Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:22]C)=[N:17][N:16]=[C:15]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.Br>O1CCOCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([OH:22])=[N:17][N:16]=[C:15]3[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1nnc(-c2ccccc2)c2cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc12
Agent: Br
Solvent: C1COCCO1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(O)nnc(-c3ccccc3)c2c1
Temperature: 40 °C
Reaction time: 48 h
Yield: 15.5 %

Procedure:
A mixture of 1-methoxy-4-phenyl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (80 mg, 0.189 mmol), dioxane (2 mL) and 48% HBr (4 mL) was stirred at 40° C. for 48 hours. Concentration followed by chromatography (Hex/EtOAc) afforded 1-hydroxy-4-phenyl-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (12 mg) as a white solid, 1H (500 MHz, CDCl3, 55° C.) δ: 7.47 (d, 1H), 7.52 (t, 1H), 7.56-7.65 (m, 5H), 7.84 (d, 1H), 7.90-7.96 (m, 2H), 8.21 (d, 1H), 8.29 (s, 1H), 8.65 (d, 1H), 10.40 (s, 1H) ppm. m/z 410.00.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH:4]1[CH2:13][C:14]([OH:16])=O.[CH2:17]([C@H:24]1[CH2:28][NH:27][C@H:26]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)=[O:30])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([C@H:24]1[CH2:28][N:27]([C:14](=[O:16])[CH2:13][CH:4]2[C:5](=[O:12])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]2=[O:2])[C@H:26]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[CH:34][CH:33]=2)=[O:30])[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CC1C(=O)c2ccccc2C1=O
Agent: Cl
Product: O=C1c2ccccc2C(=O)C1CC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 40.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 97, (2S,4R)-4-benzyl-1-(2-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (13.9 mg, 40.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.94 (s, 1H), 7.86 (m, 4H), 7.51 (d, 2H), 7.31-7.13 (m, 9H), 6.91 (m, 2H), 4.52 (d, 1H), 4.47-4.40 (m, 2H), 3.84 (m, 1H), 3.39 (m, 1H), 2.67 (m, 3H), 1.94 (m, 2H). MS (EI) for C34H28FN3O5. found 578.6 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:22]1[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:22]1[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(-c2ccc(C(=O)O)s2)cccc1[N+](=O)[O-]
Yield: 85.6 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 6a (10 g, 35.85 mmol), 5-bromothiophene-2-carboxylic acid (6.68 g, 32.2 mmol), tetrakis(triphenylphosphine)palladium (2.07 g, 1.79 mmol) and sodium carbonate (7.59 g, 71.6 mmol) were dissolved in the solvent mixture of 200 mL of 1,4-dioxane and 30 mL of water. The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 150 mL of water and adjusted to pH 3 with 1 N hydrochloric acid. The mixture was filtered and the filter cake was washed with 50 mL of the solvent mixture of n-hexane/ethyl acetate (V:V=1/1) and dried to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)thiophene-2-carboxylic acid 12a (7.7 g, yield 77%) as a light yellow solid.
Reaction SMILES: O=O.[CH2:3]([O:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[O:22][C:23]=2[CH3:24])=[CH:13][C:12]=1[CH3:32])/[C:7]([OH:9])=[O:8])[CH3:4].[OH-].[Na+].[H][H].Cl>ClCCl.CO>[CH2:3]([O:5][C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[O:22][C:23]=2[CH3:24])=[CH:13][C:12]=1[CH3:32])[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCO/C(=C\c1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C)C(=O)O
Reactant: [H][H]
Agent: Cl
Agent: O=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1C)C(=O)O
Reaction time: 16 h
Yield: 72.9 %

