br)cc21

Procedure:
Important starting materials for the synthesis of the preferred compounds of the invention are 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and the isomeric bromo compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H). Compound G can be obtained as described in J. Med. Chem. 1995, 38, 4764-4767, and as shown in Reaction Scheme 1. Thus, referring now specifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (Compound B, made by esterification of 3-bromophenylacetic acid) is reduced with diisobutylaluminum hydride (DIBAL H) to yield (3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with (carbethoxymethylene)triphenylphosphorane to provide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds are hydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with the Grignard reagent derived from methylbromide to give the tertiary alcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should be apparent to those skilled in the art, that the choice of the Grignard reagent used in this reaction step determines the nature of the R1 substituent in the resulting compounds of the invention.) Compound E is then treated with acid to cyclize it and to form 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F). Compound F is oxidized with chromium trioxide to yield 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). The isomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can be obtained, starting with ethyl (4-bromophenyl)acetate, in accordance with the sequence of reactions illustrated in Reaction Scheme 1 for Compound G. 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) can also be obtained in accordance with the published literature procedure: Mathur et al. Tetrahedron, 41, 1509-1516 (1985).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]1[C:12]([OH:14])=[O:13].C(N(CC)CC)C.[C:23]([S:31][CH2:32][CH:33]([CH3:37])[C:34](Cl)=[O:35])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:23]([S:31][CH2:32][CH:33]([CH3:37])[C:34]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH3:15])([CH3:2])[CH:4]1[C:12]([OH:14])=[O:13])=[O:35])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)Cl
Reactant: CC1(C)c2ccccc2NC1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CSC(=O)c1ccccc1)C(=O)N1c2ccccc2C(C)(C)C1C(=O)O
Reaction time: 1 h

Procedure:
To the suspension of 1.0 g of 3,3-dimethylindoline-2-carboxylic acid hydrochloride in 25 ml of methylene chloride, 1.33 g of triethylamine are added and the resulting solution cooled to -10°. The solution of 1.065 g of 3-benzoylthio-2-methylpropanoyl chloride in 5 ml of methylene chloride is added dropwise and the mixture stirred at -5° for 1 hour, and then at room temperature for 2 hours. It is evaporated, 10 ml of 3N hydrochloric acid are added to the residue and the mixture is extracted with methylene chloride. The extract is dried and evaporated, to give the 1-(3-benzoylthio-2-methylpropanoyl)-3,3-dimethylindoline-2-carboxylic acid.
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][C:7]=1[C:8]([OH:10])=O.[CH2:16]([CH2:18][NH2:19])[OH:17].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[NH2:5][C:6]1[N:14]=[CH:13][C:12]([Br:15])=[CH:11][C:7]=1[C:8]([NH:19][CH2:18][CH2:16][OH:17])=[O:10]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: NCCO
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Nc1ncc(Br)cc1C(=O)NCCO

Procedure:
EDC (2.91 g, 15.2 mmole) was added to a solution 2-amino-5-bromonicotinic acid (3.00 g, 13.8 mmole), ethanolamine (0.93 g, 15.2 mmole), HOBt.H2O (2.05 g, 15.2 mmole), and diisopropylethylamine (2.64 mL, 15.2 mmole) in DMF (50 mL) at RT and the reaction solution was stirred overnight. The reaction contents were poured into H2O (200 mL) and the resulting mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with H2O and brine and then dried over Na2SO4. Concentration of the organic extracts afforded the title compound as a yellow solid which was used without further purification: MS (ES) m/e 261 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:6][C:5]=1[CH:19]=[O:20])([CH3:3])=[CH2:2].[BH4-].[Na+]>C1COCC1>[C:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[S:6][C:5]=1[CH2:19][OH:20])([CH3:3])=[CH2:2]
Reactant: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1cc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-Isopropenyl-5-(4-trifluoromethyl-phenyl)-thiophene-2-carbaldehyde (0.084 g, 0.283 mmole) in THF (3 mL), is added to NaBH4 (0.023 g, 0.622 mmole) in one portion at 0° C. The reaction is kept at 0° C. for 15 minutes and warmed up to room temperature for 2 hours. The reaction is quenched using saturated NH4Cl(aq) (20 mL) at 0° C. The THF is removed on rota vapor, the aqueous solution is then extracted with ethyl acetate (2×10 mL). The combined organic solution is washed with brine (3×20 mL), dried over Na2SO4 and concentrated to provide the titled compound as yellow solid, which is used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C([O-])([O-])=O.[K+].[K+].C([O:14][C:15](=O)[CH:16](Br)[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)C.O>CCO>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH:16]2[S:5][CH2:4][CH2:3][NH:2][C:15]2=[O:14])=[CH:18][CH:19]=1
Reactant: NCCS
Reactant: CCOC(=O)C(Br)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1NCCSC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.1 %

