Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:21][CH3:22])=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[CH2:5][NH:4]1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[CH2:37]Cl.[Cl-].[NH4+]>CN(C=O)C.O>[CH2:1]([CH:3]1[CH2:12][CH:11]2[C:6](=[CH:7][C:8]([O:21][CH3:22])=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH2:5][N:4]1[CH2:37][C:36]1[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:34]([O:33][CH3:32])[CH:35]=1)[CH3:2]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CCC1Cc2cc(OCc3ccccc3)c(OC)cc2CN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCC1CC2CC(OCc3ccccc3)=C(OC)C=C2CN1Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 261 (297 mg, 1.0 mmol) in anhydrous DMF (3.0 mL), DIPEA (264 mg, 2.0 mmol) and 3,4,5-trimethoxybenzyl chloride (238 mg, 1.1 mmol) was heated to 80° C. for 12 h, cooled to room temperature and poured into water (50 mL) and ammonium chloride (saturated, 2 mL). The mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography using Flashmaster (SiO2: 20 g, hexane 100% to hexane/ethyl acetate 50:50). The title compound was obtained as pale yellow oil (350 mg, 73%). 1H NMR (270 MHz, CDCl3) δ 0.97 (3H, t, J 7.0, CH2CH3), 1.43 (1H, sept, J 7.0, one of CH2CH3), 1.67 (1H, sept, J 7.0, one of CH2CH3), 2.42-2.58 (1H, m, one of ArCH2CH), 2.72-2.95 (2H, m, one of ArCH2CH, CHN), 3.51-3.74 (4H, m, 2×ArCH2N), 3.80 (3H, s, OCH3), 3.83 (6H, s, 2×OCH3), 3.88 (3H, s, OCH3), 5.10 (2H, s, OCH2Ph), 6.45-6.56 (1H, m, CH), 6.56-6.70 (3H, m, 3×CH), 7.24-7.52 (5H, m, OCH2C6H5).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:42]([CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]3)=[O:43])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (70%→90% ethyl acetate in hexanes) affording the desired product (70) as a solid. ESMS:MH+ 590.6
Reaction SMILES: C(N)C1C=CC=CC=1.C(=O)(O[CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)OC.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC1(C)C(C=CC2CCC/C(=C/C=C3/C(C)(C)C4C(N/3CCCCS(O)(=O)=O)=CC=CC=4)/C=2OC2C=CC(OCCCCNCC3OC(O)C(N)C(O)C3O)=CC=2)=[N+](CCCCS([O-])(=O)=O)C2C1=CC=CC=2.C(Cl)(Cl)Cl>[C:16]1([CH:15]([C:24]2([NH2:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH2:25]2)[CH:14]=[CH2:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)OCC=Cc1ccccc1
Reactant: Nc1ccccc1
Agent: CC1(C)C(/C=C/C2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Agent: CC1(C)C(C=CC2=C(Oc3ccc(OCCCCNCC4OC(O)C(N)C(O)C4O)cc3)/C(=C\C=C3/N(CCCCS(=O)(=O)O)c4ccccc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccccc21
Solvent: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=CC(c1ccccc1)C1(N)C=CC=CC1
Reaction time: 2 h
Yield: 81 %

Procedure:
By the procedure for reaction of benzylamine with methyl cinnamyl carbonate, the reaction of aniline (130 mg, 1.40 mmol) and methyl cinnamyl carbonate (188 mg, 0.980 mmol) with [(COD)Ir(κ2-L1)L1] (Ir-2) (13.8 mg, 0.0100 mmol) and [(COD)IrCl]2 (3.4 mg, 0.0050 mmol) as catalyst was conducted at room temperature for 2 h. 1H NMR analysis of the crude reaction mixture indicated that the ratio of regioisomers was greater than 99/1. The mixture was then purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give 81% yield. HPLC analysis indicated that the enantiomeric excess of the product was 97% [Diacel Chiralcel® OD-H (0.46 cm×25 cm); hexanes/2-propanol=99.75/0.25; flow rate=0.6 mL/min; detection wavelength=254 nm; TR=19.1 (major) min., 20.3 min. (minor)]. [α]D20=−12.0 (c 2.10, CHCl3); 1H NMR (400.13 MHz, C6D6) δ 7.44-7.24 (m, 5H), 7.20-7.10 (m, 2H), 6.69 (t, J=7.2 Hz, 1H), 6.60 (d, J=8.0 Hz, 2H), 6.04 (ddd, J=16.8, 10.4, 6.4 Hz, 1H), 5.28 (dt, J=17.2, 1.2 Hz, 1H), 5.22 (dt, J=10.0, 1.2 Hz, 1H), 4.94 (t, J=4.4 Hz, 1H), 4.04 (br s, 1H). 13C NMR (100.5 MHz, C6D6) δ .61.1 (s, CH), 114.2 (s, CH═CH2), 115.9 (s, CH═CH2), 118.2, 127.7, 127.8, 129.1, 129.6, 139.6 (all s, Ar—CH), 142.4 (s, Ar—C), 147.8 (s, Ar—C).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1)=[O:4].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:2][C:3]([O:5][C:6]2[CH:11]=[CH:10][C:9](/[C:12](/[C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[CH:24][CH:23]=3)=[C:13](\[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)/[CH2:14][CH3:15])=[CH:8][CH:7]=2)=[O:4])[CH2:36][CH2:35]1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CCl)cc1)c1ccccc1
