Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][CH:21]=[C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])=O)[CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][C:7]([C:6]3[CH:5]=[C:4]([CH:23]=[CH:22][CH:21]=3)[C:3]([OH:2])=[O:24])=[N:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(C(=O)NCC(=O)c2ccc(OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnc(-c3cccc(C(=O)O)c3)o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
A solution of 1.7 g (5.5 mmol) N-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-isophthalamic acid methylester from Preparation 3 in a 3:1:1 mixture of THF/methanol/water was added 10 mL (10 mmol) 1N NaOH. The mixture was stirred 4 hours at room temperature before concentrating on a rotary evaporator. The residue was treated with 6M HCl then filtered, washed with water (1×) and dried in a vacuum oven overnight at 70° C. to provide 1.5 g (91%) desired product.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12](=[O:36])[NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([NH:25][C:26]2[C:27]([CH3:35])=[CH:28][N:29]3[C:34]=2[CH:33]=[CH:32][CH:31]=[CH:30]3)=[O:24])[CH:18]=1)([CH3:10])([CH3:9])[CH3:8].Cl[C:38]([C:40]1[CH:41]=[CH:42][C:43]([NH:56][C:57](=[O:62])[C:58]([F:61])([F:60])[F:59])=[C:44]([CH:55]=1)[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])=[O:39]>ClCCl>[C:7]([O:11][C:12]([NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[C:23]([NH:25][C:26]1[C:27]([CH3:35])=[C:28]([C:38]([C:40]2[CH:41]=[CH:42][C:43]([NH:56][C:57](=[O:62])[C:58]([F:61])([F:59])[F:60])=[C:44]([CH:55]=2)[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[O:39])[N:29]2[C:34]=1[CH:33]=[CH:32][CH:31]=[CH:30]2)=[O:24])=[O:36])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Reactant: Cc1cn2ccccc2c1NC(=O)c1cccc(OCCNC(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(NC(=O)c2cccc(OCCNC(=O)OC(C)(C)C)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
4.43 ml (43.7 mmol) of pyridine and 8.95 g (21.9 mmol) of tert-butyl[2-(3-{[(2-methylindolizin-1-yl)amino]-carbonyl}phenoxy)ethyl]carbamate are added to the suspension of 9.27 g (24.0 mmol) of benzyl 5-(chlorocarbonyl)-2-[(trifluoroacetyl)amino]benzoate in 180 ml of dichloromethane. The reaction medium that has turned greenish is stirred at ambient temperature for 16 hours. It is concentrated to dryness and the residue is taken up in diisopropyl ether and ethanol. The solid in suspension is filtered, washed with diisopropyl ether and dried. 6.29 g (38%) of a yellow powder are obtained.
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].CCCCCC.[CH3:19][N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]#[N:26].CN([CH:30]=[O:31])C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:25]([C:21]1[N:20]([CH3:19])[C:24]([CH:30]=[O:31])=[CH:23][CH:22]=1)#[N:26]
Reactant: CN(C)C=O
Reactant: Cn1cccc1C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C#N)ccc1C=O
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
Diisopropylamine (17.5 ml, 124.38 mmol) was introduced into THF (100 ml) under nitrogen. N-Butyllithium solution in hexane (15% strength, 75.9 ml, 124.38 mmol) was added dropwise at −78° C. The mixture was subsequently stirred for 45 minutes at −20° C. and then cooled again to −78° C. At this temperature, a solution of 1-methylpyrrole-2-carbonitrile (12 g, 113.07 mmol) in THF (50 ml) was added dropwise. After stirring for 45 minutes at −78° C., DMF (43.9 ml, 546.46 mmol) was added dropwise, and the mixture was stirred at this temperature for a further 2 hours. After addition of citric acid monohydrate (20.56 g), the mixture was warmed to room temperature, and water (112 ml) was added. The THF was removed in a rotary evaporator, and the aqueous phase was saturated with sodium chloride and extracted with diethyl ether (3×200 ml). The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed in a rotary evaporator and the crude product was purified by means of flash chromatography (silica gel, dichloromethane). Yield: 8.25 g (54%).
