Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:29])[CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]([OH:29])[CH2:25][N:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 40.2 %

Procedure:
Following general procedure A-1, {6-bromo-4-[4-(2-(dimethylamino)-1-hydroxyethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (50 mg, 0.110 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (30 mg, 0.165 mmol) to afford the desired product (23 mg, 40%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) 9.41 (s, 1H), 8.22 (dd, J=8.8, 2.0 Hz, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.23 (s, 1H), 7.09-7.02 (m, 1H), 5.20 (dd, J=10.6, 3.8 Hz, 1H), 3.31-3.20 (m, 2H), 3.03 (s, 3H), 2.97 (s, 3H), 2.89-2.80 (m, 1H), 1.25-1.14 (m, 4H); ESI MS m/z 520 [C29H27ClFN3O3+H]+; HPLC 94.8% (AUC), tR=11.31 min.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=[O:13])=[O:9])[CH3:7])=[O:4].[N+:28](C1C=CC=CC=1NCC(O)=O)([O-])=O.OS([O-])=O.[Na+].[OH-].[Na+]>CO>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([NH2:28])=[O:13])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)CNc1ccccc1[N+](=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
Z-Gly-Ala-Pro-2-nitrophenylglycine (SEQ ID NO:13) amide (0.025 mmol) in MeOH (12.5 ml) was added to 80 mM NaHSO3 (12.5 ml) and pH was adjsuted to 9.5 with 5N NaOH. The reaction mixture was purged with N2 for 15 min and subsequently photolyzed under nitrogen cover at a distance of 20 cm from the SP 200 lamp through Pyrex. The photolysis was followed by extraction of samples at 0, 30, 60 and 120 min. Each sample was analyzed using HPLC system-5 and the results compared with those from the 0 min sample as well as with the results from the CPD-Y hydrolysis and the transpeptidation mixture. Purification and identification were performed as previously described.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=3)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OP([CH2:32][C:33]#[N:34])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=3)=[CH:32][C:33]#[N:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOc1cc(C(=O)c2ccc3c(c2)OCCO3)ccc1OC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc3c(c2)OCCO3)ccc1OC

Procedure:
(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxyphenyl)methanone (0.83 g, 2.64 mmol), cyanomethylphosphonic acid diethyl ester (0.83 ml, 5.28 mmol) in anhydrous THF (20 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 5.28 ml, 5.28 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give a foam, which was lyophilized to give 3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile as a waxy oil (0.70 g, 78%): 1HNMR (DMSO-d6) 7.09-6.73 (m, 6H, Ar), 6.12 (s, 0.5H, double bond proton of one isomer), 6.07 (s, 0.5H, double bond proton of the other isomer), 4.33-4.25 (m, 4H, CH2CH2 for the two isomers), 4.05-3.97 (m, 2H, CH2CH3), 3.83 (s, 1.5H, OCH3 of one isomer), 3.79 (s, 1.5H, OCH3 of the other isomer), 1.31 (t, J=6 Hz, 3H, CH2CH3); 13C NMR(DMSO-d6) 161.0, 160.8, 151.0, 150.1, 147.8, 147.4, 145.5, 144.7, 143.2, 143.0, 131.3, 130.5, 130.1, 129.2, 122.6, 122.3, 120.0, 118.8, 118.7, 118.0, 117.1, 117.1, 117.0, 113.7, 112.1, 111.5, 111.3, 93.0, 92.9, 64.3, 64.2, 64.0, 64.0, 63.8, 55.5, 55.5, 14.6, 14.6. Anal. Calcd. For C20H19NO4 (+0.45H2O): C, 70.08; H, 5.76; N, 4.09. Found: C, 69.91; H, 5.54; N, 4.13.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+]>O.Cl>[Cl-:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N+:6]#[N:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(Cl)cc1
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
To a suspension of 4-chloroaniline (21.14 g, 0.166 mol) in water (156 ml) and 12N HCl (46 ml) at 0° was added sodium nitrite (12.62 g, 0.182 mol) in water (156 ml) over 20 minutes keeping the reaction temperature below 10°. The solution of 4-chlorobenzenediazonium chloride was filtered, kept at 0° for 30 minutes and then used in the next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[NH:22][N:21]=2)[C:16]([Cl:31])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:31][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: FC(F)(F)COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(OCC(F)(F)F)[nH]n2)n1)c1ncc(F)cn1
Temperature: 165 °C
Yield: 59.6 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 81 mg, 0.46 mmol), 2,5-dichloro-N-[5-(2,2,2-trifluoroethoxy)-1H-pyrazol-3-yl]pyrimidin-4-amine (Method 40, 100 mg, 0.31 mmol), and DIEA (110 mg, 0.9 mmol). Anhydrous n-BuOH (2.5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (80 mg, 62%). LC-MS, 433 (M+1). 1H NMR δ 12.19 (s, 1H), 9.76 (s, 1H), 8.83 (s, 2H), 7.92-8.10 (m, 2H), 5.67 (s, 1H), 5.13 (s, 1H), 4.75 (m, 2H), 1.49 (m, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:82]=[CH:81][C:7]([CH2:8][O:9][C:10]([NH:12][C@@H:13]([CH2:74][S:75][S:76][C:77]([CH3:80])([CH3:79])[CH3:78])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([NH:66]C(OC(C)(C)C)=O)[C:22]([O:24][C@H:25]2[C@@H:29]([OH:30])[C@H:28]([N:31]3[CH:39]=[N:38][C:37]4[C:32]3=[N:33][CH:34]=[N:35][C:36]=4[NH2:40])[O:27][C@H:26]2[CH2:41][O:42][P:43]([O:46][C@H:47]2[CH2:51][C@H:50]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:49][C@@H:48]2[CH2:60][O:61][P:62]([OH:65])([OH:64])=[O:63])([OH:45])=[O:44])=[O:23])=[O:15])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>ClCCl>[NH2:66][C@H:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10]([O:9][CH2:8][C:7]1[CH:81]=[CH:82][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=1)=[O:11])[CH2:74][S:75][S:76][C:77]([CH3:80])([CH3:79])[CH3:78])[C:22]([O:24][C@H:25]1[C@@H:29]([OH:30])[C@H:28]([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][C:36]=3[NH2:40])[O:27][C@H:26]1[CH2:41][O:42][P:43]([O:46][C@H:47]1[CH2:51][C@H:50]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:49][C@@H:48]1[CH2:60][O:61][P:62]([OH:65])([OH:64])=[O:63])([OH:45])=[O:44])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)SSC[C@H](NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)NCCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 27.6 %

