Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:25][CH:24]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(OC(F)(F)F)cc3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(OC(F)(F)F)cc1

Procedure:
The 2-trifluoroacetamido-3-(4-trifluoromethoxyphenyl)-6-benzoyl-imidazo[1,2-a]pyridine (10.6 g, 21.5 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 8.24 g. (96.7%). EA, MS(FD).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-].C1COCC1.Cl>CO.O>[C:11]1([C:8]2[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cnc(-c2ccccc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (3.15 g) and LiOH (0.71 g) in a mixture of MeOH, THF and water (1:1:1 in volume, 120 mL) is stirred at rt overnight. MeOH and THF are evaporated off to give an aqueous solution. The aqueous solution is acidified with 5% hydrochloric acid to adjust pH to between 2.5 and 3. The precipitate is filtered off and washed with water, dried in vacuo to yield 2.94 g (˜100%) of 2-phenyl-pyrimidine-5-carboxylic acid as a solid. MS: 201 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=O.[CH:18]1([C:22](=O)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:22]([CH:18]1[CH2:21][CH2:20][CH2:19]1)[C:23]([C:24]#[N:25])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1
Reactant: N#CCC(=O)C1CCC1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cccc(Cl)c1
Product: N#Cc1c(C2CCC2)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(3-chloro-phenyl)-methanone (prepared as described in example 91 step A) and 3-cyclobutyl-3-oxo-propionitrile (prepared as described in example 104 step A). Yellow foam. MS (ESI): 353.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Br:10]C1C=C(O)C=CC=1>>[Br:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][CH:2]=1
Reactant: Oc1cccc(Br)c1
Reactant: COc1ccc(Br)cc1
Agent: *C(F)(F)C(*)(F)F
Product: COc1cccc(Br)c1
Yield: 40 %

Procedure:
2.9 mmol of parabromo-anisole and 15 cm3 of 1.7 M HF--SbF5 superacid are contacted for 55 hours at ambient temperature in a poly(tetrafluoroethylene) container. Chromatographic analysis of the reaction products shows that a mixture of meta-bromo-phenol (25%) and meta-bromoanisole (40%) is formed, in a 65% yield.
Reaction SMILES: [CH3:1][N:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[C:12]2[C:7](=[C:8]([O:13]C)[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[N:4]=1.B(Br)(Br)Br.[OH-].[Na+].Cl>ClCCl>[CH3:1][N:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[C:12]2[C:7](=[C:8]([OH:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[N:4]=1
Reactant: COc1cccc2c(N(C)c3ccccc3)nc(Nc3ccccc3C)nc12
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2cccc(O)c2n1
Reaction time: 3 h
Yield: 37.8 %

Procedure:
4-(N-Methylphenylamino)-2-(2-methylphenylamino)-8-methoxyquinazoline (prepared as described in co-pending EP-A-88311461.3) (1.81 g, 0.0049 mol) was dissolved in dichloromethane (50 ml) and cooled to 0°-5° under nitrogen. Boron tribromide (6.25 g, 0.025 mol) was added dropwise via a syringe through a rubber septum over a period of 10 minutes Reaction was stirred 3 hours at 0°-5° and then allowed to rise to room temperature overnight. The reaction mixture was poured onto ice and the pH adjusted to ~12 with sodium hydroxide and then back to neutral with dilute HCl. The organic layer was separated, dried and evaporated to dryness. The solid residue was crystallised from methanol/water to give the title compound (0.66 g), m.p. 174°-175°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]1[O:10][CH:8]1[CH3:9]>>[OH:10][CH:8]([CH3:9])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC1CO1
Reactant: C1COCCN1
Product: CC(O)CN1CCOCC1
Reaction time: 168 h
Yield: 96.1 %