Reaction SMILES: [NH2:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[N:12]3[C:13]4[N:8]([C:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=5)=[CH:10][CH2:11]3)[N:7]=[CH:6][C:5]=4[C:4](=[O:24])[N:3]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2nc(=O)c3cnn4c3n2CC=C4c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 200 mg amount of 5-amino-8-[3-(trifluoro-methyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) was suspended in 3 ml of pyridine, then 0.2 ml of p-methoxybenzoyl chloride was added in one portion and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched in 100 ml of water and the solid which formed was collected by filtration and washed with ether to give 164 mg of the desired product as a white solid, m.p. 271°-273° C.
Reaction SMILES: [C:1]([C:5]1[CH:51]=[CH:50][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[C:34]([O:38][Si:39]([CH:46]([CH3:48])[CH3:47])([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])=[C:33]([F:49])[CH:32]=2)[CH2:20][CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:56]=[N+:57]=[N-:58])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:30][C:31]2[CH:32]=[C:33]([F:49])[C:34]([O:38][Si:39]([CH:40]([CH3:42])[CH3:41])([CH:43]([CH3:44])[CH3:45])[CH:46]([CH3:48])[CH3:47])=[C:35]([F:37])[CH:36]=2)[CH2:20][CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]3[NH:58][N:57]=[N:56][N:27]=3)=[CH:24][CH:23]=2)=[CH:50][CH:51]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(-c3nnn[nH]3)cc2)cc1F)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 625 mg (85% pure, 0.75 mmol) of E-4-[5-[2-(4-tert-butylbenzyloxy)phenyl]-3-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)pent-4-enyl]benzonitrile in 12 ml of toluene is mixed with 1.76 ml (13.24 mmol) of trimethylsilyl azide and 329.6 mg (1.3 mmol) of di-n-butyltin oxide and stirred at 80° C. for 12 h. After conversion is complete, the mixture is extracted with sodium bicarbonate solution. The aqueous phase is back-extracted twice with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulfate and concentrated. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:2→ethyl acetate). 447.3 mg (0.51 mmol, 86% purity, 58% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH3:12])[C:10]#[N:11].[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[NH:15][CH2:14][CH2:13][N:11]=1)[CH3:12]
Reactant: NCCN
Reactant: CC(C#N)c1cccc(F)c1F
Product: CC(C1=NCCN1)c1cccc(F)c1F

Procedure:
rac-2-[1-(2,3-Difluoro-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,3-difluoro-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): off-white solid; MS (EI): 210.1 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH3:18])[NH:11][C:10]2=[N:19][NH:20][C:21]([OH:22])=[C:9]12.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:39]([O:43][C:44](=O)[O:45]C(C)(C)C)([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44]([O:22][C:21]1[C:9]2[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH3:18])[NH:11][C:10]=2[NH:19][N:20]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCC1=C(C#N)C(c2ccccc2Cl)c2c(n[nH]c2O)N1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC1=C(C#N)C(c2ccccc2Cl)c2c(OC(=O)OC(C)(C)C)n[nH]c2N1
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-3-hydroxy-6-propyl-2H-pyrazolo[3,4-b]pyridine (12.5 g) in THF (400 mL) was added triethylamine (4.5 g), dimethylaminopyridine (0.5 g) and di-t-butylcarbonate (9.6 g) and the mixture was stirred for 3 hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (12 g) as colorless crystals.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([CH3:17])([CH3:16])[C:9](=[O:15])[N:10]=2)[C:5]=1[OH:18])[CH:2]=[CH2:3].[Br:19]N1C(=O)CCC1=O>>[Br:19][CH2:3][CH:2]1[O:18][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH2:1]1)[NH:10][C:9](=[O:15])[C:8]([CH3:17])([CH3:16])[CH2:7]3
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCc1cc(C)c2c(c1O)=CC(C)(C)C(=O)N=2
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CBr)C2
Yield: 181.5 %

Procedure:
