Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:9]([O:11]C(C)(C)C)=[O:10])[CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(O)C.C([O-])(O)=O.[Na+]>O>[CH:1]1([C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)C1CCC=CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCC=CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.9 %

Procedure:
A 100 mL round bottom flask was charged with t-butyl cyclooct-4-ene carboxylate (1.0 g, 4.8 mmol) and trifluoroacetic acid (2 mL) and stirred at room temperature for two days. A 4:1 ethanol:water mixture (10 mL) was then added and the pH of the resulting mixture was adjusted to ˜4.0 with aqueous saturated NaHCO3. The mixture was then extracted with 4×25 mL portions of ethyl ether and the ether phases were combined and concentrated. The liquid was then purified by flash chromatography on silica (3:7 ethyl acetate:hexanes mobile phase) to afford cyclooct-4-ene carboxylic acid (0.051 g, 69%). The material was crudely dried immediately before polymerization by dissolving the material in benzene and carrying out azeotropic distillation using a rotary evaporator (three cycles). IR (film on NaCl): 3017, 2932, 2859, 1736 (C═O), 1467, 1449, 1392, 1334, 1165, 747, 714 cm−1 (O—H stretch not assigned due to weakness). 1H NMR (300 MHz, CDCl3): δ 11.6 (br, 1H), 5.6–5.8 (m, 2H), 2.30–2.54, (m, 2H), 2.02–2.24 (m, 4H), 1.84–1.96 (m, 1H), 1.50–1.82 (m, 3H), 1.32–1.48 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 184.34, 130.45, 129.34, 43.10, 31.28, 29.10, 27.65, 25.75, 23.92 ppm. HRMS-FAB for C8H14O2: Theoretical: 126.1045; Found: 126.1048.
Reaction SMILES: C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.[OH:22][C:23]1[CH:40]=[CH:39][C:26]([NH:27][C:28]2[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:29]=2[C:30]([OH:32])=O)=[CH:25][CH:24]=1.Cl.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>ClCCl.CCOCC>[OH:22][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:28]2[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:29]=2[C:30]([NH:50][O:49][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:32])=[CH:39][CH:40]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI, 0.22 g, 1.1 mmol) and HOBt (0.17 g, 1.1 mmol) were added to a solution of crude 2-(4-hydroxyanilino)-4,5-difluoro-benzoic acid (Example M, 0.265 g, 1.00 mmol) in 70 mL of dichloromethane at 0° C. After 1 hour, O-benzylhydroxylamine hydrochloride (0.176 g, 1.1 mmol), and triethylamine (0.15 mL, 1.1 mmol) were added, and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with 100 mL of ether and washed with water and 0.1N HCl, water, and brine, dried over sodium sulfate. Solvents were evaporated to give 0.35 g of the title compound as a crude solid.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][NH:14][C:15](=[O:22])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19].C(N(CC)CC)C.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.C(O)(C(F)(F)F)=O>Cl.C(O)C>[CH3:31][N:32]1[CH2:37][CH2:36][C:35]2[N:8]([CH2:12][CH2:13][NH:14][C:15](=[O:22])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])[C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:34]=2[CH2:33]1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Reactant: O=C(NCCBr)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)OCC(Cl)(Cl)Cl)CCN(C)C1
Yield: 15.3 %