Reactant: CN1CCNCC1
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)CN2CCN(C)CC2)cc1)c1ccccc1

Procedure:
Treatment of compound 32 with N-methylpiperazine as described in Example 19 (Step 2) afforded the title compound, 34, as an off-white solid. 1HNMR (400 MHz, DMSO-d6): δ 0.85 (t, 3H), 2.11 (s, 3H), 2.27 (br, 4H), 2.39 (q, 2H), 2.50 (br, 4H), 3.38 (s, 2H), 6.49 (d, J=16 Hz, 1H), 6.79 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 7.09-7.19 (m, 5H), 7.23 (d, J=8.1 Hz, 2H), 7.49 (d, J=16 Hz, 1H), 7.65 (d, J=8 Hz, 2H), 12.36 (br, 1H); MS m/z 511 (M+H)+.
Reaction SMILES: O.NN.C(O)C.[C:7]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2C(=O)C3C(=CC=CC=3)C2=O)[CH:12]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:11]1)(=[O:9])[CH3:8]>C(OCC)(=O)C>[C:7]([N:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH:12]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:11]1)(=[O:9])[CH3:8]
Reactant: CC(=O)N1CCC(N2C(=O)c3ccccc3C2=O)C(NC(=O)OC(C)(C)C)C1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(N)C(NC(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Hydrazine monohydrate (1 ml) was added to an ethanol (5 ml) solution containing tert-butyl (1-acetyl-4-(1,3-dioxoisoindolin-2-yl)piperidin-3-yl)carbamate (301 mg) obtained in the 3rd step, followed by heating and stirring at 50° C. for 0.5 hours. Ethyl acetate was added to the reaction solution. The reaction solution was washed with water and saturated saline and dried over anhydrous sodium sulfate. Next, the solvent was distilled away under reduced pressure. Colorless oily matter of tert-butyl (1-acetyl-4-aminopiperidin-3-yl)carbamate (147 mg) was thus obtained.
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH2:21]([C:23]1[CH-:24][C:25]2[C:30]([CH:31]=1)=[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:28]=[CH:27][CH:26]=2)[CH3:22].[Li+]>CCOCC>[CH3:17][Si:7]([CH3:18])([CH:24]1[C:25]2[C:30](=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH:31]=[C:23]1[CH2:21][CH3:22])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16]
Reactant: CCc1cc2c(-c3ccccc3)cccc2[cH-]1
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Agent: [Li+]
Solvent: CCOCC
Product: CCC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)C1C(C)=C(C)C(C)=C1C
Reaction time: 20 h

Procedure:
To a green solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (2-ethyl-4-phenylindenide) (5.53 g, 24.4 mmol, 1.07 equiv.) in portions to give a hazy yellow solution near room temperature. The reaction was stirred for 20 hours, then evaporated under vacuum, leaving a light yellow semi-solid. The residue was extracted with pentane (3×40 mL) and the extract was filtered to give a yellow solution and pale yellow-white solid. The solution was evaporated under vacuum to yield thick, yellow oil. Yield 9.28 g (102%). 1H NMR(C6D6): δ 7.64 (d, 2H), 7.43 (d, 1H), 7.35 (d, 1H), 7.29 (t, 2H), 7.19 (t, 2H), 6.95 (s, 1H), 3.74, (s, 1H), 3.17 (br s, 1H), 2.46 (m, 1H), 2.32 (m, 1H), 1.95 (s, 3H), 1.89 (s, 3H), 1.82 (s, 6H), 1.05 (t, 3H), −0.22 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
105.7 g (0.32 mol) of crude rac-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one, dissolved in 1 liter of acetone, are treated with 88.6 g (0.64 mol) of potassium carbonate and 39.9 ml (0.64 mol) of methyl iodide and the mixture is stirred at room temperature for 22 hours. The mixture is evaporated to dryness and the residue is taken up in methylene chloride. The organic phase is washed with water, dried and evaporated. Recrystallisation of the residue from methylene chloride/ethanol gives rac-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 170°-174° C.