Procedure:
An amount, 871.2 grams, of morpholine (10 moles) and 580.8 grams of propylene oxide (10 moles) were mixed in a 2 liter flask and set aside for seven days at room temperature. At the end of this time, the solution was distilled under vacuum to give 1396.0 grams (96.1%) of N-(2-hydroxypropyl)-morpholine as a colorless oil, bp 63°-65° C. at 0.25 mm of Hg. Gas chromatographic analysis of the product showed the presence of only one compound which indicated no position isomer was formed. The identity of the product was confirmed by elemental analysis, calc. 57.9 C, 10.4 H, 9.65 N; found 57.5 C, 10.3 H, 9.5 N.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:3]1=[O:23].Br[C:25]1[CH:26]=[C:27]([NH:40][S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[O:31][C:30]1[CH:25]=[CH:26][C:27]([NH:40][S:41]([CH2:44][CH3:45])(=[O:42])=[O:43])=[CH:28][C:29]=1[C:6]1[CH:5]=[C:4]([C:17]#[C:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[C:3](=[O:23])[N:2]([CH3:1])[CH:7]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(C#C[Si](C)(C)C)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cc(C#C[Si](C)(C)C)c(=O)n(C)c2)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 38.7 %

Procedure:
A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilylethynyl)pyridin-2-one (200 mg, 0.6 mmol), N-[3-Bromo-4-(2,4-difluorophenoxy)phenyl]ethanesulfonamide (197 mg, 0.5 mmol), Pd(dppf)Cl2 (37 mg, 0.05 mmol) and K3PO4 (267 mg, 1.26 mmol) in dioxane (6 mL) and H2O (0.6 mL) was stirred at 70° C. under an atmosphere of argon for 12 h. After the mixture was concentrated, the residue was purified by column chromatography on silica gel (PE:EA=2:1) to give the title compound (100 mg, 38%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.82 (d, J=2.4 Hz, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.16-7.12 (m, 1H), 6.99-6.91 (m, 2H), 6.87-6.83 (m, 1H), 6.78 (m, 1H), 6.65 (s, 1H), 3.61 (s, 3H), 3.14 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 024 (s, 9H). LCMS (M+H)+=517.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6].[C:10]([O:14][C:15]([NH:17][C@H:18]([C:21](O)=[O:22])[CH2:19][OH:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].CN1CCOCC1>C(#N)C>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH:6][C:19](=[O:20])[C@H:18]([CH2:21][OH:22])[NH:17][C:15]([O:14][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)[C@H](CS)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 17.2 g of L-cysteine methyl ester hydrochloride and 20.5 g of N-(t-butoxycarbonyl)-L-serine in 300 ml of acetonitrile was treated at 0° C. with 10.1 g of 4-methylmorpholine. To the stirred solution was added dropwise at 10° C. within 30 minutes a solution of 20.6 g N,N-dicyclohexylcarbodiimide in 300 ml of acetonitrile. After stirring the reaction mixture for 3 hours at 0° C. the precipitate formed was filtered off, and the filtrate was evaporated in vacuo. The oily residue was dissolved in 200 ml of ethyl acetate and the solution washed consecutively with 0.5N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The crude product was chromatographed on silica gel using ethyl acetate/n-hexane as eluent, and the so purified product was crystallized from diethyl ether/n-hexane to give N-[N-(t-butoxycarbonyl)-L-seryl]-L-cysteine methyl ester as white crystals with mp 72°-74° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=[CH:12][CH:11]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: N#CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCCCOc1ccc(Cl)cc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
6-Bromohexanenitrile (2.65 mL, 20 mmol) and 4-chlorophenol (2.57 g, 20 mmol) were dissolved in DMF (50 mL). After addition of K2CO3 (5.53 g, 40 mmol) the mixture was stirred at 95° C. for 3 h. The solvent was evaporated under reduced pressure and the residue was partitioned between water (80 mL) and Et2O (200 mL). The org. layer was separated, washed with pH 7 phosphate buffer solution (1×50 ml), dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound, pure enough for further reactions.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.N>C(O)C>[CH3:13][C:4]1[CH:3]=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([C:15]([F:14])([F:23])[F:24])=[CH:17][CH:18]=2)[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: CSc1nc2nc(C)cc(Cl)n2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: N
Solvent: CCO
Product: CSc1nc2nc(C)cc(Nc3ccc(C(F)(F)F)cc3)n2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 7-chloro-5-methyl-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 8 (0.2 g, 0.932 mmol) in ethanol (5 mL), 4-(trifluoromethyl)aniline (ALDRICH, 0.117 mL, 0.932 mmol) was added and the mixture was stirred at room temperature for 3 h. Anhydrous ammonia (0.133 mL, 0.932 mmol) was added and solvent was removed in vacuo. The residue was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures form 95:5 to 40:60%) to yield the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([N:17]1[CH2:16][CH2:15][CH:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH2:19][CH2:18]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C2CCN(Cc3ccccc3)CC2)CC1

