Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Sn](C)(C)C)[CH:5]=[C:4]([CH3:12])[N:3]=1.Br[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][N:21]2[CH:24]2[CH2:26][CH2:25]2)=[CH:16][C:15]=1[F:33]>O1CCOCC1.O>[CH:24]1([N:21]2[C:22]3[C:17](=[CH:16][C:15]([F:33])=[C:14]([C:6]4[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:12])[CH:5]=4)[CH:23]=3)[C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(Br)c(F)cc2c1=O
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Yield: 72.1 %

Procedure:
2,6-dimethyl-4-(trimethylstannyl)pyridine (2.6 g) in dioxane (6 ml) is slowly dropped into a stirred mixture of ethyl 7-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (3.1 g), dioxane (55 ml) and hexamethylenphosphoramide (2.6 ml) kept under argon. To the stirred mixture, dichlorobis (triphenylphosphine) palladium (0.4 g) is added. The reaction mixture is heated under reflux for 24 hours. After cooling it is poured in water (200 ml) and repeatedly extracted with dichloromethane. The organic extracts are dried and evaporated to dryness. The residue, after trituration with ethyl ether, gives ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (2.4 g) m.p. 196°-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1.C1(S(O)(=O)=O)C2C(=CC=CC=2)C=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: C1=COCCC1
Agent: O=S(=O)(O)c1cccc2ccccc12
Solvent: c1ccccc1
Product: Clc1cc(Cl)c(OC2CCCCO2)cc1Cl
Temperature: 25 °C

Procedure:
2,4,5-trichlorophenol (9.85 g., 0.05 moles) and dihydropyran (9.1 ml., 0.10 moles) are mixed in 100 ml. of benzene as a solvent. Upon addition of 1.0 g. of naphthalene sulfonic acid, as catalyst, the reaction is exothermic and the solution turns a light purple color. The reaction mixture is cooled to room temperature and allowed to stand for about one-half hour. The reaction mixture is washed with dilute sodium carbonate solution and the color turns to a light orange. The solution is dried over magnesium sulfate and then the solvent is evaporated in vacuo to yield 14.5 g. of an orange oil, nD30 =1.5408.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:21]O>>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:3][C:4]([O:6][CH3:21])=[O:5]
Reactant: NC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Yield: 62 %

Procedure:
A solution of 79.5 g (0.378 mol) D, 3-amino-3-(3-nitrophenyl)propionic acid, in 21 of methanol is admixed with 200 ml of sulphuric acid (conc.). The solution is heated at boiling point for 1 h. Most of the methanol is removed under reduced pressure and the residue is poured into ice-water. Using sodium carbonate, the pH is adjusted to 8. The aqueous phase is extracted with dichloromethane. Drying of the organic phase and removal of the solvent under reduced pressure gives the ester E, methyl 3-amino-3-(3-nitrophenyl)propionate, (52.8 g, 62%) as a white solid. 10 g (44.6 mmol) of E are dissolved in 20 ml of DMF. The solution is admixed with 12.3 g (88.2 mmol) of potassium carbonate, and 15.2 g (88.2 mmol) of benzyl chloroformate are added dropwise. The mixture is stirred at 23° C. for 2 h. The mixture is diluted with 200 ml of toluene and washed three times with water, and the organic phase is dried using sodium sulphate and concentrated under reduced pressure to give the colourless oil of methyl 3-benzyloxycarbonylamino-3-(3-nitrophenyl)propionate (12.6 g, 79%). MS (DCI/NH3): 376 (M+NH4)+.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:19]=[C:20]([C:24]4([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:21]=[CH:22][CH:23]=3)=[CH:13][CH:12]=2)[N:7]=[C:6]1[CH3:32])[CH3:4]>C(O)(C)C.CO>[CH2:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:19]=[C:20]([C:24]4([C:30]([NH2:31])=[O:1])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:21]=[CH:22][CH:23]=3)=[CH:13][CH:12]=2)[N:7]=[C:6]1[CH3:32])[CH3:4]
Reactant: [OH-]
Reactant: CCn1c(C)nn(-c2ccc(Sc3cccc(C4(C#N)CCOCC4)c3)cc2)c1=O
Agent: [K+]
Solvent: CC(C)O
Solvent: CO
Product: CCn1c(C)nn(-c2ccc(Sc3cccc(C4(C(N)=O)CCOCC4)c3)cc2)c1=O
Temperature: 95 °C

