Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:12]=2)/[C:3]([OH:27])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1S(C)(=O)=O
Temperature: 47.5 °C
Yield: 99.4 %

Procedure:
A solution of (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (273 mg, 0.7 mmol) in ethanol (5 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (20 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclopentyl-2-[3-methanesulfonyl-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (262 mg, 100%) as a yellow solid: EI-HRMS m/e calcd for C17H20N4O4S (M+) 376.1205, found 376.1204.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:16]([CH3:32])=[N:17][C:18]([N:21]3[CH2:25][CH2:24][C@@H:23]([N:26]4[CH2:30][CH2:29][CH2:28][C@@H:27]4[CH3:31])[CH2:22]3)=[CH:19][CH:20]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O>CO.C(Cl)Cl>[CH3:32][C:16]1[C:15]([N:14]2[CH2:13][CH2:12][CH2:11][C:5]3([CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)[C:3]2=[O:2])=[CH:20][CH:19]=[C:18]([N:21]2[CH2:25][CH2:24][C@@H:23]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])[CH2:22]2)[N:17]=1.[NH3:14]
Reactant: COC(=O)C1(CCCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCCC2(CCOCC2)C1=O
Product: N
Yield: 5 %

Procedure:
The title compound is synthesized in essentially the same manner using the procedures as set forth in Step 2 of Example 1, by cyclizing 4-{3-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamino]-propyl}-tetrahydro-pyran-4-carboxylic acid methyl ester (44 mg, 0.10 mmol) to obtain 13.5 mg (33% yield over two steps) of the title compound after flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNS(=O)(=O)c1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To 4-cyano-benzenesulfonyl chloride in dichloromethane (10 mL) was added amino-acetic acid methyl ester hydrochloride (250 mg, 2 mmol) and triethylamine (1.01 g, 10 mmol). The mixture was stirred for 20 min at r.t and was washed with water. The crude was triturated in methanol to give (4-cyano-benzenesulfonylamino)-acetic acid methyl ester (240 mg, 47%). This material was dissolved in NH3 in methanol (30 mL) followed by addition of Raney Ni (3 g). The mixture was hydrogenated under H2 (60 psi, 1 h, r.t) to provide the title compound (1:5, 230 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3c(OC)cccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methoxy-phenylboronic acid to give [1-(3-methoxy-phenyl)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19].C1(N=C=NC2CCCCC2)CCCCC1.Cl>CC(C)=O.CCOCC.C(Cl)Cl>[ClH:12].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH:3]([N:2]([CH3:1])[CH3:11])[CH3:4])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CC(C1CCCCN1)N(C)C
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C1CCCCN1C(=O)Cc1ccc(Cl)c(Cl)c1)N(C)C
Reaction time: 48 h

Procedure:
Gr 1.6 (moles 0.01) of 2-(1-dimethylaminoethyl) piperidine and gr2.25 (moles 0.011) of 3,4-dichlorophenylacetic acid, dissolved in 20 ml. of CH2Cl2 were added with gr.3.1 (moles 0.015) of dicyclohexylcarbodiimide dissolved in 20 ml. of CH2Cl2. After 48 hours standing, the reaction mixture was worked up as in Ex. No 1 C) giving 2.8 g. of oily mixture of diastereoisomers. This was chromatographed on g.60 of silicagel, eluting with CH2Cl2 containing increasing amounts of methanol (0.2% to 1%). The fast moving diastereoisomer A was so obtained. It was dissolved in acetone and transformed into the hydrochloride by acidifying with HCl dissolved in ether. The precipitate was crystallized from acetone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:14][NH2:15])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:4].[C:16]([CH2:19][C:20](=O)[CH3:21])(=O)[CH3:17].C(N(CC)CC)C>CO>[N+:11]([C:10]1[CH:9]=[CH:8][C:7]([N:14]2[C:20]([CH3:21])=[CH:19][C:16]([CH3:17])=[N:15]2)=[CH:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:13])=[O:12]
Reactant: CC(=O)CC(C)=O
Reactant: COC(=O)c1cc(NN)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-n2nc(C)cc2C)ccc1[N+](=O)[O-]

