Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O1CCOCC1>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:15]#[N:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(C)C)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)O)cc1C#N
Temperature: 60 °C
Yield: 97.8 %

Procedure:
A mixture of methyl 4-tert-butyl-3-cyano-benzoate (380 mg, 1.75 mmol), LiOH (3.5 mL of 2.0 M, 7.0 mmol) and 1,4-dioxane (3.5 mL) was heated at 60° C. for 2 h. The reaction mixture was made acidic and was washed with dichloromethane (2×8 mL). The organics were combined, dried over sodium sulfate and evaporated to dryness to give 4-tert-butyl-3-cyanobenzoic acid (348 mg, 98%). 1H NMR (400 MHz, CD3CN) δ 9.77 (s, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.17 (dd, J=8.4, 1.9 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 1.55 (s, 9H). 4-Cyano-3-methylbenzoic acid was also prepared using the procedures described above.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([OH:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][CH:4]([O:18][C:24](=[O:25])[NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)=[O:6]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(O)CCBr
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)OC(CCBr)C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
By a procedure similar to that described in Step 1a above, 4-bromo-2-hydroxy-N(3-trifluoromethylphenyl)butanamide (0.52 g, prepared as described in Example 10, Step 1b above) was treated with t-butylisocyanate and triethylamine in dichloromethane to give the title compound (0.03 g, m.p. 107°-109° C.). NMR (CDCl3): δ 1.4(9H,s); 2.4(2H,m); 3.6(2H,t); 5.1(1H,bs); 5.3(1H,t); 7.3(2H,m); 7.6(1H,d); 7.8(1H,bs); 8.8(1H,bs). MS: M+ 424, 426. Under the extended time of this reaction, the major product was that of base-catalysed cyclisation (0.16 g, m.p. 114°-116° C.), identical to material described in Example 10, Step 3 above and Example 11, Step 2 below.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[C:10]([CH:12]1[CH2:14][NH:13]1)#[N:11].C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>C(OCC)C.O1CCCC1>[CH3:1][C:2]1[S:3][C:4]([C:7]([N:13]2[CH2:14][CH:12]2[C:10]#[N:11])=[O:9])=[CH:5][N:6]=1
Reactant: N#CC1CN1
Reactant: Cc1ncc(C(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ncc(C(=O)N2CC2C#N)s1
Reaction time: 8 h

Procedure:
1.6 g. 2-Methylthiazole-5-carboxylic acid (m.p. 209° C.) and 0.76 g. 2-cyanoaziridine in 20 ml. tetrahydrofuran are mixed at 0° to 5° C. with 2.4 g. dicyclohexylcarbodiimide. The reaction mixture is stirred for 1 hour at 0° C. and for 3 hours at ambient temperature, whereafter the precipitated dicyclohexylurea is filtered off with suction and washed with the above-mentioned solvent and with diethyl ether. The filtrate is evaporated in a vacuum and the evaporation residue is taken up in ethyl acetate and shaken out with a saturated aqueous solution of sodium bicarbonate. The organic phase is dried and evaporated in a vacuum to give 2.38 g. of an oil. This oily residue is dissolved in 90 ml. diethyl ether, left to stand overnight, precipitated dicyclohexylurea is filtered off with suction, the ethereal solution is evaporated and the evaporation residue is triturated with a little diethyl ether, 1.4 g. 1-(2-methylthiazole-5-carbonyl)-2-cyanoaziridine being obtained; m.p. 90°- 92° C.
Reaction SMILES: Cl.[NH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[C:3]([NH2:5])=[NH:4].Cl.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28](O)[OH:29].C(O)(=O)CCCC(O)=O.Cl.Cl.Cl.NCCCC(N)CCCNC(=O)C(NC(=O)CCCCCCNC(N)=N)O>O>[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH:28]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[OH:29]
Reactant: NCCCNCCCCNC(=O)C(O)O
Reactant: N=C(N)NCCCCCCC(N)=O
Agent: Cl
Agent: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCC(N)CCCN
Agent: O=C(O)CCCC(=O)O
Solvent: O
Product: N=C(N)NCCCCCCC(=O)NC(O)C(=O)NCCCCNCCCN
Temperature: 60 °C
Yield: 50.5 %

