Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-:4].[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[CH:8][C:7]=1[C:15](F)(F)F>C(Cl)Cl>[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[CH:8][C:7]=1[C:15]([Cl:4])([Cl:3])[Cl:1]
Reactant: [Cl-]
Reactant: Fc1cc(C(F)(F)F)c(F)c(F)c1F
Agent: [Al+3]
Solvent: ClCCl
Product: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Temperature: 0 °C

Procedure:
85 g (0.64 mol) of aluminium chloride (anhydrous) are initially introduced into 500 ml of methylene chloride, and 109 g (0.5 mol) of 2,3,4,5-tetrafluoro-benzotrifluoride are added dropwise at room temperature, while stirring. The mixture is then subsequently stirred at 40° C. for 1 hour, allowed to cool and poured onto 600 g of ice, the organic phase is separated off, the aqueous phase is extracted with ether and the combined phases are washed with water and dried over anhydrous magnesium sulphate. After concentration, the residue is distilled. 108.3 g (81% of theory) of product are obtained; boiling point: 89°-90° C./22 mbar.
Reaction SMILES: Br[C:2]1[CH:3]=CC(O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[NH:37]1C=CC=C1C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[NH:37][CH:3]=[CH:2][CH:7]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1ccc[nH]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc[nH]4)ccc3c1)n2C1CCCCC1
Yield: 9 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(1H-pyrrol-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (11 mg, 9% yield).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[C:18]([F:26])[C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:27])[C:15]([C:28]([OH:30])=[O:29])=[CH:14]2)[C:10]([F:31])=[CH:9][C:8]=1[F:32].Cl.Cl.[NH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([F:23])=[C:22]3[C:17]([C:16](=[O:27])[C:15]([C:28]([OH:30])=[O:29])=[CH:14][N:13]3[C:11]3[C:10]([F:31])=[CH:9][C:8]([F:32])=[C:7]([NH2:6])[N:12]=3)=[C:18]([F:26])[C:19]=2[F:25])[CH2:37]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(F)c(F)c(F)c(F)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(F)c(F)c(N4CC(N)C4)c(F)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 50 mg of the title compound as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.C(O)(=O)C.[N-:24]=[C:25]=[O:26].[K+]>O>[N+:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH2:24])=[O:26])=[CH:19][C:6]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.75 g. of 5-amino-2-nitro-3-phenylbenzofuran in 5 ml. of glacial acetic acid and 3 ml. of water is added an equimolar amount of potassium isocyanate dissolved in 5 ml. of warm water. The reaction is stirred at about 20° C. for 30 minutes then filtered to separate the solid product. The solid is recrystallized from aqueous methanol to provide yellow crystals of 2-nitro-3-phenyl-5-ureidobenzofuran, m.p. 230°-232° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1ccc(CCBr)cc1
Product: Cc1nc2c(ccn2CCc2ccc(F)cc2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(2-bromoethyl)-4-fluorobenzene. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.46 (d, J=1.6 Hz, 1 H), 7.18-7.07 (m, 3 H), 6.99-6.89 (m, 4 H), 6.31 (dd, J=3.5, 7.6 Hz, 1 H), 5.52 (d, J=6.0 Hz, 1 H), 4.82-4.73 (m, 1 H), 4.68-4.58 (m, 1 H), 4.30 (t, J=5.1 Hz, 2 H), 3.16 (tq, J=7.0, 14.3 Hz, 2 H), 2.94-2.77 (m, 5 H), 2.15-2.04 (m, 2 H), 0.99-0.89 (s, 9 H); LC/MS (m/z) ES+=517.4 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:11]Br.N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][C:9]1[CH:8]=[N:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: BrBr
Reactant: c1cnc2ccncc2c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Brc1cncc2cccnc12
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a stirred solution of [1,6]-naphthyridine (4.73 g, 36.4 mmol) in CCl4 (200 mL) was added Br2 (2.25 mL, 43.7 mmol) in CCl4 (35 mL) dropwise via an addition funnel. The resulting solution was heated at reflux for 1 hour. Pyridine (2.94 mL, 36.4 mmol) in CCl4 (30 mL) was added dropwise to the refluxing solution, and the mixture was refluxed overnight. The cooled reaction mixture was filtered, and the solids were digested with 1 M NaOH (200 mL) for 1 hour. The basic solution was extracted into CH2Cl2 (2×200 mL), and the organic fractions were combined, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography (10% EtOAc/CH2Cl2) affording 2.03 g (27%) of the title compound as yellow crystals: mp 79-81° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][CH2:6][CH:7]([O:9][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:8]
Reactant: BrCc1ccccc1
Reactant: COC(CCCC(C)O)OC
Solvent: CN(C)C=O
Product: COC(CCCC(C)OCc1ccccc1)OC
Temperature: 5 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
5-benzyloxyhexanal dimethyl acetal: a sodium hydride dispersion (7.2 g of 50% dispersion, 150 mmol, 1.2 equivalents) was washed with hexane (3×50 ml), suspended in DMF (250 ml) and cooled to 5° C. before adding the 5-hydroxyhexanal dimethyl acetal (20.28 g, 125.0 mmol) prepared in (b) in DMF solution (20 ml); the suspension being allowed to warm then up to 20° C. over 1 hour. After 30 minutes benzyl bromide (25.6 g, 150 mmol) was added at 5°-10° C. over 15 minutes and the resulting thick slurry quenched after 30 minutes by the careful addition of water (200 ml). Pentane (250 ml) was added and the layers separated, the aqueous phase was extracted with pentane (3×100 ml) and the combined pentane layers washed with water (2×100 ml) and brine (150 ml) dried (MgSO4) and concentrated. Distillation gave pure 5-benzyloxyhexanal dimethyl acetal (101°-102° C. at 0.05 mm Hg, 122.4 mmol, 98%)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]=[CH:26][CH:27]=2)=[O:36])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1)c1ccnc2ccccc12