Procedure:
A solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk25) (6.7 mg, 5.44 μmol) in dichloromethane (0.4 mL) was cooled in an ice bath, after which trifluoroacetic acid (0.1 mL) was added and the mixture was stirred at room temperature for 25 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-((R)-2-((((4-azidobenzyl)oxy) carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Lys(Acbz-Cys(StBu))-pdCpA) (Compound tk26) (1.7 mg, 28%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.C=O.[CH3:12]C1C=NC=CN=1.C[I:20]>CO>[I-:20].[CH3:12][N+:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=1
Reactant: OCCc1cnccn1
Reactant: CI
Reactant: Cc1cnccn1
Agent: C=O
Solvent: CO
Product: C[n+]1ccnc(CCO)c1
Product: [I-]

Procedure:
2.0 g of 2-(2-hydroxyethyl)pyrazine (301) prepared by a known method by condensing formaldehyde and 2-methylpyrazine, was dissolved in 5 ml of methanol and 5 ml of methyl iodide added. The solution was refluxed for 3 days, concentrated and the residue purified by gel permeation chromatography. Freeze-drying gave 3.2 g of yellow solid product (300). It was recrystallized from ethyl acetate/ethanol, m.p. 94°-5°. UV H2O max: 226 (4.13), 281 (3.85). 13C NMR: 163.25, S (C3); 150.71, D (C5); 138.69, D, 136.25, D (C2, C6); 60.38, T (CH2OH); 49.88, Q (NCH3); 38.75, T (--CH2 --). 1H NMR: 9.35, D, T (H6); 8.97, S (H2); 8.85, D (H5); 4.49, S (NCH3); 4.08, T; 3.35, T (ArCH2, CH2OH).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[OH-].[Na+].[CH2:19](I)[CH3:20]>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH2:19][CH3:20])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CCI
Reactant: O=C1CC[C@@H]2c3ccc(Cl)cc3CC[C@H]2N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1C(=O)CC[C@@H]2c3ccc(Cl)cc3CC[C@H]21
Temperature: 25 °C

Procedure:
A 9.4 g portion of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined in a flask with 94 ml of THF, 20 mL of 50% aqueous sodium hydroxide and 9.36 g of ethyl iodide, and was stirred at reflux, about 66°, for about 16 hours. The mixture was cooled to ambient temperature, and the layers were separated. The organic layer was evaporated to an oil, which was dissolved in ethyl acetate and extracted three times with 100 mL portions of water. It was then dried and evaporated to half its volume while heptane was added in portions. The resulting white crystalline product was filtered, washed with heptane and dried under vacuum at 25° to obtain 3.15 g of the desired product, m.p. 108°-110°.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:32]=[CH:31][C:20]3[CH:21]=[C:22]([C:24]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:25])[O:23][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33].[BH4-].[Na+].[CH2:39]1COCC1>>[CH2:15]([C:12]([C:17]1[CH:32]=[CH:31][C:20]2[CH:21]=[C:22]([C:24]([N:26]([CH2:27][C:28]([OH:30])=[O:29])[CH3:39])=[O:25])[O:23][C:19]=2[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:34])[C:2]([CH3:1])([CH3:35])[CH3:36])=[C:7]([CH3:33])[CH:8]=1)[CH2:13][CH3:14])[CH3:16]
Reactant: C1CCOC1
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)NCC(=O)O)oc2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)CC(=O)O)oc2c1
Reaction time: 2 h
Yield: 59 %