Procedure:
To a solution of 2-aminoethanethiol hydrochloride (6.93 g; 61 mmol) in EtOH (400 mL) was added K2CO3 (16.86 g; 122 mmol), at RT, followed after 15 minutes by bromo-(4-bromo-phenyl)-acetic acid ethyl ester (12 mL; 61 mmol). The resulting mixture was stirred at RT for two days, subsequently, water was added and the resulting mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from EtOH to afford 2-(4-bromo-phenyl)-thiomorpholin-3-one (12.8 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:14]([Mg]Br)[CH3:15]>C1COCC1>[CH2:14]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1)[CH3:15]
Reactant: Clc1ccc(-c2ccccc2)nc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
5-Chloro-2-phenylpyridine (16 g, 84 mmol) and Ni(dppe)Cl2 (0.891 g, 1.687 mmol) were added to 300 mL of THF and the reaction mixture was degassed with nitrogen for 20 min. before being cooled to 0° C. Ethylmagnesium bromide (169 mL, 169 mmol) was added dropwise over a period of 60 min. and the reaction mixture stirred for and additional 3 h at before warming to room temperature overnight. The reaction mixture was recooled to 0° C. and quenched with 250 mL of water, extracted with EtOAc and the organic layer dried over sodium sulfate and filtered. The crude material was chromatographed on silica with 95/5 hexane/EtOAc to give 2.9 g (19%) of 5-ethyl-2-phenylpyridine as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)[CH:6]=CC=1)#N.O.[C:20]([OH:23])(=[O:22])[CH3:21]>Cl>[CH:16]([C:14]1[N:15]=[C:11]([CH:10]=[CH:9][C:5]2[CH:6]=[C:21]([CH:1]=[CH:3][CH:4]=2)[C:20]([OH:23])=[O:22])[S:12][CH:13]=1)([CH3:18])[CH3:17]
Reactant: CC(=O)O
Reactant: CC(C)c1csc(C=Cc2cccc(C#N)c2)n1
Agent: Cl
Solvent: O
Product: CC(C)c1csc(C=Cc2cccc(C(=O)O)c2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
2-(2-(3-Cyanophenyl)ethenyl)-4-isopropylthiazole prepared in Synthetic Example (2.54 g, 10.0 mmol) was dissolved in a mixed solvent of acetic acid (5 ml) and concentrated hydrochloric acid (10 ml) and the resulting mixture was heated under stirring at 100° C. for 4 hours. After water was added, the reaction mixture was extracted with ethyl acetate and dried. The solvent was distilled out to afford the indicated compound (2.51 g) with a yield of 92%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=4[CH3:26])=[N:15][NH:14][C:13](=O)[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:13]1[C:9]2[NH:10][C:11]3[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=3[C:8]=2[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=2[CH3:26])=[N:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Product: CC(=O)c1ccc2c(c1)[nH]c1c(Cl)nnc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 110 °C
Yield: 86.7 %

Procedure:
To 7-acetyl-1-(2-methyl-3-nitrophenyl)-3H-pyridazino[4,5-b]indol-4(5H)-one (1.88 g, 91.7% pure, 4.75 mmol) at room temperature was added phosphoryl trichloride (350 mL, 3755 mmol), and the mixture was heated at 110° C. for 1 hr. The excess of phosphoryl trichloride was removed under vacuum. The residue was dissolved in ice cold ethyl acetate (900 mL), washed with water (100 mL), saturated NaHCO3 solution (2×100 mL), water (100 mL), and brine (100 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum to dryness to provide the desired product (1.57 g, 4.12 mmol, 86% yield over 2 steps) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8]O)[CH:7]=1.P(Br)(Br)[Br:14].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:14][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
5-methyl-2-nitrobenzoic acid (10.0 g, 55.2 mmol) were dissolved in THF (100 mL) followed by dropping 2.0 M borane dimethisulfide comples (110 mL, 221.1 mmol) and heating at 80° C. After 1.5 hours, 100 ml of 1 M HCl were dropped into this reaction system while cooling with ice and stirring. The system was extracted with ethyl acetate, and then was dried with Na2SO4 followed by concentration under reduced pressure and drying to obtain benzylic alcohol (9.1 g, 99% yield) as viscous colorless oil. (5-methyl-2-nitrophenyl) methanol (9.1 g, 54.5 mmol) were dissolved in dry CH2Cl2 (100 mL) followed by the addition of phosphorous tribromide (7.4 g, 27.3 mmol) and stirring at room temperature. After 30 minutes, saturated NaHCO3(aq. 100 mL) were added followed by stirring for 10 minutes and extracting with CH2Cl2 (200 ml×2). The organic phase was then concentrated under reduced pressure and dried to obtain the benzyl bromide analogue, 49, (11.9 g, 95% yield) as a white solid: mp 51-52° C.