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 105 mg (0.660 mmol) of quinoline-4-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR85## is obtained (278 mg, 97%) as oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =517, 519; IR: 3395, 1755, 1620 cm-1.
Reaction SMILES: [ClH:1].Cl.[C:3]([N:6]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][C:29]([C:35](=[NH:37])[NH2:36])=[CH:30][CH:31]=4)[CH:26]=3)[C:19]([O:21]CC)=[O:20])=[CH:14][CH:13]=2)[CH2:7]1)(=[NH:5])[CH3:4]>Cl>[ClH:1].[ClH:1].[C:3]([N:6]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][C:29]([C:35](=[NH:36])[NH2:37])=[CH:30][CH:31]=4)[CH:26]=3)[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH2:7]1)(=[NH:5])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(O[C@H]2CCN(C(C)=N)C2)cc1
Agent: Cl
Product: CC(=N)N1CC[C@H](Oc2ccc(C(Cc3ccc4ccc(C(=N)N)cc4c3)C(=O)O)cc2)C1
Reaction time: 232 h
Yield: 198.4 %

Procedure:
While keeping the inner temperature at -5° C. or below, 110.1 g of ethyl (+)-2-[4-[((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy]phenyl]-3-(7-amidino-2-naphthyl)propionate dihydrochloride was dissolved in 3,300 ml of concentrated hydrochloric acid, and the resulting solution was allowed to stand still for 232 hours at 5° C. The resulting reaction solution was concentrated by distilling off hydrochloric acid and water under a reduced pressure. The resulting residue was purified by subjecting it to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/ acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with a small amount of dilute hydrochloric acid, and then concentrated to dryness. In this way, 103.6 g of the title compound was obtained in the form of a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH2:21]([CH:29]1[CH2:33][C:32](=[O:34])[O:31][C:30]1=[O:35])[CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:32]([CH2:33][CH:29]([CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:30]([OH:35])=[O:31])=[O:34]
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CCCCCC=CCC1CC(=O)OC1=O
Solvent: Cc1ccccc1
Product: CCCCCC=CCC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (0.1 g, 0.37 mmol; prepared in a manner similar to that described in Example 23), 3-oct-2-enyldihydrofuran-2,5-dione (0.078 g, 0.37 mmol) and toluene (10 ml) was heated under reflux for 20 hours, then the solvent was removed in vacuo to give crude 2-{[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]methyl}dec-4-enoic acid (0.133 g) as an oil which was used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14][CH2:15][C:16](Br)=[O:17]>>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:16](=[O:17])[CH2:15][Br:14])([CH3:13])[CH3:12]
Reactant: O=C(Br)CBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CBr

Procedure:
2,6-diisopropylaniline and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12](=[CH2:14])[CH3:13].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)([CH3:14])([CH3:13])[CH3:11]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-hydroxybenzoic acid (2.00 g, 14.5 mmol) in 1,4-dioxane (10.0 mL) saturated with isobutylene at -78° C. in a metal bomb was added concentrated sulfuric acid (0.150 mL). The bomb was sealed and warmed to room temperature. After 72 hours at room temperature, the reaction mixture was cooled to -78° C., poured into saturated sodium bicarbonate (30.0 mL) and extracted with diethyl ether (2×50.0 mL). The combined organic phases were concentrated and the residue chromatographed on silica gel (eluted with 5% methanol in methylene chloride to give 290 mg (Y: 10%) of the title product; 1H-NMR (CDCl3): δ 7.89 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 1.57 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)=[O:28])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:37][C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([Cl:38])[CH:34]=1)[CH2:30][O:29][C:27]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:39])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:28]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1cc(Cl)cc(Cl)c1

Procedure:
(2′-{[(3,5-Dichloro-benzyloxycarbonyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.088 g, 0.15 mmol) in THF (1 mL) and MeOH (0.8 mL) was hydrolyzed with 1N aqueous NaOH (0.5 mL) for 2.5 hours. The mixture was acidified with 1N aqueous HCl and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, decanted, and concentrated, and the residue was purified by preparative HPLC to give the title compound. M+H is 571.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[CH:6]1)[CH2:2][CH2:3][CH3:4].[CH3:17][C:18]([N:26]1[N:30]=[N:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[CH:42]=[CH:41][C:40]([CH:43]=[O:44])=[CH:39][CH:38]=2)=[N:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:6]1[CH:43]([C:40]1[CH:39]=[CH:38][C:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:28]2[N:29]=[N:30][N:26]([C:18]([CH3:19])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:17])[N:27]=2)=[CH:42][CH:41]=1)[OH:44])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(C=O)cc2)n1
Reactant: CCCCn1cc(C(=O)O)c2ccccc21
Product: CCCCn1c(C(O)c2ccc(-c3ccccc3-c3nnn(C(C)(C)c4ccccc4)n3)cc2)c(C(=O)O)c2ccccc21