Procedure:
A solution of (6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carbonyl)-amino]-acetic acid (66 mg, 0.130 mmol) (Example 57) in THF (2 mL) is treated with NaBH4 (11 mg, 0.26 mmol) at room temp. The resulting mixture is stirred for 2 hours. The mixture is concentrated and neutralized to pH 3 and extracted with EtOAc (3×5 mL). The organic layer is dried over sodium sulfate, concentrated to afford the desired compound (39 mg, 59%). MS (ES) m/e: 508.3 (M−1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>[C-]#N.[C-]#N.[Zn+2].[Zn]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)nc1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: Cc1ccc(C#N)nc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
2-Bromo-5-methylpyridine ((8.6 g, 50 mmol) was mixed with Zn(CN)2 (4.1 g, 35 mmol), Pd(dppf)2C12 (0.89 g, mmol) and zinc dust (0.14 g, mmol) in DMF (86 ml) at 155° C. for 15 minutes. The reaction mixture was cooled down to room temperature and quenched with water and ethyl acetate. The mixture was filtered through celite and the organic layer was separated and dried with sodium sulfate. The product was purified by column chromatography with 10˜25% ethyl acetate in hexanes to give 3.4 g of 5-methyl-pyridine-2-carbonitrile (yield: 57.6%). 1H NMR (CDCl3), δ(ppm): 8.52 (s, 1H), 7.59 (m, 2H), 2.42 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:31]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC(=O)c2ccc(Cl)cc2Cl)ccc1Oc1cncc(Cl)c1
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To a solution of the aniline produced in Example 1 (100 mg, 0.34 mmol) in CH2Cl2 (2 mL) was added pyridine (81 μL, 1 mmol) and 2,4-dichlorobenzoyl chloride (140 mg, 0.68 mmol). The mixture was stirred for 90 min. The product was purified by column chromatography on silica gel (gradient elution: 30:1 hexane/ethyl acetate to 7:1 hexane/ethyl acetate) followed by recrystallization from Ch2Cl2/hexanes to yield 126 mg (79%) of the title compound. mp 125-127° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][C:6]#[CH:7].I[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>C1COCC1.C(NC(C)C)(C)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][C:6]#[C:7][C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1
Reactant: Ic1ccc(Oc2ncccn2)cc1
Reactant: C#CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC#Cc1ccc(Oc2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Under an argon atmosphere, copper iodide (2.8 mg) and dichlorobis(triphenylphosphine)palladium (5.2 mg) were added to a solution of 2-(2,6-dichlorobenzamido)pent-4-ynoic acid methyl ester (74 mg) and 2-(4-iodophenoxy)pyrimidine (81 mg) in THF/diisopropylamine (3/1) mixture (5 ml), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and ethyl acetate was added to the residue. The insoluble matter was removed by filtration, and the filtrate was washed once with water and once with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane/chloroform=2/1→cyclohexane/chloroform=1/3) to obtain 2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yloxy)phenyl]pent-4-ynoic acid methyl ester (100 mg).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].OCC(CO)O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#N)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(O)CO>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:2][CH2:1][CH2:3][N:4]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCC(O)CO
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3=NCCO3)cc2)CC1
Temperature: 105 °C
Yield: 37.1 %