Procedure:
Solid potassium hydroxide (0.035 g, 0.6333 mmol) was added to a solution of 4-(3-{[4-(4-ethyl-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl]thio}phenyl)tetrahydro-2H-pyran-4-carbonitrile (0.070 g, 0.166 mmol) (example 9) in isopropyl alcohol and methanol mixture (3 mL). The reaction mixture was heated at about 90-100° C. for about 12-15 hours. The solvent was evaporated under vacuum and water was added. A white solid separated out, which was filtered and dried under vacuum to afford the title compound. Yield: 0.045 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[NH:7][C:6]4=[O:14])[CH2:28][CH2:29]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Temperature: 25 °C
Yield: 30 %

Procedure:
A mixture of 2.3 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 3.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours. The reaction mixture is cooled to room temperature and water is added. The undissolved product is filtered off and purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water, yielding 1.3 parts (30%) of 5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 242.5° C.
Reaction SMILES: COP([CH2:7][C:8](=[O:21])[C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH:11]=[CH2:12])(OC)=O.[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[CH:26][C:25]=1[N+:35]([O-:37])=[O:36])=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CCO>[C:16]([O:15][C:14]([NH:13][C@@H:9]([CH2:10][CH:11]=[CH2:12])[C:8](=[O:21])/[CH:7]=[CH:22]/[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[CH:26][C:25]=1[N+:35]([O-:37])=[O:36])=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)Nc1ccc(C=O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)/C=C/c1ccc(NC(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 90 %

Procedure:
To a vigorously stirred solution of 5E (4.47 g, 13.92 mmol) and 5D (2.6 g, 11.60 mmol) in THF (anhydrous) (115 mL) and EtOH (absolute) (1.148 mL) under nitrogen was added portion wise K2CO3 (anhydrous) (2.56 g, 18.56 mmol) at 0° C. The reaction mixture was allowed to raise to rt and then the mixture was heated at 55° C. The reaction mixture was then filtered with the aid of EtOAc and the filtrate evaporated to a residue which was dissolved in a small amount of methylene chloride and purified by normal phase chromatography to give 5F (4.38 g, 90%) as yellow solid. MS (ESI) m/z: 420.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.83-7.73 (m, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.02 (d, J=15.9 Hz, 1H), 5.77 (ddt, J=17.0, 10.2, 6.7 Hz, 1H), 5.16-5.01 (m, 2H), 4.32 (td, J=8.5, 4.9 Hz, 1H), 3.71 (s, 3H), 2.34-2.23 (m, 1H), 1.36 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:10]([CH2:13][CH:14]1[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]2([CH3:24])[CH2:23][O:22]2)[CH2:15]1)=[N+:11]=[N-:12].C([O-])(=O)C.[Na+]>C(O)C>[N:10]([CH2:13][CH:14]1[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([OH:22])([CH3:23])[CH2:24][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])[CH2:15]1)=[N+:11]=[N-:12]
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(CN2CC(CN=[N+]=[N-])OC2=O)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)(CN1CC(CN=[N+]=[N-])OC1=O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (350 mg, 2.37 mmol), 5-azidomethyl-3-(2-methyloxiran-2-ylmethyl)oxazolidin-2-one (500 mg, 2.37 mmol), sodium acetate (214 mg, 2.61 mmol) and ethanol (5 ml) was stirred at 70° C. for 8 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/2) to afford 5-azidomethyl-3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]oxazolidin-2-one (640 mg, yield 75%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[C:10]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(Br)c(F)c1

Procedure:
To 1-bromo-2-fluoro-4-hydroxybenzene (100 g, 0.52 mol) and K2CO3 (179.4 g, 1.3 mol) in 1300 mL acetone was added dimethyl sulfate (98.38 g, 0.78 mol). After refluxing overnight, the reaction mixture was cooled, filtered and dried over Na2SO4, and the filtrate was concentrated to afford 1-bromo-2-fluoro-4-methoxybenzene as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5](B(O)O)=[CH:4][CH2:3]1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][N:23]([CH3:25])[C:22](=[N:26][C:27]#[N:28])[N:21]([CH3:29])[CH2:20]2)=[CH:15][C:14]=1Br>>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][N:23]([CH3:25])[C:22](=[N:26][C:27]#[N:28])[N:21]([CH3:29])[CH2:20]2)=[CH:15][C:14]=1[C:5]1[CH2:6][CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][CH:4]=1
Reactant: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=NC#N
Reactant: CC1(C)CC=C(B(O)O)CC1
Product: CN1CC(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CN(C)C1=NC#N

