Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:22]([N:24]2[CH2:41][CH2:40][CH2:39][C@H:25]2[C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])=[CH:10][CH:9]=1)=[O:7])([OH:3])=O.Cl.[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[C:1]([CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:22]([N:24]2[CH2:41][CH2:40][CH2:39][C@H:25]2[C:26]([NH:28][CH:29]([CH:36]([CH3:37])[CH3:38])[C:30](=[O:35])[C:31]([F:34])([F:32])[F:33])=[O:27])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])=[CH:12][CH:13]=1)=[O:7])=[O:3]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Nc1ccc(C(=O)NCC(=O)O)cc1)C(C)C)C(=O)C(F)(F)F
Reactant: CNC
Agent: Cl
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Nc1ccc(C(=O)NCC(=O)N(C)C)cc1)C(C)C)C(=O)C(F)(F)F
Yield: 35.8 %

Procedure:
3(RS)-[[4-(Dimethylaminocarbonylmethylaminocarbonyl)phenylaminocarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-2-oxo-4-methylpentane (0.03 g) was prepared from 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylaminocarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-2-oxo-4-methylpentane (0.08 g) and dimethylamine hydrochloride (0.012 g) by a similar method to that of Example 1.
Reaction SMILES: [Cl:1][C:2]1([S:8](Cl)(=[O:10])=[O:9])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH3:14])[S:8]([C:2]1([Cl:1])[NH:6][C:5]([Cl:7])=[CH:4][S:3]1)(=[O:10])=[O:9]
Reactant: CNC
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Product: CN(C)S(=O)(=O)C1(Cl)NC(Cl)=CS1

Procedure:
In analogy to Example 2, the N,N-dimethyl-2,4-dichlorothiazole-sulphonamide was prepared by reacting 2,4-dichlorothiazole-sulphonyl chloride from Example 1 with 45% strength dimethylamine solution. Following recrystallization from petroleum ether/acetone 6:1, 21.7 g of product were obtained (83% of the theoretical yield), m.p.: 89°-90° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[O:8]([CH2:15][CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][C:19]=1[NH2:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:28][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[NH:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:6]
Reactant: Nc1cnc2ccccc2c1NCCOc1ccccc1
Reactant: COCCC(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: COCCC(=O)Nc1cnc2ccccc2c1NCCOc1ccccc1
Yield: 110.2 %

Procedure:
3-methoxypropanoyl chloride (0.86 ml, 7.9 mmol) was added dropwise over a 30 minute period to a chilled (ice bath) solution of N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol) in dichloromethane (100 ml). After a few hours, a precipitate formed. The solvent volume was reduced under vacuum to near dryness and hexane (100 ml) was added. Vacuum filtration provided 2.9 g of 3-methoxy—N-{4-[(2-phenoxyethyl)amino]quinolin-3-yl}propanamide as a hydrochloride salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:10][C:2]1=2.O=[C:20]([C:26](OCC)=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:12]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:18]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]3=[O:27])[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1ccccc1Nc1ccc2c(c1)OCCO2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Yield: 62.2 %

Procedure:
5.0 g (21 mmol) of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzene-1,2-diamine and 3.9 g (22 mmol) of diethyl ketomalonate were dissolved in toluene (60 ml), and the solution was heated to reflux for 12 hours while removing water using a Dean-Stark apparatus. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=2:3) to obtain 4.6 g (yield: 63%) of ethyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a milky yellow powder.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2([CH2:14][C:13](=[O:15])[C:12]3[C:16]([OH:23])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=3[O:10]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([CH2:14][C:13](=[O:15])[C:12]3[C:16]([O:23][CH3:24])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=3[O:10]2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCC2(CC1)CC(=O)c1c(ccc([N+](=O)[O-])c1O)O2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c([N+](=O)[O-])ccc2c1C(=O)CC1(CCN(C(C)=O)CC1)O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 101.7 %

