Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]4[N:22]=[C:21](O)[CH:20]=[CH:19][CH:18]=4)=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:25].C(=O)([O-])[O-].[K+].[K+]>>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Br:25])[N:22]=4)=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc(-c2nnc3ccc(N4CCCCCC4)nn23)n1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1cccc(-c2nnc3ccc(N4CCCCCC4)nn23)n1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 6-(6-azepan-1-yl-1,2,4-triazolo[4,3-b]pyridazin-3-yl)pyridine-2-ol (700 mg) and phosphorus tribromide (7 ml) was stirred at 130° C. for 6 hours. After allowing to cool to room temperature, an ice-water was added, and the mixture was neutralized with saturated aqueous solution of potassium carbonate, and extracted with chloroform. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2) and recrystallized from ethanol to obtain 6-azepan-1-yl-3-(6-bromopyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (240 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[CH:29][CH:28]=3)=[CH:21][N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CN(C)Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1
Solvent: CCO
Product: CN(C)Cc1ccc(Cc2cnc(NCCSCc3ccc(CN(C)C)o3)[nH]c2=O)cc1

Procedure:
A mixture of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamine (1.71 g) and 2-nitroamino-5-(4-dimethylamino methylbenzyl)-4-pyrimidone (1.97 g) in ethanol (12 ml) was heated under reflux for 42 hr. The ethanol was evaporated at reduced pressure yielding 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(4-dimethylaminomethylbenzyl) 4-pyrimidone as a brown oily residue which was washed with hot water, cooled and mixed with dilute ethanolic hydrochloride acid. Excess of ethanol was evaporated under reduced pressure and the residue was recrystallised from isopropanol/methanol and from ethanol to give the trihydrochloride (1.85 g) as an off-white solid m.p. 180°-184° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.II.[CH:13](=[O:15])[CH3:14].[Cl-].[NH4+]>O1CCCC1>[OH:15][CH:13]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1)[CH3:14]
Reactant: C=Cc1ccc(Br)cc1
Reactant: CC=O
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
This Example illustrates the synthesis of polymeric blocked developer PBDI. First, 4-(1-hydroxyethyl)styrene was prepared. A suspension of 4.82 g (0.198 mol) of magnesium in 200 mL of dry tetrahydrofuran (THF) under nitrogen was treated with 36.3 g (0.198 mmol) of 4-bromostyrene plus a trace of iodine. The reaction, mixture was heated at reflux for 4 h, and then cooled using an ice bath. Acetaldehyde (9.6 g, 0.218 mol) was added, and the mixture was stirred overnight. The reaction mixture was poured onto 300 g of ice plus 25 g of ammonium chloride, and then extracted with ether (3×200 mL). The combined ethereal extracts were concentrated, and the residue was vacuum distilled. The product (17.3 g, 59%) was obtained as a slightly yellow, bp 67-99° C./0.10 mm. 1H NMR (CDCl3) δ 1.50 (d, J=6.4, 3H), 1.8 (br s, 1H), 4.89 (q, J=6.4, 1H), 5.24 (d, J=11.0, 1H), 5.74 (d, J=17.7, 1H), 6.7 (m, 1H), 7.34 (d, J=8.2, 2H), 7.40 (d, J=8.2, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CC(C)([O-])C.[K+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=1>CN(C=O)C.O>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH2:41])=[O:40])[CH:34]=3)=[C:2]([F:1])[CH:3]=2)=[O:11])[C:13](=[O:25])[N:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.6 %