Reaction SMILES: C(Cl)CCl.[C:5](=[N:8][OH:9])([NH2:7])[CH3:6].[C:10]([O:14][C:15]([N:17]([C@@H:22]1[CH2:24][C@H:23]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][C:19](O)=O)=[O:16])([CH3:13])([CH3:12])[CH3:11]>COCCOCCOC>[CH3:6][C:5]1[N:7]=[C:19]([CH2:18][N:17]([C@H:22]2[CH2:24][C@H:23]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:15](=[O:16])[O:14][C:10]([CH3:13])([CH3:11])[CH3:12])[O:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC(N)=NO
Solvent: COCCOCCOC
Solvent: ClCCCl
Product: Cc1noc(CN(C(=O)OC(C)(C)C)[C@H]2C[C@H]2c2ccccc2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
EDC (107 μL, 0.585 mmol) and acetoamidoxime (41 mg, 0.532 mmol) was added to a stirred solution of 2-(tert-butoxycarbonyl((trans)-2-phenylcyclopropyl)amino)acetic acid (163 mg, 0.532 mmol) in diglyme (2 mL) under argon atmosphere. The mixture was stirred at 50° C. overnight and then at 110° C. for 14 hours. After removal of solvent under vacuum, the reaction mixture was purified by flash chromatography eluting with hexane/MTBE (80:20 to 0:100) to afford tert-butyl (3-methyl-1,2,4-oxadiazol-5-yl)methyl((1S,2S)-2-phenylcyclopropyl)carbamate as a colourless oil (35 mg. Yield=20%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:33]([F:34])=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C@H:19]([C:24]([O:26]C3CCCC3)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:10][C:9]=2[F:35])[C:6](=[O:36])[CH:5]=[CH:4][C:3]=1[C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[N:7]([C:8]2[C:9]([F:35])=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:32][C:33]=2[F:34])[C:6](=[O:36])[CH:5]=[CH:4][C:3]=1[C:37](=[O:45])[C:38]1[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=1
Reactant: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1)C(=O)OC1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NCCCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
From Example 55. To a solution of cyclopentyl N-(5-{4-[6-amino-5-(4-fluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenoxy}pentyl)-L-leucinate (33 mg, 0.05 mmol) in THF (1 ml) and water (1 ml) was added LiOH (25 mg, 1.05 mmol, 20 eq). The mixture was stirred at room temperature for 16 hours, before being heated at 80° C. for 10 hours. The mixture was concentrated under reduced pressure and water (5 ml) added. The pH was adjusted to 7 using 1M HCl and the aqueous layer extracted with 1-butanol (3×5 ml). The combined organic extracts were concentrated under reduced pressure. The solid residue was triturated with Et2O, collected by filtration and purified by preparative HPLC to provide the title compound as a white solid as the mono-TFA salt (7 mg, 24% yield). LC/MS: m/z 560 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ: 7.62-7.51 (3H, m), 7.34 (2H, m), 7.05 (2H, m), 5.72 (1H, d, J=9.8 Hz), 4.09 (2H, t, J=5.7 Hz), 3.23 (1H, m), 2.80 (2H, m), 1.79-1.43 (9H, m), 0.89 (6H, t, J=6.7 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]1[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23]1>>[O:22]1[CH:26]=[CH:25][C:24]([C:27]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:28])=[CH:23]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1ccoc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccoc3)CC1)O2

Procedure:
Compound 43 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-furoyl chloride and conditions outlined in procedure N. M.p.=234-235° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.05 (d, 1H), 7.67 (d, 1H), 7.65 (t, 1H), 7.50 (t, 1H), 7.24 (s, 2H), 6.58 (s, 1H), 3.46 (m, 2H), 2.96 (s, 2H), 2.20 (m, 2H), 1.92 (m 2H), 1.58 (brs, 2H); LCMS: 396 [M+H].
