Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:21]=[CH:20][C:19]3[S:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:22])[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.S(=O)(=O)(O)[OH:27].OO>O>[C:1]1([S:7]([C:8]2[CH:21]=[CH:20][C:19]3[S:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11](=[O:22])[C:10]=3[CH:9]=2)=[O:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: O=c1c2ccccc2sc2ccc(Sc3ccccc3)cc12
Agent: OO
Solvent: CC#N
Solvent: O
Product: O=c1c2ccccc2sc2ccc(S(=O)c3ccccc3)cc12
Temperature: 40 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
While 11.2 parts of 2-(phenylthio)thioxanthone synthesized in Production Example 1, 215 parts of acetonitrile, and 0.02 parts of sulfuric acid were stirred at 40° C., 4.0 parts of a 30% aqueous hydrogen peroxide solution was dropped thereto slowly and then a reaction was performed at 40 to 45° C. for 14 hours. Subsequently, the reaction solution was cooled to room temperature (about 25° C.) and then was poured into 200 parts of distilled water, so that the product was precipitated. This was filtered and the residue was washed with water until the pH of the filtrate became neutral. Then the residue was dried under reduced pressure, affording a yellow powdery product. The product was purified by column chromatography (eluate: ethyl acetate/toluene=⅓:volume ratio) to afford 2-[(phenyl)sulfinyl]thioxanthone in a yield of 83%. The product was identified by 1H-NMR {d6-dimethyl sulfoxide, δ (ppm) 8.75 (1H, s), 8.45 (1H, d), 8.01 (2H, d), 7.75-7.85 (4H, m), 7.53-7.62 (4H, m)}.
Reaction SMILES: [C:1](OC(C1CCCN1C(=O)C(NC(=O)C1C=CC(N)=C(Cl)C=1)C)=O)(C)([CH3:3])[CH3:2].[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35]CC2C=CC=CC=2)[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30]1>>[CH2:35]([O:34][CH:32]1[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30][C:29](=[O:28])[O:33]1)[CH:1]([CH3:3])[CH3:2]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(C)COC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1
Yield: 38 %

Procedure:
Prepared from 97a and syn-(2-isobutoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 93 mg (38% yield) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 0.74-0.76 (t, 0.6H), 0.80-1.00 (m, 5.4H), 1.40-1.50 (m, 3H), 1.90-2.22 (m, 3H), 2.33-2.45 (m, H), 2.80-2.90 (m, H), 3.32-3.38 (m, H), 3.55-3.80 (m, 3H), 4.38 (br, H), 4.50-4.60 (m, H), 4.70-4.80 (m, H), 4.90-5.00 (m, H), 5.42-5.45 (m, H), 6.74-6.76 (d, H), 6.86-6.88 (d, H), 7.31-7.33 (d, H), 7.51-7.53 (m, H), 7.74-7.75 (d, H); retention time on analytical HPLC: 9.63 & 9.80 min; LC-MS: m/z=495 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[O-:12][CH2:13][CH3:14].[Na+].Cl>C(O)C>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH3:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC[O-]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncc(C(=O)O)cc1Br
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A slurry of 5-bromo-6-chloronicotinic acid (240 mg, 1.0 mmol) and sodium ethoxide (138 mg, 2.0 mmol) in anhydrous ethanol (2 mL) was heated under microwave conditions at 100° C. for 15 min; an additional portion of sodium ethoxide (79 mg, 1.0 mmol) was added and heating was continued for 1 hr. After cooling the reaction mixture was adjusted to a pH of 4 with 1 N aqueous hydrochloric acid, the resulting solids collected and dried in vacuo to afford 5-bromo-6-ethoxynicotinic acid (140 mg). 1H NMR (400 MHz, DMSO-d6) d ppm 1.33 (t, J=7.02 Hz, 3H) 4.43 (q, J=7.09 Hz, 2H) 8.32 (d, J=2.15 Hz, 1H) 8.64 (d, J=1.95 Hz, 1H) 13.28 (br. s., 1H); m/z=248.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:34])([F:33])[O:21][C:22]1[CH:23]=[C:24](/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:33])([F:34])[F:19])[CH:23]=3)=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)/C=C/c3cccc(OC(F)(F)F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid. LC-MS-conditions 05: tR=0.87 min; [M+H]+=436.88.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[N:7][CH:8]=1)#[N:2].[F:19][C:20]([F:36])([F:35])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=2)[C:29](O)=[O:30])[N:22]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:23]4[N:22]=[C:21]([C:20]([F:36])([F:35])[F:19])[O:25][N:24]=4)[CH:27]=3)[CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[N:7][CH:8]=1)#[N:2]
Reactant: COC(=O)C1CN(c2ccc(C#N)cn2)CCN1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: COC(=O)C1CN(c2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 73 %