Procedure:
The title compound was prepared according to the Suzuki coupling procedure of Example 3, step (a), using 4,4-dimethyl-cyclohex-1-enyl boronic acid and 5-(4-amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide Mass spectrum (ESI, m/z): Calcd. for C21H29N5, 352.2 (M+H). found 352.4
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:48][O:49][CH3:50])[C:10]([NH:12][CH:13]2[C:46](=[O:47])[N:15]3[C:16]([C:30]([O:32][CH:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])=[C:17]([CH2:20][S:21]/[CH:22]=[CH:23]\[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.O>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:48][O:49][CH3:50])[C:10]([NH:12][CH:13]2[C:46](=[O:47])[N:15]3[C:16]([C:30]([O:32][CH:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])=[C:17]([CH2:20][S:21]/[CH:22]=[CH:23]\[C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CS/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Temperature: 35 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1.21 g) in methanol (24 ml) was added conc. hydrochloric acid (0.52 ml) at ambient temperature. The mixture was stirred for 1.5 hours at 35° C. The mixture was concentrated in vacuo to give a residue, which was dissolved in a mixture of ethyl acetate and water. The mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo, and the residue was triturated in diisopropyl ether to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1.05 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:10][C:4]1([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]([CH3:1])([CH3:32])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(O)CC2(C)C)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 88 %

Procedure:
A flask was charged with 1.5 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (3.33 mmol, 1.0 equiv). The ketone was dissolved in 16 mL of nitrogen-sparged tetrahydrofuran and cooled in an ice water bath. A solution of lithium aluminum hydride (3.33 mL, 6.66 mmol, 2 equiv, 2 M in THF) was added dropwise over 3 minutes to the solution. The solution was warmed to room temperature and stirred for 7 hours. The reaction mixture was quenched by the slow addition of aqueous hydrochloric acid (50 mL, 1 M). The solution was stirred vigorously until homogeneous. The phases were partitioned and the aqueous layer was collected. The aqueous layer was washed with ethyl acetate (4×20 mL), then the combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated. The resulting white solid was purified by column chromatography using an Isco CombiFlash Companion® with a Teledyne Isco RediSepRf column (40-g, flow rate: 40 mL/minute, gradient: 1 column volumes heptane, ramp up to 60:40 heptane:ethyl acetate over 7 column volumes, hold at 60:40 for 2 column volumes). The title compound was isolated as a white solid (1.32 g, 95 area % by HPLC at 254 nm, 88% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.88-7.81 (m, 1H), 7.40-7.28 (m, 2H), 7.23-7.17 (m, 1H), 7.00 (s, 2H), 4.04 (tt, J=10.2, 3.5 Hz, 1H), 2.94 (hept, J=6.9 Hz, 1H), 2.50 (hept, J=6.7 Hz, 2H), 1.92-1.74 (m, 2H), 1.71-1.57 (m, 2H), 1.38 (d, J=3.8 Hz, 6H), 1.32 (d, J=6.9 Hz, 6H), 1.20 (d, J=6.8 Hz, 6H), 1.04 (s, 3H), 0.99 (s, 3H), 0.95 (d, J=6.7 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ=149.4 (d, J=36 Hz), 147.1, 145.5, 136.8 (d, J=6 Hz), 135.7 (d, J=3 Hz), 133.5 (d, J=32 Hz), 132.7 (d, J=7 Hz), 127.8, 125.0, 120.0, 66.4, 51.1 (d, J=12 Hz), 34.2, 33.7, 33.4 (d, J=4 Hz), 33.2, 30.8, 27.8 (d, J=4 Hz), 26.5, 24.3, 23.1. 31P NMR (CDCl3, 202 MHz), δ ppm 0.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:14]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:13]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=1[F:11])=[CH:5][NH:6]2
Reactant: O=Cc1ccc(F)cc1F
Reactant: Clc1cccc2[nH]ccc12
Product: Fc1ccc(C(c2c[nH]c3cccc(Cl)c23)c2c[nH]c3cccc(Cl)c23)c(F)c1

Procedure:
The compound Bis(4-chloroindol-3-yl)-(2,4-difluorophenyl)methane was prepared following procedure A, starting from 4-chloro indole and 2,4-difluoro benzaldehyde. LC: Tr 2.63 min, MS: 427 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[CH2:17](C(CC)(CC)C([O-])([O-])[O-])[CH3:18]>C(OC(=O)C)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=[C:17]2[CH3:18])=[CH:10][CH:11]=1)#[N:16]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: N#Cc1ccc(Nc2ccncc2N)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2n1-c1ccc(C#N)cc1