Procedure:
A mixture of 1'-acetyl-3,4-dihydro-5-hydroxy-6-nitro-spiro[2H-1-benzopyran-2,4'-piperidine]-4-one (3.84 g, 12 mmol), potassium carbonate (1.66 g, 12 mmol) and methyl iodide (3.74 ml, 8.51 g, 60 mmol) in DMF (30 ml) was stirred in a sealed vessel at room temperature for 3 days, adding further portions of methyl iodide (1 ml) after 24 and 48 h. The solvent was evaporated under reduced pressure, water (60 ml) was added, the pH was adjusted to 6.5 with HCl-H2O (2M) and the mixture was extracted with methylene chloride (3×60 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The crude product was re-subjected to the above procedure, the solvent was evaporated under reduced pressure, water (60 ml) was added and the mixture was extracted with methylene chloride (3×60 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure to give the ketone (4.08 g) as a yellow solid, m.p. 160°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)=[C:11]=[O:12]>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([NH:10][C:11]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=2[F:9])=[O:12])=[CH:14][CH:15]=1)[CH3:21]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (0.5 g, 0.0026 mol) and TEA (0.38 mL, 0.0026 mol) in DCM (15 mL) was added ethyl 4-isocyanatobenzoate (0.503 g, 0.0026 mol). The reaction mixture was stirred at room temperature for 3 h. The white solid was obtained and was filtered and dried to afford the title compound [0.7 g, 70%]; LC-MS (ESI): Calculated mass: 380.0; Observed mass: 381.0 [M+H]+ (RT: 1.78 min).
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH2:10])([CH2:4]3)[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27])=[O:20]>CS(C)=O.CCOC(C)=O>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27])=[O:20])([CH2:4]3)[CH2:2]2
Reactant: NC12CC3CC(CC1C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a stirred mixture of tricyclo[3.3.1.03,7]nonan-3-amine (0.28 g, 2.0 mmol) and K2CO3 (0.83 g, 6.0 mmol) in DMSO (8 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.34 g, 2.0 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[(tricyclo[3.3.1.03,7]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile as a viscous liquid (0.23 g) in 42% yield. m/z (M+1) 274; 1H NMR (CDCl3) 300 MHz δ 4.87-4.76 (m, 1H), 3.71-3.40 (m, 2H), 3.41 (s, 2H), 2.35-2.05 (m, 7H), 1.92-1.74 (m, 6H), 1.68-1.48 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH3:13]
Reactant: CCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C=O)cc1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (0.5 g, 4.1 mmol), 1-bromopropane (0.3 ml) and K2CO3 (0.69 g, 5 mmol) in anhydrous DMF (5 ml) was stirred for 1 h at reflux. This was diluted to 100 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title compound (0.55 g, 82.3%), as yellow oil 1H-NMR (CDCl3) 1.0 (tr, 3H, J=7.41 Hz); 1.7-2.0 (m, 2H); 3.95 (tr, 2H, J=6.57 Hz); 6.95 (d, 2H, J=8.73 Hz); 8.00 (d, 2H, J=8.76 Hz).
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][C:9]([N:11]2[CH2:15][C:14]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]=5[C:13]=3[CH2:12]2)[CH:19]=[CH:18][CH:17]=4)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:32]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:9][N:11]2[CH2:15][C:14]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]=5[C:13]=3[CH2:12]2)[CH:19]=[CH:18][CH:17]=4)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC2=C(C1)c1cccc3cccc2c13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C(CCN2CC3=C(C2)c2cccc4cccc3c24)(c2ccccc2)c2ccccc2)cc1