Procedure:
To a solution of N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (7.18 g, 21.1 mmol) in DMF (200 mL) was added potassium tert-butoxide (7.08 g, 63.2 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (4.27 g, 25.2 mmol). The reaction was heated at 120° C. for 3 hours, then cocentrated to 2 mL in vacuo, and diluted with water (60 mL). The precipitate was obtained by filtration, and then washed with water (10 mL). The crude product was purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=1/1/0.05) to give the title compound as a yellow solid (4.15 g, 43% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:24][CH2:25][CH:20]([C@@:18]3([CH3:26])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CCc1cnc(Cl)nc1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cnc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-ethyl-pyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 4): tR=0.91 min; Mass spectrum (ESI+): m/z=484 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH:4]1[CH2:13][C:12]2[CH:11]=[C:10]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36]>C(Cl)Cl>[CH:35]([NH:38][C:39]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:3]([CH2:1][CH3:2])[CH:4]2[CH2:5][CH2:6][C:7]3[C:12](=[CH:11][C:10]([NH:14][C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])=[CH:9][CH:8]=3)[CH2:13]2)[CH2:27][CH2:26]1)=[O:40])([CH3:37])[CH3:36]
Reactant: CC(C)N=C=O
Reactant: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-2,2,2-trifluoro-acetamide (1.7 mmol) in methylene chloride (20 mL) under an inert atmosphere was added triethylamine (1.0 mL, 6.6 mmol) and isopropyl isocyanate (230 μL, 2.3 mmol). The reaction was stirred for 20 h and then concentrated in vacuo. This material was partitioned between 5% KOH and water. The organic layer was dried (MgSO4) and concentrated to afford 4-({ethyl-[7-(2,2,2-trifluoro-acetylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide as a clear oil (630 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[C:16]2[C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][C:12]([CH3:20])([CH3:19])[C:11]=2[CH:10]=[C:9]([O:21][CH3:22])[C:8]=1/[CH:23]=[CH:24]/[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25](/[CH:24]=[CH:23]/[C:8]2[C:9]([O:21][CH3:22])=[CH:10][C:11]3[C:12]([CH3:19])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[C:16]=3[C:7]=2[O:6][CH3:5])=[CH:32][CH:31]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(c(OC)c1/C=C/c1ccc(CN)cc1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2c(c(OC)c1/C=C/c1ccc(CNC(C)=O)cc1)C(C)(C)CCC2(C)C
Reaction time: 1 h

Procedure:
1 ml of acetyl chloride in 5 ml of absolute tetrahydrofuran was added dropwise, at 20° C., to a solution of 3 g (8 millimoles) of the benzylamine derivative from Example 30, 1.6 g (16 millimoles) of triethylamine and 50 mg of DMAP (4-N,N-dimethylaminopyridine) in 25 ml of absolute tetrahydrofuran. After 1 hour at 0° C., the mixture was poured onto 100 ml of water and extracted with methylene chloride. The organic phase was dried and evaporated down, and the oily residue was heated with heptane. The mixture was cooled, the supernatant heptane phase was decanted, and the process was repeated several times. Finally, 0.8 g of the title compound of melting point 126°-127° C. crystallized out from the heptane solution and was filtered off under suction.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:6]([C:8]1([CH3:23])[CH2:11][CH2:10][N:9]1[C:12](=[O:22])[CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=1)=[O:7].CCO.[OH-].[Na+]>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]([C:8]2([CH3:23])[CH2:11][CH2:10][N:9]2[C:12](=[O:22])[CH2:13][C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[O:7])=[CH:26][CH:27]=1
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC(=O)O)Cc2ccc(Cl)cc2)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid methyl ester, compound 48 (1 eq.) in either EtOH or MeOH was added aqueous NaOH (2N) (2 eq.). The reaction was stirred at 20° C. for 2 h. The solvent was removed under reduced pressure and the crude was partitioned between water and EtOAc. The organic layer was discarded and the aqueous layer was acidified by addition of aqueous HCl (2N) and thoroughly extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated to afford ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: COc1cccc(N=C=O)c1
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)Nc2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 mL) and 3-methoxyphenyl isocyanate (0.016 mL, 0.12 mmol) was added. The solution was stirred at room temperature for 1.5 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2:3 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.3, 161.7, 161.0 (dd), 157.9 (dd), 155.3, 151.2, 141.6, 141.2, 138.3, 136.2, 135.0, 132.7, 132.6, 130.6, 128.7, 127.4 (dd), 126.0 (dd), 122.8, 121.1, 116.7, 113.0, 112.7, 112.6 (dd), 109.5, 106.3, 105.8 (dd), 55.7, 19.7
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[C:7]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:7]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[C:1]=[O:2])=[CH:17][CH:16]=2)=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1
Reactant: Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Reaction time: 0.33 h