Reaction SMILES: C[O-].[Na+].[NH2:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11].[C:12](OC)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1C=CC=CC=1>[C:12]([NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H]1CCCC[C@H]1N
Yield: 67.2 %

Procedure:
Sodium methoxide (0.60 g) was added to a solution of 1.14 g of trans-1,2-diaminocyclohexane and 2.96 g of methyl oleate in 15 ml of benzene, and the mixture was heated under reflux for 20 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate-water. The organic layer was washed with saturated saline, and dried over anhydrous sodium sulfate. After drying it over anhydrous sodium sulfate, the residue obtained was purified by silica gel column chromatography to obtain 2.54 g of the objective compound (yield: 68%).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([F:39])[CH:32]=3)[N:11]([C:14]3[C:15](=[O:30])[N:16](CC4C=CC(OC)=CC=4)[CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:40][O:41][C:42]1[N:47]=[C:46]([O:48][CH3:49])[C:45](B(O)O)=[CH:44][N:43]=1.BrC1N(C(C)C)C2C(C3C=CC(C#N)=CC=3)N(C3C(=O)N(CC4C=CC(OC)=CC=4)C=C(Cl)C=3)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:45]4[C:46]([O:48][CH3:49])=[N:47][C:42]([O:41][CH3:40])=[N:43][CH:44]=4)[N:6]([CH:7]([CH3:8])[CH3:9])[C:5]=3[CH:10]2[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([F:39])[CH:32]=2)[C:15](=[O:30])[NH:16][CH:17]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: COc1ccc(Cn2cc(Cl)cc(N3C(=O)c4cc(Br)n(C(C)C)c4C3c3ccc(C#N)c(F)c3)c2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(Cn2cc(Cl)cc(N3C(=O)c4cc(Br)n(C(C)C)c4C3c3ccc(C#N)cc3)c2=O)cc1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)c(F)c2)N(c2cc(Cl)c[nH]c2=O)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 125 but in the step corresponding to Step 125.1, 4-{2-bromo-5-[5-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl}-2-fluoro-benzonitrile (Intermediate BE) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 4-{2-bromo-5-[5-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl}-benzonitrile and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. Moreover, in this step, Pd(PPh3)4 was used instead of PdCl2(dppf).CH2Cl2 adduct. The title compound was obtained as a white solid. tR: 5.84 min (H PLC 2); ESI-MS: tR=0.94 min, [M+H]+ 549/551 (LC-MS 1); TLC: Rf=0.19 (EtOAc).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][N:29]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][N:29]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
After a mixture of ethyl 3-[3-phenyl-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (970 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (820 mg, yield: 90%). This was recrystallized from acetone-hexane. Melting point: 149–150° C.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:24])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(C(C)C)C(C)C.[CH2:45]([O:47][C:48](=[O:52])[C:49](Cl)=[O:50])[CH3:46]>C(Cl)Cl>[CH2:45]([O:47][C:48](=[O:52])[C:49]([N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:35])=[CH:20][CH:19]=1)[CH:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:50])[CH3:46]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CNC(C)c2cccc3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)OCC)C(C)c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The resin-bound N-dodecyl-4-({[1-(1-naphthyl)ethyl]amino}methyl)benzamide (described in step c, 0.0426 mmol) was swelled in DCM (1.0 mL) for 15 min at 0° C. DIEA (28 mg, 0.213 mmol) and chloro-oxo-acetic acid ethyl ester (29 mg, 0.213 mmol) were added and the reaction mixture was shaken 3 h at 0° C. then 14 h at rt. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound ethyl{{4-[(dodecylamino)carbonyl]benzyl}[1-(1-naphthyl)ethyl]amino}-(oxo)acetate which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16]([NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:16]([NH:26][C:13]([C@@H:11]1[CH2:12][C@H:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
The title compound was prepared from trans-2-(4-nitrophenyl)cyclopropanecarboxylic acid and decylamine, substantially according to the procedure of Preparation 30. A 98% yield of a white, waxy solid, m.p. 127°-129° C., was obtained.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([F:18])[C:12]=2[F:19])[N:8]=[C:7]([C:20]([O:22][CH3:23])=[O:21])[C:6]=1[Cl:24])(=O)C.C(Cl)(=O)C>CO>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[C:13]([F:18])[C:12]=2[F:19])[N:8]=[C:7]([C:20]([O:22][CH3:23])=[O:21])[C:6]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2ccc(Br)c(F)c2F)cc(NC(C)=O)c1Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2F)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
Methyl 4-acetamido-6-(4-bromo-2,3-difluorophenyl)-3-chloropicolinate (0.515 g, 1.227 mmol) was suspended in methanol (20 mL) and acetyl chloride (1.559 mL, 21.93 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate solution. The organic phase was concentrated onto silica gel and purified by flash chromatography (SiO2, eluting with 5-60% ethyl acetate in hexanes) to provide the title compound as a white solid (0.231 g, 55.8%).