Procedure:
A mixture of 360 mg (1.62 mmoles) of 7-guanidinoheptanamide hydrochloride, 568 mg (1.94 mmoles) of N-[4-(3-aminopropyl)aminobutyl]-2,2-dihydroxyethanamide dihydrochloride, 214 mg (1.62 mmoles) of glutaric acid and 0.36 ml of water was heated at 60° C. for 24 hours. After completion of the reaction, 5 ml of water was added to the reaction mixture and the resulting mixture was purified in a manner similar to that in Example 1, using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to obtain 317 mg (39% yield) of a white powder of N-[4-(3-aminopropyl)-aminobutyl]-2-(7-guanidinoheptanamido)-2-hydroxyethanamide trihydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].O=S(Cl)Cl.[CH3:21][O:22][C:23](=[O:33])[C:24]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:25]=1[NH2:32].CCCCCC>CCOC(C)=O>[CH3:21][O:22][C:23](=[O:33])[C:24]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:25]=1[NH:32][C:10](=[O:12])[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=1)[CH3:13]
Reactant: COC(=O)c1c(N)cc(Br)cc1Br
Reactant: COc1ccc(C(C)C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1c(Br)cc(Br)cc1NC(=O)C(C)c1ccc(OC)c([N+](=O)[O-])c1
Yield: 59.3 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-methoxy-3-nitro-phenyl)-propionic acid (0.22 g, 0.98 mmol), SOCl2 (0.35 mL, 0.49 mmol), and 2-amino-4,6-dibromo-benzoic acid methyl ester (0.15 g, 0.49 mmol). After normal workup, the pure objective compound (0.15 g, 59%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=3:1): 1H NMR (200 MHz, DMSO-d6) δ 1.39 (d, J=6.8 Hz, 3H, CH3), 3.55 (s, 3H, OCH3), 3.88 (s, 3H, CO2CH3), 3.89 (m, 1H, CH), 7.32 (d, J=9.0 Hz, 1H, ArH), 7.63 (dd, J=8.8, 1.8 Hz, 1H, ArH), 7.80-7.84 (m, 2H, ArH), 8.13-8.15 (m, 1H, ArH).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[C:22]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][CH2:30][NH:31][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: NCCCc1ccccc1
Product: Cn1c(C(=O)NCCCc2ccccc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and 3-phenylpropylamine the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=309.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(N3CCOCC3)nncc2c1
Temperature: 180 °C

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.1 g, 411 μmol), morpholine (72 mg, 821 μmol) and potassium carbonate (57 mg, 411 μmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. All the starting material was converted to product (M+1=296, 298). The mixture was concentrated under vacuum, and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give 6-bromo-1-morpholinophthalazine as yellow solid. Found MS (ES+): 296, 298(M+H)+.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C([O-])(=O)C.[Na+].CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.[CH3:33][CH:34]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39]>ClCCl>[CH3:33][CH:34]([O:41][CH2:42][CH2:43][CH2:44][CH:45]=[O:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40]
Reactant: CC(C)CCCC(C)OCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: CC(C)CCCC(C)OCCCC=O
Yield: 82 %

Procedure:
A 250 mL 3-necked flask was equipped with a thermocouple pocket, magnetic stirrer and condenser. PCC (13.9 g, 0.64 mols), sodium acetate (1.22 g, 0.015 mol), stavox (0.01 g) and dichloromethane (100 mL) were added to the flask. 4-[(1,5-dimethylhexyl)oxy]butan-1-ol (10.0 g, 0.05 mol) was added over 5 minutes with stirring. The reaction was stirred for 3 hrs at room temperature. After this time the reaction mixture contained ca. 82% of the desired product (RPA GC).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.Br[CH2:16][C:17]#[N:18]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17]#[N:18])[CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: CN1CCC(CN2CCNCC2)CC1
Product: CN1CCC(CN2CCN(CC#N)CC2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(1-Methyl-piperidin-4-ylmethyl)-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=237.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[O:14]1[C:18]2([CH2:23][CH2:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:12][C:11]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7][C:8]([C:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH:20]=2)=[CH:9][CH:10]=1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: CCOC(=O)c1nc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(C2=CCC3(CC2)OCCO3)ccc1N