Procedure:
reacting the 2-lithiated 1-butyl-1H-indole-3-carboxylic acid with protected 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carbaldehyde to give 1-butyl-2-{2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-yl(hydroxy)methyl}-1H-indole-3-carboxylic acid;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[OH-].[Na+].O1CCCC1>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][CH:27]([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1
Reactant: CCOC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 30 %

Procedure:
A mixed solution of ethyl 1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidine-4-carboxylate (60.0 mg, 0.124 mmol), an aqueous 1 N sodium hydroxide solution (0.992 ml, 0.992 mmol), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at 80° C. for 5 hours. The solvent was distilled off under reduced pressure. The residue was adjusted to pH 3 by addition of an aqueous 1 N sodium hydroxide solution. A solid was separated by filtration and washed with water to give 17.0 mg (30.0%) of the desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[BH4-].[Na+]>CO>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[NH:39][C:38](=[O:40])[O:37][N:36]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a mixture of 7-butyl-4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.08 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added sodium borohydride (0.007 g), and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.04 g, 48%).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C([O:11][C:12]([CH:14]([C:27](=O)[CH3:28])[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[F:26])=O)C>CO>[NH2:7][C:6]1[N:8]=[C:12]([OH:11])[C:14]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=2[F:26])=[C:27]([CH3:28])[N:5]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(Cc1ccc(C(=O)OC)cc1F)C(C)=O
Agent: O=C(O)O
Solvent: CO
Product: COC(=O)c1ccc(Cc2c(C)nc(N)nc2O)c(F)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 60.5 %

Procedure:
Guanidine carbonate (6.86 g) was added to a stirred solution of the product from step (i) (11.1 g) in MeOH (200 mL). The resulting mixture was stirred at 70° C. for 15 h. The mixture was allowed to cool to rt and the resulting precipitate collected by filtration. The solid was suspended in water (50 mL), collected by filtration and washed with MeOH to give the subtitle compound as a colourless solid 6.60 g that was used without further purification.
Reaction SMILES: C(O[C:4](=[O:8])/[CH:5]=[CH:6]\[O-])C.[Na+].Cl.[CH:11]1([C:14](=[NH:16])[NH2:15])[CH2:13][CH2:12]1>O>[CH:11]1([C:14]2[N:16]=[C:4]([OH:8])[CH:5]=[CH:6][N:15]=2)[CH2:13][CH2:12]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)/C=C\[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccnc(C2CC2)n1
Reaction time: 72 h

Procedure:
Sodium (1Z)-3-ethoxy-3-oxoprop-1-en-1-olate (6.60 g, 47.8 mmol) was dissolved in water (1.5 mL) and in a second flask cyclopropanecarboximidamide hydrochloride (3 g, 24.88 mmol) was dissolved in water (2 mL) and the contents of the second flask were added to the first flask. The reaction was allowed to stir for 72 hours. The reaction was then transferred to a separatory funnel and extracted with chloroform and a small amount of methanol. The water layer was extracted again and the combined organic layers were dried over magnesium sulfate, filtered and concentrated to a pale yellow solid. Diethyl ether was then added to precipitate product. The mixture was filtered and the solid was collected and dried to give the title compound.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH:4]=[CH:3][NH:2]1.[Br:15]Br.O>CC(O)=O>[Br:15][C:4]1[C:5]2[S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]=2[C:1](=[O:14])[NH:2][CH:3]=1
Reactant: O=c1[nH]ccc2sc3ccccc3c12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]cc(Br)c2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of [1]benzothieno[3,2-c]pyridin-1(2H)-one in AcOH (0.52 M) was added Br2 (1.1 equiv) at room temperature. The mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into H2O and stirred for 30 min. The mixture was filtered and washed with H2O to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][S:17][C:16]([CH3:25])([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[S:15]2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)Cl>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:13][CH:14]2[CH2:18][S:17][C:16]([CH3:25])([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[S:15]2)=[O:40])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1c(OCCCSCC2CSC(C)(CCCC(=O)O)S2)ccc(C(C)=O)c1O
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)CC2CSC(C)(CCCC(=O)O)S2)ccc(C(C)=O)c1O
Yield: 41.8 %

Procedure:
The title compound was prepared according to the procedure of Example 48 using the sulfide obtained in Example 61 (0.15 g, 0.0003 mol) and m-chloroperbenzoic acid (0.063 g, 0.0003 mol) in methylene chloride (3 ml). The crude product was chromatographed on silica gel using ethyl acetate containing 1% acetic acid to give 0.063 g (45%) of the desired product as an oil containing one molar equivalent of acetic acid.