Procedure:
A mixture of ethanolamine (0.91 ml; 15.0 mmol), glycerol (2.7 g), ethylene glycol (5.6 g) and potassium carbonate (2.1 g; 15.0 mmol) is heated at 105° C. for 30 min. The intermediate 1A (2.3 g; 8.04 mmol) is then added and the mixture is heated for 5 days at 105° C. The precipitate formed is filtered on sintered glass and washed with water and with petroleum ether to give compound 5A (988 mg; 37%) in the form of a beige solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].COC1C=CC(O)=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1.C(O)C1C=CC=CC=1>O>[C:1]([O:5][CH2:25][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CC(=O)O
Agent: COc1ccc(O)cc1
Solvent: O
Solvent: OCc1ccccc1
Product: C=CC(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
144 g (2 mols) of acrylic acid, which have been inhibited with 1.4 g of hydroquinone monomethyl ether, are dissolved in 139 g of a high-boiling aromatics mixture in a 1 l four-necked flask with stirrer, contact thermometer, water separator and gas inlet tube. 3.2 g of p-toluenesulfonic acid are added thereto, the mixture is heated to 70° C. and, at this temperature, 216 g (2 mols) of benzyl alcohol are allowed to run in over a period of 10 minutes. After the end of the addition, the mixture is heated to reflux. To accelerate the removal of water, air is passed through the solution. The reaction is complete after about 5 hours. The progress of the reaction is monitored via the acid number. After 5 hours, the latter gives a conversion of about 97%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].[CH2:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])C.[O:43]([CH2:55][C:56]([O:58]N1C(=O)CCC1=O)=O)[CH2:44][C:45]([O:47]N1C(=O)CCC1=O)=O>CN(C=O)C>[O:43]([CH2:55][C:56]([NH:1][CH2:2][CH2:3][O:58][CH2:56][CH2:55][O:43][CH2:44][CH2:45][O:47][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:40]2[C:32]3[C:42](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:41][N:38]([CH3:36])[CH2:39]2)[CH:18]=1)(=[O:16])=[O:15])=[O:58])[CH2:44][C:45]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15])=[O:47]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: CCN(CC)CC
Reactant: O=C(COCC(=O)ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)COCC(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (compound 28) (150 mg, 0.28 mmol, 1.00 equiv) in DMF (5 mL), triethylamine (56 mg, 0.55 mmol, 2.01 equiv) and bis(2,5-dioxopyrrolidin-1-yl) 2,2′-oxydiacetate (intermediate 178.1) (44 mg, 0.14 mmol, 0.49 equiv). The resulting solution was stirred overnight at room temperature, at which time the mixture was concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC with the following conditions: Column, C18 silica gel; mobile phase, methanol/water=0.05/100 increasing to methanol/water=90/100 within 19 min; Detector, UV 254 nm. This resulted in 72.4 mg (44%) of the title compound as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.79 (d, J=7.2 Hz, 2H), 7.71 (s, 2H), 7.49-7.58 (m, 4H), 7.36-7.37 (m, 2H), 6.82 (s, 2H), 4.39-4.44 (m, 2H), 4.06 (s, 4H), 3.80 (d, J=16.2 Hz, 2H), 3.65 (d, J=16.2 Hz, 2H), 3.55-3.61 (m, 16H), 3.43-3.52 (m, 12H), 3.02-3.08 (m, 6H), 2.65-2.70 (m, 2H), 2.49 (s, 6H). MS (m/z): 1190 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1)[CH3:11].N1CCC[C@H]1C(O)=O>C(O)C>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]1[CH2:17][C:18]2=[N:1][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=[C:19]2[CH2:20][CH2:21]1)[CH3:11]
Reactant: CCOC(=O)CCC1CCCC(=O)C1
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CCC1CCc2cc3cccnc3nc2C1
Temperature: 25 °C

Procedure:
A solution of 2-amino-pyridine-3-carbaldehyde (1-3)(0.244 g, 2.0 mmol) and 3-(3-oxo-cyclohexyl)-propionic acid ethyl ester (14-1) (0.245 g, 2.00 mmol; for prep., see J. R. Wiseman et.al., J. Am. Chem. Soc., 1970, 92, 956-962) in ethanol (10 mL) was treated with L-proline (0.230 g, 2.00 mmol) and heated at reflux for 12 h. The solution was cooled to ambient temperature and concentrated. The residue was purified by flash chromatography (10% acetone in CH2Cl2) to give 14-2.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH3:11])[CH:2]=C.I([O-])(=O)(=O)=[O:13].[Na+].[OH2:18]>C(Cl)(Cl)(Cl)Cl.C(#N)C.O.[Ru](Cl)(Cl)Cl>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][C:2]([OH:13])=[O:18])=[C:5]([CH3:11])[CH:6]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1ccc(Br)cc1C
Reactant: O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)ccc1CC(=O)O
Reaction time: 5 h
Yield: 88 %

Procedure:
To a solution of 16A (12 g, 56.8 mmol) in CCl4 (200 mL), acetonitrile (200 mL) and water (300 mL) at rt was added ruthenium (III) chloride hydrate (1.474 g, 7.11 mmol) and sodium periodate (48.6 g, 227 mmol). The suspension was stirred vigorously for 5.0 h. The solvent was removed under vacuum. The residue was filtered though wet CELITE®, washed with EtOAc. The mixture was further extracted with EtOAc (3×400 mL). The volume of organic layers was reduced to ca 500 mL, washed with sat. sodium sulfite/with conc. HCl (pH ca 2-3). The organic layer was dried over sodium sulfate and concentrated. After evaporation of solvent, 16B (11.47 g, 50.1 mmol, 88% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.27 (s, 3H) 3.60 (s, 2H) 7.04 (d, J=7.91 Hz, 1H) 7.28 (dd, J=8.13, 1.98 Hz, 1H) 7.32 (s, 1H).