Procedure:
Preparation of the title compound was carried out using p-Tolylhydrazine hydrochloride (396 mg, 2.5 mmol), 2,2,2-trichloroethyl 2-bromoethylcarbamate (750 mg, 2.5 mmol), triethylamine (1 ml, 7.4 mmol) and N-methyl-4-piperidone hydrochloride (394 mg, 2.6 mmol) in ethanol-HCl (15 ml) to obtain 160 mg of 2,2,2-trichloroethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethylcarbamate as TFA salt after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:13]([O:12][C:10](=[O:11])[NH:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:14]
Reactant: Nc1cccnc1Br
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccnc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
3-Amino-2-bromopyridine described in Preparation Example S-1 (1.4 g, 8.1 mmol) was dissolved in pyridine (10 mL), ethyl chloroformate (0.93 mL, 9.7 mmol) was added dropwise on an ice bath, and the solution was stirred for 2 hours at room temperature. After the reaction was completed, the reaction solution was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), and the title compound (0.56 g, 2.3 mmol, 28%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[O:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:9]=2[NH:8][C:7]=1[CH3:27])=[O:5])[CH3:2].Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:24]1([CH2:23][O:22][C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[C:14]2[C:9]3[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:7]([CH3:27])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester (example D.a2) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].C([Li])CCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>C1COCC1>[CH3:8][C:3]1[C:2]([B:14]([OH:19])[OH:15])=[C:6]([CH3:7])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(C)c1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
To a 500 mL three RB flask fitted with magnetic stirrer was charged 4-bromo-3,5-dimethyl-1,2-oxazole (4.0 g, 22.7 mmol) in THF (40 mL), cooled −78° C. To the stirred solvent was added n-butyl lithium (28.4 mL, 1.6M solution, 45.0 mmol) drop wise and stirred at −65° C. about 30 minutes. The RM was brought to −78° C., was added tri-isopropyl borate (12.81 g, 68.0 mmol), once the temperature to reached room temperature and stirred about 16 h. Then removed the solvent under reduced pressure and quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4 and removed the solvent under reduced pressure. The obtained crude material was purified by silica gel column chromatography to obtain white solid. (0.4 g, yield: 12.5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:14]([OH:17])[C:15]#[CH:16].[H-].[Na+].O>O1CCCC1>[C:8]1([C:6]2[CH:7]=[C:2]([O:17][CH2:14][C:15]#[CH:16])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOc1cc(-c2ccccc2)ncn1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 194 mg of 4-chloro-6-phenylpyrimidine and 68 mg of 2-propyn-1-ol, to which 50 mg of sodium hydride (60% in oil) was added with stirring at room temperature, followed by further stirring for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-phenyl-6-(2-propynyloxy)pyrimidine (the present compound (37)), m.p.: 65.1° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH2:18][C:19](O)=[O:20])[CH:17]=2)[N:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:38][CH:39]([CH3:42])[C:40]#[N:41].CCCP(=O)=O>CN(C=O)C>[C:40]([CH:39]([NH:38][C:19](=[O:20])[CH2:18][N:16]1[CH:17]=[C:13]([NH:12][C:8]2[N:7]=[C:6]([NH:5][CH2:4][C:3]3[C:2]([F:1])=[CH:25][C:24]([F:26])=[CH:23][C:22]=3[F:27])[CH:11]=[CH:10][N:9]=2)[CH:14]=[N:15]1)[CH3:42])#[N:41]
Reactant: CC(N)C#N
Reactant: O=C(O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C#N)NC(=O)Cn1cc(Nc2nccc(NCc3c(F)cc(F)cc3F)n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid I-2 (0.1 g, 0.26 mmol, prepared by Procedure B), DIPEA (0.15 mL, 0.8 mmol), 2-aminopropanenitrile hydrochloride (34 mg, 0.3 mmol), propylphosphonic anhydride solution (50% in DMF) (0.17 g, 0.5 mmol) in DMF was stirred overnight at room temperature then extracted into water and washed with DCM. The aqueous layer was neutralised with aqueous sodium bicarbonate and extracted with three times with DCM. The combined organic layer was concentrated in vacuo and purified by prep. HPLC to afford N-(1-cyanoethyl)-2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide I-5 (80 mg, 0.18 mmol). LC-MS (Method B), RT=5.15 min. (ES+) 431.
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]([CH3:23])([CH3:22])[CH2:20][O:21][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1)=[O:4].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:23][C:19]1([CH3:22])[C:18]2[C:13]([O:12][C:9]3[N:10]=[CH:11][C:6]([N:5]4[C:3](=[O:4])[C@@H:2]([CH2:24][CH3:25])[NH:1][C:27]4=[O:29])=[CH:7][N:8]=3)=[CH:14][CH:15]=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of (2R)-2-amino-N-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}butanamide (Intermediate 67, 3 mg) in dry dichloromethane (0.5 ml), TEA (6.11 μL, 0.044 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (1.170 mg, 3.94 μmol) in dry dichloromethane (0.125 ml) was then added dropwise and the reaction mixture was stirred at the 0° C. for 30 minutes. The reaction was quenched with water (3 ml), and the organic phase was separated, dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column Isolute (1 g) and dichloromethane/methanol from 99.5:0.5 to 9:10 as eluent to afford the title compound (0.7 mg) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:50])[C:7]([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[C@H:28]([CH2:44][N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:27]1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:13])[CH3:3].[CH3:51][I:52]>CC(C)=O>[I-:52].[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:50])[C:7]([S:25][C@@H:26]1[CH2:30][N:29]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[C@H:28]([CH2:44][N+:45]3([CH3:51])[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:27]1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:3]
Reactant: CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CN4CCCC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: CC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C[N+]4(C)CCCC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Product: [I-]

Procedure:
To a solution of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(pyrrolidin-1-yl)methylpyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.35 g) in acetone (3.5 ml) was added methyl iodide (0.15 ml) at ambient temperature. The mixture was stirred for hours. The reaction mixture was evaporated in vacuo to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[(2S,4S)-2-(1-methyl-1-pyrrolidinio)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (0.35 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:14]([CH:13]([CH2:16][CH3:17])[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:7][CH:8]=1)[N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:15]
Reactant: CCC(CC)C(c1ccc(NC(=O)CCl)cc1)n1cncn1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC(CC)C(c1ccc(NC(=O)CN2CCN(C)CC2)cc1)n1cncn1
Yield: 35.8 %