Procedure:
A solution of 2.84 g (10 mmol) of 3-methoxycarbonyl-4-nitro-phenylhydrazine, 1.0 g (10 mmol) of acetylacetone and 3.0 ml of triethylamine in 40 ml of methanol is stirred overnight at ambient temperature. Then it is evaporated to dryness, the residue is dissolved in about 50 ml of dichloromethane, the solution is washed with 5% sodium hydrogen carbonate solution, dried and evaporated down again. The crude product thus obtained is purified by column chromatography over silica gel (eluant: dichloromethane).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(=[O:20])C.[Na+]>C(O)(=O)C>[OH:17][CH2:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:20])[NH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)[O-]
Reactant: OCCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1ccc(N2CCC(CCCO)CC2)n[nH]1
Reaction time: 4 h

Procedure:
A mixture of 6 parts of 1-(6-chloro-3-pyridazinyl)-4-piperidinepropanol, 1.9 parts of sodium acetate and 150 parts of acetic acid was stirred for 4 hours at reflex temperature. The reaction mixture was evaporated and the residue was taken up in 200 parts of a hydrochloric acid solution 10%. After stirring for 1 hour at reflux temperature, the whole was evaporated. The residue was taken up in water and treated with ammonium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding a first fraction of 6-[4-(3-hydroxypropyl)-1-piperidinyl]-3(2H)-pyridazinone;
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:22]([NH:24][CH3:25])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1)[C:22]([NH:24][CH3:25])=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(Cl)c1
Temperature: 105 °C
Yield: 25.7 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (132 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-chloro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (53.1 mg, 0.117 mmol, 25.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.02 (m, 3H) 2.10-2.24 (m, 1H) 2.51 (br. s., 4H) 2.75 (d, J=4.55 Hz, 3H) 3.03 (br. s., 4H) 3.36-3.45 (m, 3H) 3.52-3.65 (m, 1H) 3.93-4.03 (m, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.17 (d, J=8.34 Hz, 1H) 7.63 (d, J=1.77 Hz, 1H) 7.75 (dd, J=8.34, 2.02 Hz, 1H) 7.86 (d, J=2.02 Hz, 1H) 8.41 (q, J=4.13 Hz, 1H) 10.45 (s, 1H). [M+H] calc'd for C23H27ClN6O2, 455. found, 455.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:4]=1.[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Br-:1].[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[CH:4]=[C:3]([CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:2][P+:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccc(F)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(F)cc1
Product: [Br-]
Yield: 54.6 %

Procedure:
A solution of methyl 4-bromomethyl-2-(4-fluorophenyl)benzoate (12.85 g; 0.04 mol) and triphenyl phosphine (10.53 g; 0.04 mol) in toluene (230 ml) was treated at reflux for 3 hours. The resulting solid was filtered, washed with ether and pentane and dried to give 3-(4-fluorophenyl)-4-methoxycarbonylbenzyltriphenylphosphonium bromide (12.78 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[OH:12])=[CH:4][CH:3]=1.O[CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[O:12][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1
Reactant: COC(=O)CO
Product: COC(=O)COC(CCCc1ccc(Cl)cc1)c1ccc(O)cc1
Temperature: 80 °C

Procedure:
A mixture of the alcohol of Step 3 (138 mg), methyl hydroxyacetate (80 μL), dry fused ZnCl2 (82 mg) in 1,2-dichloroethane (5 mL) was heated to 80° C. for an hour. The title compound was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 5:95 and 7.5:92.5. (For reference, see J. Org. Chem., 52 3917 (1987)).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH:13]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14].CCCCCCC.CCOC(C)=O>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:15]/[CH:13]=[O:14]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C/C=C/c1ccc2ccccc2n1
Yield: 11.3 %