Procedure:
Following the procedures set out in Example 1, 3.0 parts of 3,3,3-triphenylpropionyl chloride and 2.0 parts of acenaphto[1,2-C]pyrrolidene are reacted to provide 8-(3,3,3-triphenylpropionyl)acenaphto[1,2-C]pyrroldine, melting at 159°-168°. 3.5 Parts of this amide are reacted with 3.6 parts of lithium aluminum hydride in tetrahydrofuran to provide 8-(3,3,3-triphenylpropyl)acenaphtho[1,2-C]pyrrolidine. This compound has the following structural formula. ##STR44##
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:8]=1[C:9]([O:11]C(C)(C)C)=[O:10])=[O:5]>FC(F)(F)C(O)=O>[OH:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:8]=1[C:9]([OH:11])=[O:10])=[O:5]
Reactant: CN1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Trifluoroacetic acid (10 mL) was added to the obtained tert-butyl 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (1.2 g), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and a 30% aqueous solution of methanol was added to the residue. After adjusting the pH to 6.7 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected from the reaction mixture by filtration to obtain 0.86 g of 2-(2-hydroxy-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoic acid.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][CH2:61][C@H:60]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([C@@H:64]([C@@H:60]2[CH2:61][CH2:62][CH2:63][N:59]2[C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:58])[C:65]([N:16]2[CH2:15][CH2:14][N:13]([C:5]3[C:4]([CH3:3])=[CH:9][N:8]=[C:7]4[NH:10][N:11]=[CH:12][C:6]=34)[CH2:18][CH2:17]2)=[O:66])=[CH:73][CH:72]=1
Reactant: Cc1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc2[nH]ncc2c1N1CCN(C(=O)[C@@H](c2ccc(Cl)cc2)[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Yield: 67 %

Procedure:
A solution of 5-methyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (75 mg, 0.194 mmol), diisopropylethylamine (135 μL, 0.775 mmol), HATU (73.7 mg, 0.194 mmol) and (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (79.0 mg, 0.233 mmol, see Example C) in DMF (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The resulting residue was redissolved in THF (5 mL) and treated with an aqueous solution of LiOH (2 mL, 0.5M) for 30 minutes. Next, the solvent was removed, and the resulting residue was suspended in EtOAc (50 mL) and washed with water (2×10 mL). The dried (MgSO4) organic phase was concentrated in vacuo, and the resulting residue was purified by reverse phase chromatography (Biotage, C-18 12M+) on Biotage SP4 unit using a gradient of 5-80% CH3CN/water to provide (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-(4-(5-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (70 mg, 0.130 mmol, 67.0% yield) as a solid after drying under high vacuum. LCMS (APCI+) m/z 539.2, 541.2 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:9][NH:10][C:11]1[N:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([N:27]3[CH2:32][CH2:31][C@@H:30]([NH:33][C:34]([C:36]4[NH:37][C:38]([CH3:43])=[C:39]([Cl:42])[C:40]=4[Cl:41])=[O:35])[C@@H:29]([O:44][CH3:45])[CH2:28]3)[S:20][C:21]=2[C:22]([O:24]CC)=[O:23])=[N:15][CH:16]=1.O.[OH-].[Li+]>CO.O>[N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:9][NH:10][C:11]1[N:12]=[CH:13][C:14]([C:17]2[N:18]=[C:19]([N:27]3[CH2:32][CH2:31][C@@H:30]([NH:33][C:34]([C:36]4[NH:37][C:38]([CH3:43])=[C:39]([Cl:42])[C:40]=4[Cl:41])=[O:35])[C@@H:29]([O:44][CH3:45])[CH2:28]3)[S:20][C:21]=2[C:22]([OH:24])=[O:23])=[N:15][CH:16]=1
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1-c1cnc(NCC2CN3CCN2CC3)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CO[C@H]1CN(c2nc(-c3cnc(NCC4CN5CCN4CC5)cn3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
Ethyl 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 194, 100 mg, 0.14 mmol) was dissolved in methanol (3 mL) and water (1 mL). Lithium hydroxide monohydrate (18 mg, 0.44 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The methanol was completely evaporated. The resulting crude product was taken in water (20 mL) and acidified to pH 6 with 2N hydrochloric acid (1.0 mL). The aqueous layer was concentrated to a residue, which was purified by preparative thin layer chromatography to afford 64 mg (66.8%) of 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylic acid as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]O.Cl[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1.[I-].[K+]>C(N(CC)CC)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: NCCCCCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCCCCN2CCCCC2)nc1

Procedure:
Synthesis and purification were performed according to the procedure stated in example 152 using reagents 5-aminopentanol (15 mmol), 2-chloro-5-nitropyridine (15 mmol), 5 ml of triethylamine, and catalytic amounts of potassium iodide in the first step. The final product was purified by column chromatography (eluent: ethyl acetate/triethylamine (90/10)). The solvent was removed under reduced pressure. The residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][Si:15]([CH3:25])([CH3:24])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:26]1([P:32](Cl)(Cl)=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCCCCC.C1CCCCC1>[C:26]1([P:32]2(=[O:33])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][N:16]2[Si:15]([CH3:25])([CH3:24])[CH3:14])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: C[Si](C)(C)NCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: C[Si](C)(C)N1Cc2ccccc2P1(=O)c1ccccc1
Temperature: 26 °C
Reaction time: 16 h