Procedure:
A mixture of (±)-2-chloro-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]acetamide (0.0218 mol), 1-methylpiperazine (0.0436 mol) and K2CO3 (0.0436 mol) in CH3CN (150 ml) was stirred and refluxed for 4 hours. The mixture was cooled, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (8.13 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 3 g (35.8%) (±)-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-4-methyl-1-piperazineacetamide (compound 15).
Reaction SMILES: [N:1]1([CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[CH:15]=[CH:16]C3C=CC=CC=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[N:1]1([CH:6]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[NH:13][C:14](=[O:23])[CH:15]=[CH:16]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(C=Cc1ccccc1)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=c1ccc2cc(C(c3ccccc3)n3ccnc3)ccc2[nH]1
Temperature: 120 °C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
To a stirred solution of 10.5 parts of N-[4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]-3-phenyl-2-propenamide in 110 parts of chlorobenzene were added 18.5 parts of aluminium chloride. The reaction mixture was stirred for 3 hours at 120° C. After cooling to room temperature, the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and methanol. The product was filtered off and dried, yielding 1.3 parts (15.4%) of 6-[(1H-imidazol-1-yl)phenylmethyl]-2(1H)-quinolinone; mp. 226.9° C. (compound 2).
Reaction SMILES: C1COCC1.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[C-:16])=[CH:11][CH:10]=1)([O-])=O.O.C(=O)=O>CO>[NH2:6][C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[C-:16])=[CH:11][CH:10]=1
Reactant: [C-]#[N+]c1ccc([N+](=O)[O-])cc1
Agent: O=C=O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: [C-]#[N+]c1ccc(N)cc1
Yield: 76.2 %

Procedure:
Under nitrogen, 11.6 g (12.8 mmol) lithium-cobalt (I) phthalocyanine x 4.5 THF and 296 mg (2 mmol) p-nitro-phenyl isonitrile are agitated in 65 ml methanol for 72 hours at 20° C. The green reaction mixture is mixed with 5 ml water; CO2 and air are passed in for 5 min., and the blue precipitate is centrifuged which is washed with ethanol. The centrifugate collected is concentrated and the residue separated into ether and water. Concentration of the ether phase, dried with sodium sulfate, produces 180 mg (76%) p-aminophenylisonitrile.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:31]1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1.CN(C=O)C>O1CCOCC1.CO>[N:33]1[CH:32]=[C:31]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[CH:36]=[N:35][CH:34]=1
Reactant: Brc1cncnc1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)[nH]2)c1
Yield: 28.1 %

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (203.4 mg, 0.62 mmol) was added, followed by 5-bromo-pyrimidine (100 mg, 0.62 mmol). Then 1 mL of anhydrous DMF was added, the vial was capped and microwaved at 250° C. for 30 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension, the solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions containing the product were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a light-brown foamy solid (34.7 mg).
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C@@H:4]([NH:15]C(=O)OC(C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:24]([NH2:32])(=[S:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OCC)C>CC#N>[BrH:1].[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@@H:4]([C:3]2[N:32]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:31][CH:2]=2)[NH2:15])=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: NC(=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)CBr
Solvent: CCOCC
Solvent: CC#N
Product: Br
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of (S)-tert-butyl 4-bromo-1-(4-nitrophenyl)-3-oxobutan-2-ylcarbamate, 7, (1.62 g, 4.17 mmol) and thiobenzamide (0.63 g, 4.60 mmol) in CH3CN (5 mL) is refluxed for 24 hours. The reaction mixture is cooled to room temperature and diethyl ether (50 mL) is added to the solution. The precipitate which forms is collected by filtration. The solid is dried under vacuum to afford 1.2 g (67% yield) of the desired product. LC/MS ESI+ 326 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([CH3:44])([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])[CH3:32])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:32][C:31]([CH:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1)([O:33][Si:34]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:39])[CH3:40])[CH:35]([CH3:36])[CH3:37])[CH3:44]
Reactant: CC(C)[Si](OC(C)(C)C1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)[Si](OC(C)(C)C1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.2 %

Procedure:
To a solution of Intermediate A (129 mg, 0.788 mmol) in dry DMF (2 mL) at RT under Ar was added NaH (60% dispersion in oil, 45.0 mg, 1.13 mmol) (CARE: gas evolution) and the resulting opaque brown solution stirred at RT for 45 min. A solution of Intermediate 74b (326 mg, 0.750 mmol) in dry DMF (2 mL) was added and the resulting dark brown solution stirred at 60° C. for 2.5 h. The solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH (0.100 mL), applied to an SCX-2 cartridge and washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo gave a viscous dark brown oil. FCC, using 1-6% [2M NH3 in MeOH] in DCM, gave the title compound as a viscous brown oil (131 mg, 30%). LCMS (Method 3): Rt 3.53 min, m/z 578 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:31](OCC)=[O:32])[N:23]=[C:22]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][OH:32])[N:23]=[C:22]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 79.6 %

Procedure:
Following a procedure similar to that described in Example 1(b), but using 1.50 g of diethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butylimidazole-4,5-dicarboxylate [prepared as described in step (a) above] and 3.9 ml of diisobutylaluminum hydride (as a 1.5M solution in toluene), 1.1 g of the title compound was obtained as a gum.