Procedure:
A solution of 7.0 g (18.7 mmol) tert-butyl(1′-benzyl-[1,4′]bipiperidinyl-4-yl)-carbamate and 14.3 mL (185 mmol) TFA in 80 mL DCM was refluxed overnight. The mixture was evaporated down i. vac., the residue was combined with 200 mL 30% K2CO3 solution and extracted three times with 100 mL EtOAc, discarding the first 100 mL of extract. The combined organic phases were dried over Na2SO4, filtered and evaporated down. The product was reacted further without purification.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17]N(C)C=O>>[CH2:10]([N:9]([CH3:17])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
60% dispersion of sodium hydride in mineral oil (2.37 g, 0.0592 mol) was added to a solution of N-phenyl-N-benzylamine (10.33 g, 0.0564 mol) in anhydrous N,N-dimethylformamide (200 mL) at 0° C. The reaction mixture was warmed up to ambient temperature and stirred for 45 min. lodomethane (7.99 g, 0.0564 mol) was added dropwise and the stirring at ambient temperature was continued under an atmosphere of nitrogen for 20 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (250 mL) and water (200 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (2:98) as mobile phase to yield N-benzyl-N-methyl-N-phenylamine (4.4 g, 0.0223 mol) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O.S>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[S:22])[CH3:6]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(Br)cccc12
Agent: S
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN(C)C(=S)c1cccc2c(Br)cccc12
Temperature: 25 °C

Procedure:
To a stirred solution of N-[(5-bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (35.5 g, 106 mmoles, described in Example 2) in dry pyridine (100 ml), phosphorus pentasulfide (44.5 g, 200 mmoles) was added portionwise. The mixture was stirred and refluxed for 1.5 hr and then poured into a liter of water at 50° to 80° C. (caution: evolution of copious quantities of H2S). The mixture was allowed to cool to 20° to 22° C. (room temperature), filtered and the filtrate was extracted with ethyl acetate. The extract was washed with 1N aqueous HCl solution, brine, a saturated solution of sodium carbonate and brine, dried (MgSO4), filtered and evaporated to dryness. The residue was recrystallized from ethanol-water (4:1) to give the title compound; mp 85°-86° C.; NMR (CDCl3) δ 3.0 (s, 3H), 3.85 (s, 3H), 4.58 & 5.37 (2d, J=17, 2H), 7.1-8.3 (m, 6H); UV λmax (EtOH) 281 nm (ε 14,480), 218 (14,480).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CCC(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a mixture of N-t-butoxycarbonyl-N-methyl-β-alanine (1.02 g) and morpholine (0.48 g) in dry methylene chloride was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g), and the mixture was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with 1% citric acid aqueous solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution. Then the solution was dried over magnesium sulfate and concentrated under reduced pressure to give 4-(N-t-butoxycarbonyl-N-methyl-β-alanyl)morpholine (1.36 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH:40]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[CH2:42][CH2:41][CH:40]=4)=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(OC1=CCCc2ccccc21)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCCc2ccccc21
Temperature: 60 °C
Yield: 90.9 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 2, Step B (0.760 g, 1.89 mmol), 3,4-dihydro-naphthalen-1-yl trifluoromethanesulfonate (0.579 g, 2.08 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.046 g, 0.0567 mmol) were combined in N,N-dimethylformamide (9.5 mL). 2 M aqueous sodium carbonate (4.73 mL, 9.45 mmol) was added and the reaction heated to 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue purified by flash column chromatography (silica, 30% ethyl acetate in hexanes). Recrystallization from petroleum ether afforded the title compound (0.740 g) as white crystals identical to the material of Example 31.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14])=[N+:2]=[N-:3].C[O:16][C:17](=[O:28])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=O.[O-]CC.[Na+]>CCO>[Cl:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:5]([O:13][CH3:14])=[C:4]([N:1]2[C:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[C:18]([C:17]([OH:28])=[O:16])[N:3]=[N:2]2)[CH:9]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: COc1cc(OC)c(N=[N+]=[N-])cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)c(-n2nnc(C(=O)O)c2-c2ccc(F)cc2)cc1Cl