Procedure:
A mixture of 3-amino-6-bromopyridine-2-carboxylic acid ethyl ester-(Compound 232G, 0.31 g, 1.3 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-boronic acid pinacol ester (0.406 g, 1.52 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(11), complex with dichloromethane (1:1) (0.10 g, 0.12 mmol) in a 35 mL sealable microwave tube was taken up in 1,4-Dioxane (4.9 mL). This mixture was treated with a solution of Potassium carbonate (0.52 g, 3.8 mmol) in H2O (1 mL), flushed with nitrogen, sealed and irradiated in a microwave reactor for 30 minutes at 100° C. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 filtered and concentrated to a brown residue. This was taken up in DCM, treated with silica and concentrated. The resulting silica plug was loaded on to a sample cartridge and purified on an ISCO Combiflash system (0-50% EtOAc/Heptane) to isolate the desired product as 247 mg of an oil which crystallized upon standing. 1H NMR (400 MHz, DMSO-d6) d 1.30 (t, J=7.20 Hz, 3H), 1.77 (t, J=6.44 Hz, 2H), 2.32-2.40 (m, 2H), 2.60 (td, J=6.44, 1.52 Hz, 2H), 3.91 (s, 4H), 4.28 (q, J=7.07 Hz, 2H), 6.25 (t, J=4.04 Hz, 1H), 6.65 (s, 2H), 7.17 (d, J=8.84 Hz, 1H), 7.52 (d, J=8.84 Hz, 1H). MS (ES+): m/z=305.12 (100) [M+1]. HPLC: tR=3.50 min (ZQ3, polar—5 min).
Reaction SMILES: ClC1C2C=CC=CC=2SN=1.[O:11]=[S:12]1(=[O:30])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[N:13]1.Cl.C(OC(=O)CCCN)C.C(N(CC)CC)C>O1CCOCC1>[O:11]=[S:12]1(=[O:30])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[N:13]1
Reactant: CCOC(=O)CCCNC1=NS(=O)(=O)c2ccccc21
Agent: CCOC(=O)CCCN
Agent: Cl
Agent: Clc1nsc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)CCCNC1=NS(=O)(=O)c2ccccc21

Procedure:
5.68 g. (28.1 mM) of 3-chloro-1,2-benzisothiazole, 1,1-dioxide (prepared as in Example 1), 4.8 g. (28.1 mM) of ethyl-4-aminobutyrate hydrochloride and 7.84 ml. (56.2 mM) of triethylamine are refluxed in 100 ml. of dioxane for one hour. The solvent is evaporated and the residue refluxed in 1% hydrochloric acid for 2.5 hours. The product crystallizes out overnight at room temperature. The product, 4-[(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]butanoic acid is filtered out, washed with water, and recrystallized from 150 ml. water, yield 4.2 g., m.p. 200°-202°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH3:27]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH3:27])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: CNCCOC
Product: COCCN(C)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and N-(2-methoxyethyl)methylamine were converted to yield {3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-(2-methoxy-ethyl)-methyl-amine as colorless oil, MS: 374 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[N:8][C:6]=2[N:7]=1.[CH2:28]([C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[N:8][C:6]=3[N:7]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CC(C)(O)C1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2sc(CN3CCC(C(C)(C)O)CC3)nc2n1
Yield: 37.1 %

Procedure:
A mixture of 2-[1-(5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (100 mg, 0.243 mmol), 2-ethyl-1H-benzoimidazole (39 mg, 0.267 mmol), Pd2(dba)3 (11 mg, 0.0122 mmol), XPhos (23 mg, 0.049 mmol) and cesium carbonate (158 mg, 0.486 mmol) in 1,4-dioxane (1.5 mL) was purged with argon gas for 15 min. The resulting reaction mixture was irradiated with microwaves at 150° C. for 30 min. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si—PCC, 2 M NH3 in MeOH:DCM: gradient 0:100 to 5:95) to afford 420 as a brown solid (47 mg, 37%) LCMS (Method I): RT 2.53 min, [M+H]+ 522. 1H NMR (400 MHz, CDCl3): δ 8.11 (1 H, m), 7.77-7.70 (1 H, m), 7.23 (2 H, m), 4.01-3.99 (6 H, m), 3.87 (5H, m), 3.42-3.39 (2 H, m), 3.10 (2 H, m), 2.27 (2 H, m), 1.79 (2 H, m), 1.50 (2 H, d, m), 1.46-1.40 (3 H, m), 1.32 (1 H, m), 1.20 (6 H, s)
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(C(C)=O)C>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:1][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc(O)cc1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Under a nitrogen atmosphere, p-aminophenol (109 g) was suspended in methyl ethyl ketone (2000 ml). To this suspension was added triethylamine (253 g) and then was added nonadecanoyl chloride (331 g), followed by refluxing with heating for 2 hours. The reaction mixture was cooled to room temperature to precipitate a white crystal. This crystal was filtered off under reduced pressure and recrystallized from methyl ethyl ketone to obtain 323 g of the desired product. Yield 80%; m.p. 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.Cl(O)(=O)(=O)=O.[H][H]>C(O)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)CCC(O)c1ccc(-c2ccccc2Cl)cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(-c2ccccc2Cl)cc1
Yield: 70 %