Procedure:
A mixture of 3-amino-4-(4'-cyanophenyl)aminopyridine (9.31 g, 44.3 mmol), triethyl-orthoacetate (40 ml) and acetic anhydride (30 ml) was heated at reflux for 2 hours under nitrogen, cooled, then concentrated under reduced pressure. The brown residue was dissolved in 1M hydrochloric acid and washed with ethyl acetate (200 ml). The aqueous layer was rendered basic with saturated aqueous ammonia and extracted with dichloromethane (3×200 ml). The combined extracts were washed with water, dried (MgSO4) and concentrated to give 1-(4-cyanophenyl)-2-methylimidazo[4,5-c]pyridine, 6.5 g, as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH:7][C:10](=[O:12])[CH3:11])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Br)ccc1F
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Br)ccc1F

Procedure:
5-Bromo-2-fluoroaniline (14.79 g, 78 mmol) was heated at reflux in acetic acid (50 ml) and acetic anhydride (50 ml) for 8 hours. The solution was concentrated in vacuo, azeotroping with toluene. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient of hexane to ethyl acetate) to afford the title compound. MS (ES+) m/e 232/234 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:13])[F:14])=[CH:10][N:9]=1)(=[O:25])=[O:24]
Reactant: OCc1ccc(OCC(F)(F)F)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(OCC(F)(F)F)cn1
Yield: 67.5 %

Procedure:
To a dichloromethane solution (2.8 mL) of [5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methanol (138 mg, 0.67 mmol), triethylamine (468 μL, 3.33 mmol) and methanesulfonyl chloride (77.4 μL, 1.00 mmol) were added at 0° C. and the resultant solution was stirred for 30 minutes. After completion of the reaction, the reaction solution was washed with saturated ammonium chloride aqueous solution and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product (129 mg) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21](O)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]=[C:11]([C:21]([N:45]3[CH2:50][CH2:49][NH:48][C:47](=[O:51])[CH2:46]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(Cl)nc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(Cl)nc3)n2)CCN1

Procedure:
75 mg (0.18 mmol) of the compound of Example 23A is reacted analogously to the synthesis of the compound of Example 4 with 19 mg (0.19 mmol) of 2-oxopiperazine. 68 mg (87% of theory) of the title compound is obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:24][NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[C@@H:3]([NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19]C)=[O:18])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>CO.C1COCC1>[OH:1][C@H:2]([CH2:24][NH:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[C@@H:3]([NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])=[O:13])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cncc(C(C)C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cncc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(C(=O)O)c2)c1
Yield: 94.4 %

Procedure:
methyl 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoate (0.060 g, 0.126 mmol, 1 eq) was dissolved in 2 ml of 1:1 MeOH/THF. 1N NaOH (0.158 ml, 0.158 mmol, 1.25 eq) was added and the reaction was stirred over the weekend. The solvent was removed in vacuo. 1N HCl was added to pH {tilde over ( )} 3-4. The mixture was diluted with 10% MeOH in CHCl3 and dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo yielding 0.055 g (0.119 mmol, 95% yield) of 3-((2S,3R)-3-hydroxy-4-((5-isopropylpyridin-3-yl)methylamino)-1-phenylbutan-2-ylcarbamoyl)benzoic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[NH:11][N:10]=2)[CH3:8])=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>ClCCl.CO>[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([CH:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])=[N:10][N:11]=2)=[CH:45][CH:44]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(c1ccncc1)c1n[nH]c(=O)c2ccccc12
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(c1ccncc1)c1nnc(Nc2ccc(Cl)cc2)c2ccccc12

Procedure:
A mixture of 300 mg (1.19 mmol) rac 4-[1-(4-pyridyl)ethyl]-1 (2H)-phthalazinone, 683 mg (4.77 mmol) phosphorus pentoxide, 657 mg (4.77 mmol) triethylamine hydrochloride, and 609 mg (4.77 mmol) 4-chloroaniline is heated for 8 h to 205° C. The brown solution is taken up in dichloromethane/methanol 19:1, washed successively with sat. Na2CO3 solution, 3× with water and brine, and the organic phase (Na2O4) is washed and concentrated by evaporation. Chromatography (SiO2; ethyl acetate/CH3OH 19:1) yields the title compound: m.p.: 132-134° C.; Anal. calc. (C21H17N4Cl.½CH3OH) C 68.52%, H 5.08%, N 14.87%; found. C 68.4%, H5.0%, N 14.9%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NC(=O)c1ccc(N)cc1
Solvent: CCCCO
Product: NC(=O)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 114 %

Procedure:
The procedure is carried out as in Example 1, starting with 189 mg of 2,6-dichloropurine, 5 ml of butanol and 150 mg of 4-aminobenzamide. 329 mg of the expected product are thus obtained.