Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Br:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]>ClCCl.S(=O)(=O)(O)O>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([O:19][C:4]([CH3:24])([CH3:5])[CH3:1])=[O:18])=[CH:15][C:14]=2[Br:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCc1c(OCCCOc2ccc(C(=O)OC(C)(C)C)cc2Br)ccc(C(C)=O)c1O
Reaction time: 48 h
Yield: 130 %

Procedure:
To a solution of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoic acid (903 mg) in dichloromethane (100 ml) was added conc. sulfuric acid (five drops), and then into the mixture was bubbled isobutene under ice-cooling for 30 minutes. The mixture was left standing at room temperature for 2 days in a sealed vessel. To the reaction mixture was added sodium hydrogen carbonate, and then was bubbled nitrogen gas to remove isobutene. The insolubles were removed by filtration, and the filtrate was subjected to concentration under reduced pressure. The residue was dissolved in ethyl acetate, the solution was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried with magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was subjected to purification with silica gel flash chromatography [hexane-ethyl acetate (9:1)]. The eluate was concentrated under reduced pressure to give tertbutyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoate (660 mg) as slightly brown oily product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]2)[CH2:11][CH2:10]1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:27]([NH:26][CH2:24][CH3:25])=[O:28])[CH2:19][CH2:18]2)[CH2:11][CH2:10]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.56 g (1.2 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine was dissolved in dry dichloromethane (20 ml), ethylisocyanate (0.1 ml, 1.3 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was stirred with water, the precipitate was filtered, giving the title compound (0.33 g, 65%). Melting point: 235-8° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H][H]>[Pd]>[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH2:28][CH2:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Cc1cc(Nc2ncnc3ccc(C#CC4(O)CCCNC4)cc23)ccc1Oc1ccccc1
Agent: [Pd]
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(CCC4(O)CCCNC4)cc23)ccc1Oc1ccccc1
Yield: 103 %

Procedure:
A mixture of 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol dihydrochloride (100 mg, 0.19 mmol) and Pd/C (10%, 6 mg) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated to small volume and added dropwise into EtOAc with stirring. The solid was collected by suction filtration, rinsed with EtOAc, and further dried to yield 89 mg (89%) of yellow solid: 1H NMR (CD3OD) δ 1.69 (dt, 1H), 1.81(br d, 1H), 1.95 (t, 3H), 2.15 (m, 1H), 2.28 (t, 3H), 2.93 (t, 1H), 3.02 (m, 3H), 3.18 (d, 1H), 3.31(br, 1H), 6.94 (m, 3H), 7.08 (t, 1H), 7.34 (t, 2H), 7.55 (d, 1H), 7.66 (d, 1H), 7.78 (d, 1H), 8.02 (d, 1H), 8.58 (s, 1H), 8.73 (s, 1H); MS m/z (MH+) 455.2.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>CO>[CH2:8]([S:15][CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(CBr)C(=O)O
Reactant: SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(CSCc1ccccc1)C(=O)O
Reaction time: 23 h
Yield: 89 %

Procedure:
2-Bromomethylacrylic acid (3.00 g, 18.1 mmol) was dissolved in methanol (100 mL), cooled on an ice bath and treated with benzyl mercaptan. Aqueous sodium hydroxide (1N, 39.8 mL) was added dropwise and the reaction mixture was allowed to adjust to room temperature with stirring for 23 hours. Methanol was removed by rotary evaporation at reduced pressure and water (100 mL) was added to the residue, which was then washed with ether. The aqueous layer was cooled on ice and acidified to pH 2.5. The precipitated solid was isolated by filtration and dried to give 2-benzylsulfanylmethyl-acrylic acid (3.346 g, 89%).
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60](=[O:81])[NH:61][CH2:62][CH2:63][N:64](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C:65]([NH2:67])=[NH:66])[CH2:43]1>>[NH:64]([CH2:63][CH2:62][NH:61][C:60]([C@@H:44]1[CH2:43][C@H:42]([S:41][C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([OH:23])=[O:22])[CH2:46][NH:45]1)=[O:81])[C:65]([NH2:67])=[NH:66]
Reactant: N=C(N)N(CCNC(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)NCCNC(=N)N)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylguanidino)ethylcarbamoyl]pyrrolidine (prepared as described in Preparation 102) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11](O)=[O:12])(=[O:5])[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:19]>>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([Cl:19])=[O:12])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc(OC)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: CCCC(=O)c1ccc(OC)c(C(=O)Cl)c1
Temperature: 30 °C
Yield: 90 %

Procedure:
206 g of the acid obtained in Example 4 (0.927 mole), 1 liter of CHCl2, are introduced into a triple-tube flask and 1.11 mole of SOCl2 (80 ml) are added with care. The mixture is maintained for 24 hours at 30° C. and the solvents are then removed. Retreatment with 200 ml of benzene is carried out three times by removing the solvent in vacuo each time. 200 g of the product having a melting point of 65° C. (cyclohexane) are thus obtained with a yield of 90%. IR spectrum (KBr) CO: 1670 and 1780 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:13]2[C:12](=[O:22])[CH2:11][NH:10][CH2:9][C:8]=2[NH:7][C:6]=1[CH3:23])=[O:4].[CH3:24][C:25]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH:29]1[O:31][CH2:30]1>CO>[CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:13]2[C:12](=[O:22])[CH2:11][N:10]([CH2:30][CH:29]([OH:31])[CH2:28][O:27][C:26]3[CH:32]=[CH:33][CH:34]=[C:35]([CH3:36])[C:25]=3[CH3:24])[CH2:9][C:8]=2[NH:7][C:6]=1[CH3:23])=[O:4]
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)CNC2)C1c1ccccc1C
Reactant: Cc1cccc(OCC2CO2)c1C
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(CC(O)COc3cccc(C)c3C)C2)C1c1ccccc1C
Yield: 41.1 %