Procedure:
18.6 gm of 4-(2'-chloro-4-biphenylyl)-4-hydroxybutyric acid (obtained by acidifying 20 gm of its sodium salt and extraction with ethyl acetate) were hydrogenated in 200 ml of glacial acetic acid in the presence of 2 ml of perchloric acid and in the presence of palladium/barium sulfate (5%) at room temperature and at a hydrogen pressure of 5 atmospheres. After filtration, the solvent was evaporated and the residue admixed with water; the crystalline acid was collected and dried. Yield: 70% of theory; m.p. 60°-61° C. (from petroleum ether). Melting point of the cyclohexylamine salt: 143°-144° C. (from water).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:28][CH:27]1[C:39]([NH2:41])=[O:40])=[O:25].[ClH:42]>C(OCC)(=O)C>[ClH:42].[ClH:42].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:28][CH:27]1[C:39]([NH2:41])=[O:40])=[O:25]
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Reaction time: 0.75 h

Procedure:
1-(2-methoxy-4-(1-Boc-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide (423 mg, 0.75 mmol) was stirred in ethyl acetate (4 ml) in an ice bath under nitrogen. A cold, saturated solution (4 ml) of HCl in ethyl acetate was added and the mixture stirred in the cold for 45 min. Nitrogen gas was passed through the mixture for 1 hour, and the reaction was concentrated in vacuo. The residue was reconcentrated from methanol and from ether to give 1-(2-methoxy-4-(4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)piperazine-2-carboxamide dihydrochloride.
Reaction SMILES: [CH2:1]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[C:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:11]=2[NH:10][C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH2:34](I)[CH3:35]>>[CH2:1]([CH:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[C:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[CH:24][C:11]=2[N:10]([CH2:34][CH3:35])[C:9]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2
Solvent: CI
Product: CCOc1cc2c(cc1OCC)N(CC)C(=O)C(Cc1ccccc1)N=C2c1ccccc1
Yield: 36 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 3-benzyl-7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaj), and MeI by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 36%. M: 128–130° C. 1H-NMR (CDCl3, 200 MHz): d 1.10 (t, 3H, CH3), 1.40 (t, 3H, CH3), 1.55 (t, 3H, CH3), 3.66 (m, 3H, CH2Ph+CH), 3.94 (q, 2H, —OCH2), 4.15 (AB system, ? d=0.52, JAB=13.2, 2H, —NCH2), 4.19 (q, 2H, —OCH2), 6.67 (s, 1H Ar), 6.85 (s, 1H Ar), 7.33–7.63 (m, 10H Ar).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1)#[N:2].CC[N:35](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:35])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
The reaction was carried out under argon. (4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (6.0 g, 11.4 mmol, purity 85%), DMAP (140 mg, 1.143 mmol; 0.1 eq.), DIEA (1.77 g, 13.7 mmol; 1.2 eq.) and PyBOP (7.14 g, 13.71 mmol; 1.2 eq.) were initially charged in dry THF (34 ml) at RT, after brief stirring (15 min), a 0.5 M ammonia solution in THF (5 eq., 57.1 mmol) was added and the mixture was then stirred at RT for 1 h. Ethyl acetate (250 ml) was then added to the reaction mixture. The organic phase was washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (mobile phase: dichloromethane/methanol 20:1). The title compound was obtained as a colorless solid (5.0 g, 98% of theory).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([C:36]([O:38]CC)=[O:37])=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].[OH-].[K+]>C(O)C>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([CH2:17][NH:16][C:14]2[CH:15]=[C:10]([NH:9][C:6]3[CH:5]=[N:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[N:11]=[CH:12][C:13]=2[N:31]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32]2)[CH2:19]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)c1ccn(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C(=O)O)c2)C1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
tert-Butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-(ethoxycarbonyl)-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (42 mg, 0.077 mmol) was dissolved in ethanol (1 mL). KOH (43 mg, 0.770 mmol) was added and the solution was stirred at 50° C. for 72 h. The reaction mixture was evaporated to dryness and the residue was partitioned between water and dichloromethane. The two phases were separated and the organic phase was extracted with water. The combined aqueous phases were neutralised to pH 7 by the addition of 1M HCl and then evaporated to dryness. The product (7 mg, 17%) was used directly in the next step without further purification.