Procedure:
This compound was synthesized from methyl 4-(5-cyanopyridin-2-yl)piperazine-2-carboxylate and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (130 mg, yield 73%). 1H NMR (400 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 8.42 (br s, 1H), 8.24 (m, 1H), 7.73-7.64 (m, 3H), 6.71 (d, J=9.0 Hz, 1H), 4.94 (m, 1H), 4.52-4.41 (m, 1H), 3.78 (s, 3H), 3.75 (m, 2H), 3.69-3.59 (m, 1H), 3.51-3.48 (m, 1H), 3.11-3.04 (m, 1H). MS (ESI) m/z: Calculated for C22H17F3N6O4: 486.13. found: 487.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:34]>>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(Cl)n2)o1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (85 mg, 0.178 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as an off-white solid (74 mg, 91%). 1H-NMR (DMSO-d6): δ ppm 10.25 (br s, 1H), 8.27 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.83 (t, J=2.0 Hz, 1H), 7.44-7.36 (m, 2H), 7.25 (t, J=8.4 Hz, 1H), 6.69 (s, 1H), 6.63 (br s, 2H), 6.50 (d, J=5.2 Hz, 1H), 1.41 (s, 9H); MS: 458 [M+H]+.
Reaction SMILES: O([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)C1C=CC=CC=1.C([O-])(=O)C.[NH4+:40].[OH-].[Na+]>O>[NH2:40][C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]3)[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(Oc4ccccc4)nc4ccccc4c32)CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(N)nc4ccccc4c32)CC1
Temperature: 140 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A mixture of 4.40 g of tert-butyl 4-[2-(4-phenoxy-1H-imidazo[4,5-c]-quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 34.5 g of ammonium acetate was stirred at 140° C. for 3 hours. The reaction mixture was added with water, adjusted to pH 9 with 10% aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was washed with saturated brine, and dried, and then the solvent was evaporated. The resulting residue was purified by alumina column chromatography using methylene chloride—methanol (100:1 to 20:1) as eluting solvents, and washed with diisopropyl ether to give 1.88 g of colorless crystals. Recrystallization from ethyl acetate gave colorless crystals having the melting point of from 193 to 193.5° C.
Reaction SMILES: [CH:1]([C:3]1[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1cccc(COc2cccc(OC)c2C=O)c1
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccc(COc2cccc(O)c2C=O)c1

Procedure:
To a stirred solution of methyl 3-(2-formyl-3-methoxyphenoxy)methylbenzoate (3 g, 0.01 M) in dry tetrahydrofuran (30 ml) was added dropwise a solution of magnesium iodide (4.13 g, 0.015 M) in dry ether (65 ml). The mixture was then stirred under reflux (51/2 hr). The cooled mixture was poured into 10% hydrochloric acid (55 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solutions were washed with sodium bicarbonate solution, water, dried (magnesium sulphate) and evaporated. The residue was dissolved in chloroform-methanol (95:5) and filtered through a short pad of florisil. The pale yellow solution was evaporated to give methyl 3-(2-formyl-3-hydroxyphenoxy)methylbenzoate, m.p. 118°-120° C. from ethyl acetate/petrol.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Li]CCCC.CCCCCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>C1COCC1>[CH3:10][O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][C:7]=1[B:24]([OH:29])[OH:25]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)cc1B(O)O
Temperature: -30 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A solution of 4-trifluoromethylanisole (8 g; 45 mmol) in dry THF (80 ml) at −30° C. under N2 was added a solution of 2.5 M n-BuLi in hexane (20 ml; 50 mmol). The reaction mixture was stirred for 1 h at −30° C., then cooled to −70° C. and added B(Oi-Pr)3 (14.1 ml; 64 mmol). The reaction mixture was allowed to slowly warm up to rt. over night. The reaction mixture was added 2 M HCl (40 ml) and THF was removed by evaporation. The aqueous remanense was extracted with Et2O (4×20 ml) and the combined organic fractions were extracted with 1 M NaOH (5×17 ml). The combined aqueous fractions were neutralized by 10 M HCl. The precipitate formed was isolated by filtration and washed with 1 M HCl to give 8.1 g (81%) product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:14][CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Bromo-1-(bromomethyl)-2-nitrobenzene (Heterocycles 1994, 39, 767) (8.3 g, 28 mmol) was dissolved in methanol (75 ml) at 0° C. 30% Sodium methoxide in methanol solution (10.7 ml, 56 mmol) was added dropwise and the solution stirred at room temperature for 4 hours. The mixture was concentrated to a small volume and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and then washed with saturated aqueous sodium bicarbonate solution, water (×3), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane to ethyl acetate) to afford the title compound (D16). MS (ES+) m/e 246/248 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[O:13]=[S:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][NH:15]1>>[O:13]=[S:14]1(=[O:19])[CH2:18][CH2:17][CH2:16][N:15]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: O=S1(=O)CCCN1
Product: COC(=O)c1ccc(CN2CCCS2(=O)=O)nc1
Yield: 73 %