Procedure:
A solution of quinolin-2-carboxaldehyde (3.5 g, 22.3 mmol) and formylmethylenetriphenylphosphorane (6.79 g, 22.3 mmol) in CH2Cl2 (180 ml) was treated as seen in preparation 1. After a chromatography on silicagel (n-heptane/EtOAc 4/1) pure title compound was obtained (460 mg, 2.51 mmol, yield 11.3%) as grey needles, m.p.=85°.
Reaction SMILES: [CH:1]([C:5]([CH2:12][CH3:13])([CH2:8][CH2:9][C:10]#[N:11])[CH:6]=O)=[CH:2][CH2:3][CH3:4].N.O=[Si]=O.[H][H]>>[CH2:1]([C:5]1([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][NH:11][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCC=CC(C=O)(CC)CCC#N
Agent: N
Agent: O=[Si]=O
Product: CCCCC1(CC)CCCNC1
Reaction time: 23.9 h
Yield: 754.6 %

Procedure:
45.1 g per hour of 2-butenyl-2-ethyl-4-cyanobutanal (purity 64.0%, 28.9 g, 0.161 mol) and 950 ml (570 g, 33.5 mol) per hour of liquid ammonia were pumped at 250 bar and 50° C. through a tubular reactor (diameter 16 mm, fill level 50 cm, oil-heated twin jacket) upstream of the hydrogenation reactor and filled with 43.3 g (96 ml) of a Y-zeolite pelleted with Aerosil 200 (HY-zeolite: Aerosil 200=9:1, SiO2 :Al2O3 =6:1). The product stream was subsequently passed through the hydrogenation reactor from bottom to top at 250 bar and 120° C. while simultaneously passing 100 l(S.T.P.)/h (4.5 mol) of hydrogen through the reactor. The product stream was decompressed to atmospheric pressure and NH3 was removed by distillation. From the product from 23.9 hours, 205.7 g of 3-butyl-3-ethylpiperidine and 438.4 g of a mixture of 2-butyl- and 2-butenyl-2-ethylpentane-1,5-diamine (8:1), corresponding to a diamine yield of 61.9% of theory, were isolated by fractional distillation on a 30 cm packed column (3 mm glass rings).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[Na]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOS(C)(=O)=O
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1CCn1ccnc1
Temperature: 70 °C
Yield: 69 %