Using 6-allyl-5-hydroxy-3,3,8-trimethylcarbostyril (1.36 g, 3.28 mmol) and N-bromosuccinimide (1.12 g, 6.28 mmol), the procedure of Example 277 was followed (reaction, post-treatment, and recrystallization from chloroform-ether-n-hexane). 1.93 g of the title compound was obtained as colorless needles (94.9%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added phenylacetyl chloride (285 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (578 mg, 93%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50]Br)=[N:48][CH:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>O1CCCC1>[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50][C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[N:48][CH:49]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrCc1ccc(OCc2ccccc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCc2ccccc2)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
540 mg (1.50 mmol) of di-tert-butyl Boc-glutamate (prepared according to J. Peptide Res. 2001, 58, 338) were dissolved in 6 mL of tetrahydrofuran and cooled to −75° C. 3.45 mL (3.45 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise and the mixture was stirred at −75° C. for another 60 minutes. 460 mg (1.65 mmol) of 5-(benzyloxy)-2-(bromomethyl)pyridine in 5 mL of tetrahydrofuran were then added dropwise, and after stirring 2 hours at −75° C., 3.45 mL of 2N aqueous hydrochloric acid were added, and after stirring another 30 minutes at −75° C., the cooling bath was removed and the mixture was allowed to warm up to room temperature. The mixture was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic layer was dried over magnesium sulfate and evaporated. The crude residue was purified by column chromatography on silica gel (ethyl acetate in hexane 0%→100%) to give 610 mg of the desired compound as yellowish oil (66% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH2:10].[Li]CCCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:18]=[O:19])=[C:3]([CH:9]=[CH2:10])[CH:4]=1
Reactant: C=Cc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1cc(F)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a mixture of 1-bromo-4-fluoro-2-vinylbenzene (0.32 g, 1.592 mmol) in tetrahydrofuran (5 mL) at −78° C. was added BuLi (0.764 mL, 1.910 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.185 mL, 2.388 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then warmed to rt and stirred at rt for 3 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated to obtain 4-fluoro-2-vinylbenzaldehyde (0.2 g) as an oil, which was used in the next step without purification. A mixture of 4-fluoro-2-vinylbenzaldehyde (200 mg, 1.332 mmol) and NaBH4 (50.4 mg, 1.332 mmol) in MeOH (2 mL) was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOac/hexane to obtain (4-fluoro-2-vinylphenyl)methanol (150 mg, 0.986 mmol, 74.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J=8.3, 5.9 Hz, 1H), 7.25 (dd, J=10.0, 2.7 Hz, 1H), 7.09-7.02 (m, 1H), 7.02-6.95 (m, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.44 (d, J=11.0 Hz, 1H), 4.75 (d, J=4.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][S:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([S:22][CH3:21])=[CH:24][CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CSc1ccc(CN)cc1
Product: CSc1ccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (200 mg, 0.54 mmol) from above and 4-methylthiobenzylamine (99.0 mg, 0.65 mmol). The title compound was obtained as a solid (100 mg, 19% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.35 (1H, m), 8.98 (2H, s), 8.46 (1H, s), 7.22 (4H, m), 4.35 (2H, m), 2.34 (3H, s). MS m/z: 484.11, 486.14 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(Cl)c1
Temperature: 25 °C

Procedure:
3-Chloro-4-methylbenzonitrile (2.34 g, 15.4 mmol), NBS (3.0 g, 16.9 mmol) and benzoyl peroxide (0.37 g, 1.54 mmol) are taken up in carbon tetrachloride (50 mL, 0.3M) and refluxed until the reaction is judged complete by TLC. The mixture is then allowed to cool to room temperature and is filtered. The filtrate is concentrated and purified via flash column chromatography (0-5% EtOAc/hexanes) to give 4-bromomethyl-3-chlorobenzonitrile as a white solid. HRMS (ESI) m/z 229.9133 (229.9193 calcd for C8H6ClBrN, M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.FC(F)(F)C(O)=O.