Procedure:
Using methyl 6-bromomethylnicotinate (500 mg) and 1,1-dioxo-1λ6-isothiazolidine (290 mg) and by the reaction and treatment in the same manner as in Preparation Example 42, the title compound (429 mg) was obtained.
Reaction SMILES: [CH2:1]([NH:7][C:8]1[CH:40]=[CH:39][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]=[C:49]=[O:50])=[CH:44][CH:43]=1>O1CCCC1>[O:33]=[C:31]1[NH:30][C:29](=[O:34])[CH:28]([CH2:27][C:26]2[CH:35]=[CH:36][C:23]([O:22][CH2:21][C:19]3[N:18]([CH3:37])[C:17]4[CH:38]=[C:13]([O:12][C:11]5[CH:39]=[CH:40][C:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:49]([NH:48][C:45]6[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=6)=[O:50])=[CH:9][CH:10]=5)[CH:14]=[CH:15][C:16]=4[N:20]=3)=[CH:24][CH:25]=2)[S:32]1
Reactant: CCCCCCNc1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)Nc1ccc(F)cc1)c1ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1
Reaction time: 48 h

Procedure:
A mixture of 5-[4-[6-(4-n-hexylaminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.39 g), 4-fluorophenyl isocyanate (0.11 g) and anhydrous tetrahydrofuran (20 ml) was allowed to stand at room temperature for 2 days. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2 as the eluant and the product was reprecipitated from a mixture of ethyl acetate and diisopropyl ether to afford the title compound (0.32 g, Rf=0.45: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=2:1 as the eluant).
Reaction SMILES: [CH:1]([OH:3])=O.[N+:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[NH2:15])[CH:10]=[O:11])([O-:6])=[O:5].C(OC(=O)C)(=O)C>O>[N+:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[NH:15][CH:1]=[O:3])[CH:10]=[O:11])([O-:6])=[O:5]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: O=CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc(C=O)cc1[N+](=O)[O-]
Yield: 79.7 %

Procedure:
To 56.6 ml (1.50 mol) of HCOOH was added 24.9 g (150 mmol) of 3-nitro-4-aminobenzaldehyde. The solution was heated to reflux, 28.4 ml (300 mmol) of acetic anhydride was added dropwise and the solution was refluxed for 30 minutes. The resulting suspension was cooled and poured into 400 ml of cold H2O with rapid stirring. The product was filtered, air dried, and recrystallized from isopropanol to yield 23.2 g (80%) of 3-nitro-4-formamidobenzaldehyde as a bright yellow powder: melting point=183°-191°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(=S)=S>[C:19]([CH2:18][CH2:17][C:16]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:2][CH:3]=1)=[O:22])([OH:21])=[O:20]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 18 g. of methyl phenylacetate, 26 g. of aluminum chloride and 150 ml. of carbon disulfide, 20 g. of succinic anhydride are added. The reaction mixture is allowed to stand for two hours at 35°C; then it is added to a liter of ice water and extracted with methylene chloride. The extracts are combined, washed, dried, and evaporated to give methyl p-(3'-carboxy-1'-oxopropyl)-phenylacetate. This derivative is reduced with sodium borohydride and dehydroxylated with palladium charcoal catalyst by the procedures described in Part A of Example 2 to afford methyl p-(3'-carboxypropyl)-phenylacetate. This derivative is refluxed in 50 ml. of thionyl chloride for three hours and then it is evaporated. The residue, containing methyl p-(3'-chlorocarbonylpropyl)-phenylacetate, is taken up in ml. of benzene containing 40 g. of aluminum chloride, The resulting mixture is stirred for two hours at 20° C; then it is added to a liter of ice and water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, and evaporated to give 7-(methoxycarbonylmethyl)-1-tetralone.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:26]3[CH:27]=[N:28][C:23]([C:22]([F:32])([F:21])[F:31])=[CH:24][CH:25]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(C(F)(F)F)nc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 5.5 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2218 mmol), 6-Trifluoromethyl-pyridine-3-carbaldehyde (42.7 mg, 0.244 mmol), and Ammonium acetate (34.2 mg, 0.444 mmol) were reacted to produce 5.98 mg (5%) of the title compound. (300 MHz, DMSO-d6) 9.45 (s, 1H), 8.69 (d, J=9 Hz, 1H), 8.09 (m, 2H), 7.76 (s, 1H), 7.22 (s, 2H), 6.44 (m, 1H), 6.37 (m, 1H), 5.24 (t, J=17 Hz, 8 Hz, 1H), 2.89 (s, 1H), 2.79 (s, 1H), 2.66 (d, J=9 Hz, 1H), 2.63 (d, J=9 Hz, 1H), 2.25 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=493 (M+H), HPLC: 2.66 min. (G Method)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([C:17]5[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc(-c2ccc3c(c2)CCNC3)ccn1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(-c3ccncc3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[OH:12][CH:13]([CH:18]=[CH2:19])[C:14]([O:16][CH3:17])=[O:15]>>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([CH2:19][CH2:18][C:13](=[O:12])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: C=CC(O)C(=O)OC
Product: COC(=O)C(=O)CCc1cccc(C(F)(F)F)c1