Procedure:
The title compound from Step B above (2.68 g, 8.72 mmoles) (crude product, prior to chromatography) was dissolved in anhydrous DMF (30 mL) and sodium imidazole (1.18 g, 13.1 mmoles) was added. The mixture was heated at 70° C. for 2 h and then evaporated to dryness. The product was directly chromatographed on silica gel using 1% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (1.69 g, 69%): ESMS: m/z 280.1 (MH+); dH (CDCl3) 1.48 ppm (9H, s, CH3); dC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 19.1, 25.5, 28.9, 31.8, ˜39.1, 44.3; CH: 48.1, 118.9, 129.5, 137.1; C: 80.1, carbonyl not visible.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:3][CH2:4][CH3:5].Cl.[NH:17]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:18]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:19][CH2:20][C:21](=O)[OH:22].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:17]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C@H:18]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:19][CH2:20][C:21]([NH:1][C@H:2]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:3][CH2:4][CH3:5])=[O:22]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCC[C@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
The resulting H-Nva-OBzl.HCl was dissolved in methylene chloride (60 mL) and the resulting reaction solution was maintained at 0° C. To the reaction solution, Z-Glu-OBzl (N-α-carbobenzoxy-L-glutamic acid α-benzyl ester, 3.24 g, 8.72 mM), triethylamine (1.34 mL, 1.1 eq., 9.59 mM), HOBt.H2O (1-hydroxybenzotriazole hydrate, 1.47 g, 1.1 eq., 9.59 mM) and WSC.HCl (1.84 g, 1.1 eq., 9.59 mM) were added. The temperature of the reaction solution was gradually increased and stirred at room temperature overnight (16 hours). Then the reaction solution was concentrated under reduced pressure, ethyl acetate (200 mL) was added to the resulting residue, and the organic phase was then washed once with water (80 mL), twice with a 5% aqueous solution of citric acid (80 mL), once with a saturated common salt solution (80 mL), twice with a 5% aqueous solution of sodium hydrogen carbonate (80 mL), and once with a saturated common salt solution (80 mL). Then, the organic phase was dried over anhydrous magnesium sulfate. The magnesium sulfate was removed through filtration and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate and n-hexane, the crystals thus obtained were collected through filtration and dried under reduced pressure to give crystals of Z-Glu(Nva-OBzl)-OBzl (4.05 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH3:16])[CH:9]=1)[CH3:6])[CH3:2].[CH3:19][C:20]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=O.COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:16])[C:22]([C:21]2[C:20]([CH3:19])=[N:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:24])[CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CNC)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1cccc(CN(C)C(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylaminomethyl-phenoxy)-propionic acid ethyl ester (example 52C]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[3-({methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][CH:15]3[OH:21])[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][CH2:16][C:15]3=[O:21])[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)C(O)CC3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)C(=O)CC3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of 6-butyl-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.30 g) in acetonitrile (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.35 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 82%).
Reaction SMILES: Cl[CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3].[Na].[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]>CN(C)C=O>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([O:27][CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3])=[O:26]
Reactant: CC(Cl)c1nc2c(c(=O)n(C)c(=O)n2C)n1C
Reactant: O=C(O)c1cncc(Br)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(OC(=O)c1cncc(Br)c1)c1nc2c(c(=O)n(C)c(=O)n2C)n1C

Procedure:
2.87 g of 8-α-chloroethylcaffeine are dissolved in 30 ml of anhydrous dimethylformamide, and then 2.7 g of the sodium salt of dry 5-bromonicotinic acid are added.
Reaction SMILES: O1CCCC1.[OH-].[Na+].C([O:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([Cl:39])[CH:32]=3)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:40]#[N:41])[CH:25]=3)[N:20]=2)[CH2:15][CH2:14]1)=[O:12])C.Cl>O.C(O)C>[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:28]=[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([Cl:39])[CH:32]=3)[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:40]#[N:41])[CH:25]=3)[N:20]=2)[CH2:15][CH2:14]1)([OH:12])=[O:10]
Reactant: CCOC(=O)C1CCN(c2nc(NCc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CCC(C(=O)O)CC3)nc3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
30 ml of tetrahydrofuran, 30 ml of ethanol and 14 ml of a 1N aqueous solution of sodium hydroxide were added to 1.0 g of 2-(4-ethoxycarbonylpiperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was stirred at room temperature for 16 hours and neutralized with 1N hydrochloric acid, followed by the addition of 100 ml of water. The crystals thus precipitated were recovered by filtration and recrystallized from tetrahydrofuran/ethanol/water to give 860 mg of the title compound.
Reaction SMILES: C(N)C[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1.C([N:22](CC)CC)C>ClCCl>[C:3]1([NH:22][C:17](=[O:18])[C:14]2[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
Phenethylamine (1.2 mL, 9.57 mmol) was added slowly to a mixture of 4-Bromo-1-benzenecarbonyl chloride (2.0 g, 9.11 mmol) and triethyl amine (1.9 mL, 13.67 mmol) in dichloromethane (95 mL). After 3 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was re-crystallized from ethyl acetate/heptane to give N1-phenyl-4-bromobenzamide (1.925 g, 69%). 1H NMR (DMSO-d6) δ 2.84 (m, 2H), 3.47 (m, 2H), 7.28 (m, 5H), 7.67 (d, J=8.59 Hz, 2H), 7.76 (d, J=8.59 Hz, 4H), 8.64 (m, 1H).