Procedure:
Dry toluene (225 ml) was cooled to a temperature of from about 0° to 5°C. and a stream of phosgene gas passed therethrough until 17.4 grams had been absorbed. A solution of 4-((3,6-dichloro-2-pyridinyl)methoxy)benzenamine (15.8 grams; 0.058 mole) in 125 ml. of toluene was added portionwise thereto over a period of about 8 minutes while maintaining the reaction temperature at about 2° to 5°C. The cloudy reaction mixture was then stirred for about 20 minutes with the temperature thereof slowly increasing as excess phosgene was purged from the reaction mixture with nitrogen. At a temperature of about 85°C., the reaction mixture became clear. The toluene solvent was then removed from the reaction mixture under reduced pressure and the residue obtained extracted with hexane. The yellow crystalline product recovered from the hexane extract upon cooling was identified as the desired 3,6-dichloro-2-((4-isocyanatophenoxy)methyl)pyridine compound and was found to have a melting point of 61.5° - 62.5°C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12](O)=[O:13])[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][N:45]=[N:44][CH:43]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[N:44][CH:43]=2)=[O:13])[CH:4]=[N:3]1
Reactant: Nc1ccnnc1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(C(=O)Nc3ccnnc3)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 18 h

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 26; 150 mg, 0.36 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.12 ml, 0.71 mmol), 4-aminopyridazine (33.8 mg, 0.36 mmol), 1-hydroxy-7-azabenzotriazole (58.1 mg, 0.43 mmol) and EDC (116 mg, 0.61 mmol). The reaction was stirred for 18 hours and then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a yellow gum. 117 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16](F)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Yield: 71 %

Procedure:
310 mg of 5-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-fluoro-benzonitrile (Example I10) 73 mg of 1,2,4-triazole and 166 mg of potassium carbonate were stirred in 5 ml acetonitrile at room temperature for 24 hours. The solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified on silica gel (elutant diethylether) affording 5-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-[1,2,4]triazol-1-yl-benzonitrile as a solid in 71% yield. 1H-NMR (CDCl3, δ in ppm): 8.96 (s, 1H), 8.17-8.28 (m, 3H), 7.99 (d, 1H), 7.37-7.39 (m, 2H), 7.17 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[NH:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH3:24])[C:13]([OH:15])=[O:14]>C(O)(=O)C.O>[CH2:21]([C:20]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]2[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][C:18]=2[N:19]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=O)Nc1ccc(C(=O)O)cc1NCc1ccccc1Cl
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Yield: 86.9 %

Procedure:
A solution of 3-[(2-chlorophenyl)methyl]amino-4-(valeryl)aminobenzoic acid (1.5 g, 4.16 mmol) in glacial acetic acid (10 mL) was refluxed for 5 hours, cooled, diluted with water (75 mL), and the crystals that separated were filtered, washed with water and dried to afford 1.33 g of crude product. Crystallization from methanol gave 1.24 g (87%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-6-carboxylic acid; mp 238°-241° C.
Reaction SMILES: [CH3:1]C1C=CC(OCC2C=CC=CC=2)=CC=1.C1(C=NC2C=CC=CC=2)C=CC=CC=1.[C:30]1([N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH3:1][C:47]1[CH:46]=[CH:45][C:44]([N:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:49][CH:48]=1
Reactant: c1ccc(CN(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(OCc2ccccc2)cc1
Agent: C(=Nc1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N(Cc2ccccc2)c2ccccc2)cc1
Yield: 51 %