Procedure:
In a glove box (O2 content≦2 ppm), a 185 ml stainless steel autoclave was charged with 11.5 g of (Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid (28.0 mmol), 35 ml of dichloromethane, 35 ml of methanol, 2.5 ml of a 30% aqueous NaOH solution (14.0 mmol) and 22.6 mg (0.028 mmol) of [Ru(OAc)2((+)-TMBTP)]. TMBTP is 4,4′-Bis(diphenylphosphino)-2,2′,5,5′-tetramethyl-3,3′-dithiophene, its synthesis as (R) or (S) enantiomer is described in WO 96/01831 appl to Italfarmaco Sud and in T. Benincori et al, J. Org. Chem. 2000, 65, 2043. The complex [Ru(OAc)2((+)-TMBTP)] has been synthesized in analogy to a general procedure reported in N. Feiken et al, Organometallics 1997, 16, 537, 31P-NMR (CDCl3): 61.4 ppm (s). The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 60 bar of hydrogen. After 16 h the autoclave was opened and the yellow-brown solution was rotary evaporated to dryness (50° C./5 mbar). The residue was dissolved in 60 ml of ethyl acetate, 60 ml of water and 3 ml of aqueous hydrochloric acid (25%). The organic layer was separated and evaporated to dryness (50° C./5 mbar) to afford 12 g of crude product as a solid with an enantiomeric purity of 92% and a chemical purity of >99% according to HPLC. The crude product was dissolved in dichloromethane, (S)-phenylethylamine (4.12 ml, 31.1 mmol) was added and the solvent removed under reduced pressure. The brown residue was crystallized from ethyl acetate to obtain colorless crystals which were suspended in ice water/ethyl acetate 1/1. The pH of the suspension was adjusted to 1 with 1 M aqueous hydrochloric acid, the layers were separated and the aqueous layer extracted two more times with ethyl acetate. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent removed in vacuo to obtain colorless crystals which were recrystallized from ethyl acetate to afford 8.45 g (20.4 mmol, 73%) of the title compound as colorless crystals. According to chiral HPLC (Chiralcel-ODH column, 25 cm×4.6 mm, 97% heptane/3% iso-propanol with 0.15% trifluoroacetic acid, flow at 0.7 ml/min, 25° C., 274 nm. Retention times: R-acid 30.2 min, S-acid 32.8 min, α,β-unsaturated Z-acid 39.1 min), the enantiomeric excess amounts to 100%.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH:33]([C:35]1[O:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:38]2[O:39][C:35]([CH:33]=[O:34])=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: COc1cc(-c2csc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(-c4ccc(C=O)o4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(4-amino-7-iodothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.120 g, 0.217 mmol), 5-formyl-2-furylboronic acid (0.247 mmol) and the procedure described in General Procedure A.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:12]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=2)=[N:11][C:10]([CH2:31][CH2:32][CH2:33][C:34](OCC)=[O:35])=[N:9]1.O.[OH-].[Na+]>O1CCCC1>[CH3:7][N:8]1[C:12]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=2)=[N:11][C:10]([CH2:31][CH2:32][CH2:33][CH2:34][OH:35])=[N:9]1
Reactant: CCOC(=O)CCCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(CCCCO)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 18 h
Yield: 103.8 %

Procedure:
Lithium aluminium hydride (1.41 g) was added to a solution of ethyl 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-butanoate (3.3 g) in anhydrous tetrahydrofuran (100 ml), under nitrogen, and the mixture stirred at 20° for 18 h. Successively, water (1.4 ml), 5N sodium hydroxide (1.4 ml) and water (3 ml) were added, the mixture was filtered and the filtrate evaporated to give an oil (3.1 g). The oil was chromatographed on silica using dichloromethane:ethanol:0.88 ammonia 70:8:1 as eluent to give the title compound (2.4 g) as a green oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][Si](C)(C)N[Si](C)(C)C.[K].IC.[Cl-].[NH4+]>CN(C=O)C>[CH2:18]([C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:25][CH3:26])=[N:12][N:11]=1)[CH3:27]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: [Cl-]
Agent: [K]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Reaction time: 1 h
Yield: 1.3 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.00 g, 2.85 mmol) in DMF (10 mL) was added potassium hexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) at ambient temperature and the resulting mixture was stirred for 1 h. After addition of iodomethane (0.20 mL, 3.13 mmol) the reaction mixture was stirred for 20 h at this temperature. Further potassium hexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) and iodomethane (0.20 mL, 3.13 mmol) were added and stirring was continued for another 1.5 h. The reaction mixture was poured onto aqueous ammonium chloride (saturated, 50 mL) and was extracted with ethyl acetate. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 0:80:20) afforded the title compound (14 mg, 1%) as a white solid. MS: m/e=366.1 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:9]=[N:8][CH:7]=[C:6]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)[CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>C(Cl)Cl>[Cl:3][C:4]1[N:9]=[N:8][CH:7]=[C:6]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:14])[CH:5]=1
Reactant: CC(C)(Nc1cnnc(Cl)c1)C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(Nc1cnnc(Cl)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-[(6-chloropyridazin-4-yl)amino]-2-methylpropanoic acid dihydrochloride I-21b (1.23 g, 4.26 mmol), HOBT (0.979 g, 6.39 mmol), EDC (1.226 g, 6.39 mmol), and trifluoroethyl amine hydrochloride (0.866 g, 6.39 mmol) were added to DCM (20.0 ml) followed by the addition of TEA (29.7 ml, 213 mmol). The reaction was allowed to stir at room temperature for 17 hrs. The reaction was then diluted with DCM, washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and concentrated in vacuo to an oil. Purification on Biotage Normal Phase system (DCM:MeOH, 0-8% B) to afford the product I-21 as a solid. The solid was dried under vacuum (295 mg, 22.3%). LRMS (ESI) m/z 297.0 [(M+H)+; calcd for C10H12ClF3N4O: 297.0].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[Br:16][C:17]1[O:21][C:20]([C:22](O)=[O:23])=[CH:19][CH:18]=1>>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:22]([C:20]3[O:21][C:17]([Br:16])=[CH:18][CH:19]=3)=[O:23])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(Br)o1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1