[CH2:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:49])[C@@H:37]([NH2:48])[CH2:38][CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:32][CH2:31]1)=[O:29])[CH2:24][CH2:25][CH3:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36](=[O:49])[C@@H:37]([NH:48][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:38][CH2:39][O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:34][CH2:35]1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 1.8 g of 4-((S)-2-Amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid butyl ester trifluoroacetate in 12 ml of DMF, 566 mg of NEM, 1.1 g of HOBT and 1.4 g of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 650 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([S:36]([F:38])([F:39])([F:40])([F:41])[F:37])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(S(C)(=O)=O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
66 mg (0.228 mmol) of the compound of Example 6A and 74 mg (0.228 mmol) of the compound of Example 32A were dissolved in 1.5 ml of anhydrous DMF, and 104 mg (0.273 mmol) of HATU and 48 μl (0.273 mmol) of N,N-diisopropylethylamine were added in succession. The reaction mixture was stirred at RT for 4 h and then separated completely into its components by preparative HPLC (Method 9). The product fractions were combined and concentrated to dryness on a rotary evaporator. This gave the title compound in the form of its formic acid salt. For conversion into the salt-free form, the formate was dissolved in about 5 ml of methanol and passed over a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol). After re-evaporation, the residue was triturated with a little diisopropyl ether at RT. Filtration with suction and drying of the solid under high vacuum gave 72.6 mg (53% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br>CC(O)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][C:11]=2[N:10]=[C:9]1[CH:18]([Br:21])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2c(c(=O)n1Cc1ccccc1)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: CCC(Br)c1nc2c(c(=O)n1Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-benzyl-2-propyl-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-2, 0.52 g, 1.93 mmol) was dissolved in AcOH (3.0 mL) and treated with Br2 neat (0.11 mL, 2.13 mmol). The reaction was stirred overnight at 25° C. and then concentrated. The residue was purified by preparative thin layer chromatography (SiO2, 40% EtOAc/hexanes) to yield 3-benzyl-2-(1-bromopropyl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (1-3). 1H NMR (300 MHz, CDCl3) δ 7.33 (m, 4H), 7.26 (d, 1H obscured), 6.15 (d, J=16.1 Hz, 1H), 4.80 (d, J=16.1 Hz, 1H), 4.58 (t, J=7.3 Hz, 1H), 2.92 (m, 4H), 2.36 (m, 1H), 2.12 (m, 3H), 0.69 (t, J=7.3 Hz, 3H). MS 347.0 found 347.3 required.
Reaction SMILES: CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C:45]1=[O:50]>CC(N(C)C)=O>[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]5[N:34]([C:36]([C:39]([F:40])([F:41])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:46][C:45]1=[O:50]
Reactant: CN1CCNCC1=O
Reactant: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1=O
Temperature: 110 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
DIPEA (15.27 mL, 87.69 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (14.19 g, 29.23 mmol) and 1-methylpiperazin-2-one (CAS 59702-07-7, 3.67 g, 32.15 mmol) in DMA (70 mL). The resulting solution was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature, absorbed onto silica, evaporated to dryness and then purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated and the resulting gum was scratched with ether until solid. The solid was stirred in ether (100 mL) for 4 hours then collected by filtration and dried to give 1-methyl-4-[2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one (10.08 g, 68.5%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8].[Cu](C#N)[C:14]#[N:15]>>[C:14]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([NH:9][CH2:10][CH3:11])=[O:8])#[N:15]
Reactant: CCNC(=O)c1cncc(Br)c1
Reactant: N#C[Cu]C#N
Product: CCNC(=O)c1cncc(C#N)c1
Yield: 31.8 %

Procedure:
By the reaction in the same manner as in Example 42-ii) using 5-bromo-N-ethylnicotinamide (580 mg) and copper cyanide (350 mg), the title compound (141 mg) was obtained as colorless powder crystals.