Procedure:
Methyl 4-[3-(trifluoromethyl)phenyl]-2-oxobutyrate was prepared as an oil from 3-iodobenzotrifluoride and methyl 2-hydroxy-3-butenoate.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C@@H:7]2[C@@H:10]([C:13]([F:16])([F:15])[F:14])[O:11][CH2:12][C@:6]2([C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=2[F:26])[N:5]=[C:4]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([F:26])=[C:17]([C@:6]23[CH2:12][O:11][C@H:10]([C:13]([F:16])([F:14])[F:15])[C@H:7]2[C:8](=[O:9])[N:3]([CH2:1][CH3:2])[C:4]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:5]3)[CH:22]=1
Reactant: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc([N+](=O)[O-])ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Yield: 99.2 %

Procedure:
A solution of tert-butyl ((4aS,5S,7aS)-3-ethyl-7a-(2-fluoro-5-nitrophenyl)-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (0.225 g, 0.46 mmol) in ethanol (30 mL) was hydrogenated over 10% Pd/C (50 mg) at RT under a balloon of hydrogen for 2 h. The catalyst was removed by filtration through Celite-washing with ethanol. The filtrate was evaporated to give the title compound (0.21 g, colourless foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.14 (t, J=6.95 Hz, 3H) 1.53 (s, 9H) 3.90-4.12 (m, 3H) 4.31 (d, J=9.60 Hz, 1H) 4.45 (dd, J=9.60, 3.28 Hz, 1H) 4.47-4.56 (m, 1H) 6.46 (dd, J=6.32, 2.78 Hz, 1H) 6.63 (ddd, J=8.59, 3.79, 2.78 Hz, 1H) 6.94 (dd, J=11.12, 8.84 Hz, 1H) 10.49 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[C:14]([CH3:15])=[N:13][N:12]=[C:11]2[C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2C(OC(C)(C)C)=O)[CH3:9])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[C:11]([C@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)=[N:12][N:13]=[C:14]2[CH3:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1nnc([C@H]2CCCN2C(=O)OC(C)(C)C)n1[C@@H](C)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnc([C@H]2CCCN2)n1[C@@H](C)c1ccc(Cl)cc1

Procedure:
A solution of the Boc-protected triazole product of Step C (1 g) in 40 ml of 40% TFA/DCM was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and used directly as the TFA salt in the next step. MS: calculated: 290.13. Found (MH+): 291.3
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:24][O:25][C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:6]=2[CH:23]=1
Reactant: Oc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1
Reactant: COC(=O)CCCCBr
Product: COC(=O)CCCCOc1ccc2nc(-c3cccnc3)n(-c3ccc(F)cc3)c2c1

Procedure:
6-Hydroxy-1-(4-fluorophenyl)-2-(3-pyridinyl)-1H-benzimidazole was reacted with 5-bromo-pentanoic acid methyl ester according to general operating instructions 3.