Procedure:
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-bromo-2-furancarboxylic acid by method E. The product with a molecular weight of 378.27 (C17H20BrN3O2); MS (ESI): 379 (M+H+) was obtained as hydrotrifluoroacetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([C@H:24]1[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:30][C@H:27]1[CH2:26][CH2:25][C@@H:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:29][CH2:28]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@H]1CC[C@@H](C(=O)OCC)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with cis-4-amino-cyclohexanecarboxylic acid ethyl ester following general procedure B to afford 8-methoxy-4-(cis-4-ethoxycarbonyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (198 mg). Thus obtained amino-ester (175 mg, 0.44 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish cis-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-cyclohexane-carboxylic acid ethyl ester (138 mg). LCMS: m/z 508[M+1]+.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:15][N:16](C=O)C>Cl.O.C(OCC)(=O)C>[C:15]([C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[N:6][CH:7]=1)#[N:16]
Reactant: Cc1ccc(-c2ncncc2Br)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ncncc2C#N)cc1
Temperature: 50 °C

Procedure:
A mixture of 5-bromo-4-(p-tolyl)pyrimidine (10 g, 40.2 mmol) and cuprous cyanide (4.4 g, 44.2 mmol) in DMF (20 ml) was heated under reflux for 3 hours. To the reaction mixture was added a solution of ferric chloride. 6 hydrate (13 g, 48.2 mmol) in a mixture of hydrochloric acid (7 ml) and water (55 ml) and the mixture was heated at 50° C. for 10 minutes. After the reaction solution was taken up in ethyl acetate and water, the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a crystalline product. Recrystallization from isopropyl ether-hexane afforded colorless needles (5 g, 64%), m.p. 127°-128° C.
Reaction SMILES: C[O:2][C:3](=[O:27])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([C:23]([F:24])([F:26])[F:25])[CH:12]=2)/[C:3]([OH:27])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 47.5 °C
Yield: 90.3 %

Procedure:
A solution of (E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylic acid methyl ester (199 mg, 0.52 mmol) in ethanol (3 mL) was treated with a 1N aqueous sodium hydroxide solution (2 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (10 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-acrylic acid (172 mg, 90%) as a yellow paste: EI-HRMS m/e calcd for C17H17F3N4O2 (M+) 366.1309, found 366.1309.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.C(C1C=CC2C(=CC=CC=2)C=1)(=O)C>CO>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:7]3[CH:8]=[CH:9][C:10](=[O:11])[NH:1][C:2]=3[N:3]=[CH:4][CH:5]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N
Agent: CC(=O)c1ccc2ccccc2c1
Solvent: CO
Product: O=c1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2[nH]1
Yield: 51.8 %

Procedure:
Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (350 mg), 2′-acetonaphthone (50 mg) and methanol (80 ml) were irradiated for 4 hours while stirring, and the precipitated solid was filtered out to obtain 156 mg of a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[C:4]([Cl:19])[CH:3]=1.C(N(C(C)C)C(C)C)C.[I-].ClC1C=CC=C[N+]=1C.[NH:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1>ClCCl>[Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[C:8]([C:9]([N:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)=[O:11])=[CH:12][CH:13]=[CH:14][N:15]=2)=[C:4]([Cl:19])[CH:3]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)c(Br)cc1Cl
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To a solution of 2-(4-bromo-2,5-dichloro-phenoxy)-nicotinic acid (50 mg, 0.14 mmol, 1.0 equiv; Example 163, Step 1) in anhydrous dichloromethane (1.5 mL) was added N-ethyldiisopropylamine (152 mg, 200 μL, 1.18 mmol, 8.4 equiv; [CAS RN 7087-68-5]) and 2-chloro-1-methylpyridinium iodide (42 mg, 0.17 mmol, 1.2 equiv; [CAS RN 14338-32-0]) and the reaction mixture stirred at rt. After 1 h, 1,2,3,4-tetrahydro-quinoline (22 mg, 21 μL, 0.17 mmol, 1.2 equiv; [CAS RN 635-46-1]) was added and stirring at rt continued over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 41 mg (61%) of the title compound as a white powder. MS (ISP): 476.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CC4CCCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CC4CCCCC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-cyclohexylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:20][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCCN
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CCO
Product: CCCNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and propylamine in ethanol. EI-MS m/e (%). 243 (M+, 44), 242 ([M—H]+, 28), 228 ([M—CH3]+, 16), 214 ([M—C2H5]+, 100), 201 ([M—C3H6]+, 70).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].C1(C)C=CC=CC=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:21])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cnc(O)c(Cl)c1

Procedure:
6.3 g (36 mmol) of 5-chloro-6-hydroxynicotinic acid are heated under reflux in 60 ml of thionyl chloride for 4 hours. After the volatile constituents have been stripped off, 50 ml of toluene are added and the mixture is evaporated again. Colorless crystals, yield 6.9 g (quantitative), melting point: >250° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Reaction time: 3 h
Yield: 91.1 %

Procedure:
Platinum on carbon (3.6 g of 5%) was added to a solution of 1,1-dimethylethyl N-{4-[(3-nitroquinolin-4-yl)amino]butyl}carbamate (36.1 g, 100 mmol) in toluene (1.5 L). The mixture was hydrogenated at 50 psi (3.5 Kg/cm2) for 3 hours. The reaction mixture was filtered through a layer of Celite® filter aid to remove the catalyst. The filtrate was concentrated under vacuum to provide 30.1 g of crude 1,1-dimethylethyl N-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate as a gooey orange syrup.