Procedure:
1-Azido-5-chloro-2,4-dimethoxy-benzene (0.4 g, 1.9 mmol), 3-(4-Fluoro-phenyl)-3-oxo-propionic acid methyl ester (0.42 g, 2.2 mmol) and sodium ethoxide in EtOH (70 mg of sodium in 15 mL EtOH) were refluxed for 3 hours. During the reaction, the solution turned brown from dark green. After that, EtOH was evaporated off and the resulting oil was dried in vacuum. Trituration with ether (15 mL) gave light brown solids, which were removed by filtration and washed with ether. The solids then re-dissolved in CHCl3 and filtered. After evaporation of the solvent, light brown solids were obtained (0.35 g, 50%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[C:10](=[N:12]/[C:13]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:16]=[CH:15][C:14]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH3:11].C([O-])([O-])=O.[K+].[K+].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>CN(C=O)C>[CH2:37]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[C:10](=[N:12]/[C:13]1[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:15][CH:16]=[CH:17][C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)/[CH3:11])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: C/C(=N\c1c(-c2ccccc2)cccc1-c1ccccc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(=N\c1c(-c2ccccc2)cccc1-c1ccccc1)c1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 0.70 g (1.87 mmol) N-[(1E)-1-(1H-benzimidazol-2-yl)ethylidene]-N-1,1′:3′,1″-terphenyl-2′-ylamine, 1.42 g (10.3 mmol) anhydrous K2CO3 and 0.35 g (2.06 mmol) benzylbromide in 4 ml anhydrous DMF was stirred at room temperature for 10 hours. The reaction mixture was then poured into 80 ml water, stirred for 10 min and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with water (3×25 ml) and dried over anhydrous Na2SO4. The solvent was evaporated to give an yellow oil which was triturated with 5 ml methanol at −78° C., filtered while cold washed with cold (−78° C.) methanol (2×2 ml) and dried under reduced pressure. Yield 0.56 g (66.2%). 1H NMR (250 MHz, CDCl3), δ, ppm: 2.07 (s, 3H), 5.51 (m, 2H), 6.90 (m, 2H), 7.22 (m, 19H), 7.78 (m, 1H).
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=O.N[C:16]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=C[NH:18][N:17]=1>C(O)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:18]3[N:17]=[CH:16][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:14]3[N:2]=[CH:3][CH:4]=2)=[N:8][CH:9]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: Cc1ccc(C(=O)C=CN(C)C)nc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(C)cn3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(5-methyl-2-pyridyl)-2-propen-1-one and 0.01 mole of ethyl 3-aminopyrazole-4-carboxylate in glacial acetic acid is refluxed for 6 hours. The solvent is removed under reduced pressure and the residue worked up as for Example 53 to give the product of the example.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:18])=[CH:13][CH:12]=1)[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:18])=[CH:15][CH:16]=1)[CH2:6][C:7]([OH:9])=[O:8])([OH:30])=[O:2]
Reactant: CCCCCCCCCCNC(=O)c1ccc(N(CC(=O)OC)CC(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCNC(=O)c1ccc(N(CC(=O)O)CC(=O)O)cc1
Yield: 92.9 %

Procedure:
A solution of 1.88 g (4.47 mmol) of N-[4-[(decylamino)carbonyl]phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester and 17.0 ml (17.9 mmol) of 1 N NaOH in 125 ml of methanol was kept at room temperature for 18 hours. The solvent was removed, water was added to the residue and the pH was adjusted to 2 with 6 N HCl. The precipitate was filtered and recrystallized from methanol-water to give 1.63 g (93% yield, mp 155°-157°) of N-(carboxymethyl)-N-[4-[(decylamino)carbonyl]phenyl]glycine.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=1[O:19][CH2:20][CH2:21][NH:22]C(OC(C)(C)C)=O)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].[ClH:30]>O1CCOCC1>[ClH:30].[C:1]([NH:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=1[O:19][CH2:20][CH2:21][NH2:22])[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C)NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCN)NC(C)=O

Procedure:
30 ml of dioxane was added to 7.75 g (19.2 mmol) of methyl 2-acetamido-3-[2-(2-t-butoxycarbonylamino-ethoxy)-4-cyanophenyl]-acrylate, and they were stirred. 80 ml of dioxane containing 4 M of hydrogen chloride was added to the obtained mixture, and they were stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was suspended in ethyl acetate. The title compound was obtained by the filtration.