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (16 g, 0.25 mol) in hexane was added to a solution of tetramethylethylenediamine (28.6 g, 0.246 mol) in 120 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-trimethylsilylbenzylamine (21.6 g, 0.12 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 16 hours at 26° C. and then cooled to -76° C. using a solid carbon dioxide-acetone bath. A solution of phenylphosphonic dichloride (25 g, 0.128 mol) in 120 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -15° C. The reaction mixture was allowed to cool to -76° C., after which time the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 3 hours. The reaction mixture was cooled to 0° C., then quenched with the rapid addition of 24 ml. of acetic acid. After stirring the reaction mixture for 5 minutes, the cyclohexane was removed on a rotary evaporator, and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to yield an oil. Distillation of this oil at 180° C. and 0.3 mm yielded 1-phenyl-2-trimethylsilyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[CH3:18][O:19][C:20]([C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][C:24]([OH:32])([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:21]>>[CH3:18][O:19][C:20]([C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][C:24]([O:32][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:25]3)[CH2:23]1)[CH2:29]2)=[O:21]
Reactant: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(C1)CC(C(=O)OC)(C3)C2
Yield: 87 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1-methoxycarbonyl-3-hydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1-methoxycarbonyl-3-acryloyloxyadamantane (yield: 87%, white solid) was obtained.
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])[N:5]=1)C.[NH2:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[C:16]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:15]=1>O1CCCC1.CO>[CH2:10]([O:9][C:8]1[C:4]([N:31]2[CH2:32][CH2:33][N:28]([C:16]3[N:15]=[C:14]([NH2:13])[C:23]4[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=4)[N:17]=3)[CH2:29][CH2:30]2)=[N:5][S:6](=[O:12])[N:7]=1)[CH3:11]
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CCOC1=NS(=O)N=C1OCC
Solvent: C1CCOC1
Solvent: CO
Product: CCOC1=NS(=O)N=C1N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.9 g (10 mMoles) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide are added to 2.9 g (10 mMoles) of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline dissolved in 50 ml of tetrahydrofuran and 10 ml of methanol, followed by stirring for 5 hours at room temperature. The solid accumulating is separated off and recrystallized from 15 ml of dimethyl formamide and 10 ml of ethanol.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30](O)=[O:31])=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1.[O:47]1[CH2:51][CH2:50][C@@H:49]([NH2:52])[CH2:48]1>>[O:47]1[CH2:51][CH2:50][C@@H:49]([NH:52][C:30](=[O:31])[CH:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:34])[F:1])=[O:6])[CH:9]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:24][CH:25]=2)[CH3:33])[CH2:48]1
Reactant: N[C@@H]1CCOC1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C(=O)N[C@@H]1CCOC1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and (3R)-tetrahydrofuran-3-amine 4-methylbenzenesulfonate (Fluka, Cat. No. 09440). LCMS (M+H)+: m/z=553.2.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[O:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: c1ccoc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3cccnc3F)c2)cn1)c1ccco1

Procedure:
This compound is prepared by method C using compound 12i and furane
Reaction SMILES: Cl.[F:2][C:3]([F:32])([F:31])[C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8].[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(CC)CC)C>O1CCCC1>[F:30][C:27]([F:29])([F:28])[C:25]1[CH:24]=[C:6]([CH:5]=[C:4]([C:3]([F:2])([F:31])[F:32])[CH:26]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)[CH2:11][C@H:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)=[O:8]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C[C@H]1Cc1ccc(Cl)c(Cl)c1
Yield: 71.4 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine hydrochloride (200 mg), 4-nitrobenzyl chloride (158 mg) and triethylamine (268 μl) in tetrahydrofuran (5 ml) was refluxed overnight. After cooling, the precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-nitrobenzyl)piperazine (169.8 mg).