Procedure:
Methyl-4-(phenylmethoxy)benzene (1.98 g, 0.01 mol) and N-(phenylmethylene)benzenamine (1.81 g, 0.01 mol) were reacted in Na/DMF (1 g: 50 mL) at 75° C. for 30 min. Aqueous work-up, extraction with petroleum ether, 3×100 mL, and chromatography with petroleum ether/ethyl acetate 95:5 afforded a total of 1 g. of solid which by HPLC chromatography contained N,N-diphenyl-benzenemethanamine and the title compund in the ratio 6:94 (51% yield by HPLC). The purer fractions from chromatograpy on silica were combined and the solvent removed. The residual oil was dissolved in methanol and some petroleum ether. On cooling this crystallized the title compound. Two recrystallizations from methanol gave the title compund (98.1% pure; 36% yield), mp 85°-6° C. 1H NMR (200 MHz, CDCl3) δ (assignment): 2.29 (s, 3H, methyl), 4.97 (s, 2H, --NCH2Ph), 6.80-6.97 (m, 3H, aromatic) 7.06-7.27 (d, 4H, J=1.37 Hz, --NC6H4CH3), 7.14-7.36 (m, 7H, aromatic). MS [m/e (70 eV, % of base peak)] PhCH2N(Ph)(C6H4)CH3 273 (M+., 96.5), 196 (M+. -Ph., 31.7), 182 (M+. -PhCH3., 100), 167 (M+. -PhCH2. -CH3. 81.2), 91 (C7H7+, 98.3). FTIR (CDCl3): 3089, 3064, 3030, 2924, 2864, 1596, 1572, 1512, 1497, 1453 cm-1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:33](=[O:36])[CH2:34][CH3:35])[CH2:3][CH2:4]4)=[O:10])=[C:12]([CH3:32])[NH:13][C:14]=23)[CH2:30][CH2:31]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f5) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24][CH2:25][O:26][Si](C(C)(C)C)(C)C)[CH:12]([F:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:12]([F:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)C(F)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](c1ccccc1)N1C[C@@](CCCO)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 92.9 %

Procedure:
(3S)-3-[3-(tert-Butyldimethylsilyloxy)-1-propyl]-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (8.15 g) was dissolved in tetrahydrofuran (25.0 mL). Acetic acid (22.0 mL) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) (25.0 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 21.5 hours. The reaction solution was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was sequentially washed with saturated sodium bicarbonate water and brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2→1:1) to give 5.77 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][O:16]C(=O)C)[CH3:3].[OH-].[Na+]>CO>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:20])[CH2:15][OH:16])[CH3:1]
Reactant: CC(=O)OCC(=O)Nc1c(C(C)C)cccc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of N-[2,6-bis(1-methylethyl)phenyl]-2-acetoxyacetamide (Example N) (5.7 g, 20.6 mmol) in methanol (50 mL) is added 2M sodium hydroxide solution (20 mL). The solution is stirred at room temperature for 1 hour. The mixture is concentrated, diluted with water, and extracted three times with ethyl acetate. The combined organic extracts are washed with brine, dried over magnesium sulfate, and concentrated to afford 4.6 g of the title compound as an off-white solid; mp 164°-166° C.
Reaction SMILES: [Na].[CH2:2]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](C)(C)[CH2:11][C:10]1=[O:23])[CH2:7][CH3:8])[CH3:3].[C:24](Cl)(=[O:26])[CH3:25]>CC(C)=O>[C:24]([O:23][C:10]1[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14](=[O:15])[C:9]=1[C:6](=[N:5][O:4][CH2:2][CH3:3])[CH2:7][CH3:8])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCONC(CC)=C1C(=O)CC(C)(C)C(C(=O)OCC)C1=O
Agent: [Na]
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(OC(C)=O)CCC(C(=O)OCC)C1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium salt of 2-(1-ethoxyaminopropylidene)-4-ethoxycarbonyl-5,5-dimethylcyclohexane-1,3-dione (3.1 g) was suspended in 50 ml of acetone and acetylchloride (0.8 g) was added to it at room temperature. After stirring for 3 hours, the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed is vacuo and the desired product was obtained as an oily substance.