Procedure:
1,4,5,6,7,8-Hexahydro-2-methyl-4-(2-methylphenyl)-5-oxo-1,7-naphthyridine-3-carboxylic acid methyl ester (14.5 g), 6.8 g of 3-(2,3-dimethylphenoxy)-1,2-epoxypropane and 250 ml of methanol were combined and refluxed for 18 hours. The solvent was removed in vacuo. The residue was dissolved in diethyl ether and saturated with hydrogen chloride. The solid was separated and dried in vacuo at 75° C. for 18 hours. The solid was recrystallized from acetonitrile to obtain 7.7 g of the title compound as the hydrochloride salt, m.p. 220° C. dec.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:31])[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]2)[CH2:21][NH2:22])=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][CH:20]([C:17]1[CH:16]=[N:15][C:14]([CH:13]([F:31])[F:12])=[N:19][CH:18]=1)[CH2:23][C:24]1([C:27]([F:30])([F:28])[F:29])[CH2:26][CH2:25]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-(trifluoromethyl)cyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=468.0, tR (minutes, Method F)=2.84. [α]D20=+27.80 (c=3.41 mg/mL,CHCl3)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH:26]([CH3:28])[CH3:27])[CH:17]=1.C(OCC)(=O)C>CS(C)=O>[CH:26]([O:25][C:18]1[CH:17]=[C:16]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23])([CH3:28])[CH3:27]
Reactant: CN1CCC(N)CC1
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Oc1cc(NC2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 63.7 %

Procedure:
1.7 g of potassium carbonate and 1.0 g of 4-amino-1-methylpiperidine are successively added to a solution of 1.6 g of 4-fluoro-2-isopropoxy-1-nitrobenzene in 13.5 ml of dimethyl sulfoxide. The reaction mixture is heated at 120° C. for 3 h and is then cooled to ambient temperature and poured into a mixture of 150 ml of ice-cold water and 100 ml of ethyl acetate. After settling out, the organic phase is separated and the aqueous phase is extracted twice with 70 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 90 g silica cartridge, elution being carried out with a 97.5/2/0.5 v/v/v dichloromethane/methanol/20% aqueous ammonia mixture at a flow rate of 50 ml/min, so as to obtain 1.5 g of (3-isopropoxy-4-nitrophenyl)(1-methylpiperidin-4-yl)amine in the form of a bright yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[N:7]=1
Reactant: COc1cc(C)nc(Cl)n1
Reactant: c1nc[nH]n1
Solvent: C1CCOC1
Product: COc1cc(C)nc(-n2cncn2)n1
Yield: 48.2 %

Procedure:
In anhydrous tetrahydrofuran, 159 mg of 2-chloro-4-methoxy-6-methylpyrimidine was substituted with 69 mg of 1,2,4-triazole. The reaction mixture was treated according to the procedure as in Example 5 to yield 92 mg of 4-methoxy-6-methyl-2-(1,2,4-triazol-1-yl)-pyrimidine, recrystallized from n-hexane, having a melting point of 142.5°-143° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[C:6](=[O:16])[CH2:7][CH2:8]2
Reactant: CCCOC1CCNCC1
Reactant: Cc1ccc2c(c1)CCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOC1CCN(CCCN2C(=O)CCc3cc(C)ccc32)CC1
Reaction time: 20 h
Yield: 58.2 %

Procedure:
A 4 mL vial was charged with 1-(3-Chloropropyl)-6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH14) (0.128 g), 4-propoxypiperidine (0.079 g, 0.54 mmol), KI (0.166 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) in MeCN (2 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH18-2) (0.108 g, total yield 50%). 1H NMR (CD3OD) δ 7.05-7.00 (m, 3H), 3.95 (t, J=7.2, CH2), 3.41-3.30 (m, 3H), 2.84-2.76 (m, 4H), 2.57-2.53 (m, 2H), 2.47-2.43 (m, 2H), 2.27 (s, 3H, CH3), 2.27-2.22 (m, 2H), 1.90-1.81 (m, 4H), 1.63-1.52 (m, 4H), 0.91 (t, J=7.4 Hz, CH3); 13C NMR (CD3OD) δ 172.4, 137.8, 134.0, 129.8, 129.0, 128.0, 116.2, 75.3, 70.7, 56.5, 51.9, 41.2, 32.8, 31.7, 26.2, 25.5, 24.3, 20.7, 11.0; HPLC-MS (ammonium acetate) [M+H+]=345.30.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:4]([NH:6][CH:7]([C:13]([O:15]CC)=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5].[OH-].[Na+].O.Cl>C(O)C>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([NH:6][C:4](=[O:5])[C:3](=[N:2][OH:1])[CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]([OH:15])=[O:14])[CH3:12]
Reactant: CCOC(=O)C(NC(=O)C(CC(C)C)=NO)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(NC(=O)C(CC(C)C)=NO)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In to a solution of 29.19 g of diethyl N-(2-hydroxyimino-4-methylpentanoyl)aminomalonate in 200 ml of ethanol was added 2.8 g of sodium hydroxide and 200 ml of water, then the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with 10% hydrochloric acid, then concentrated. To the residue thus obtained was added 10% hydrochloric acid to make it acidified, then it was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, an aqueous solution saturated with sodium chloride in this order, then dried with magnesium sulfate. The solvent was removed by distillation to obtain 23.0 of N-(2-hydroxyimino-4-methylpentanoyl)aminomalonic acid monoethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[S:25]([CH3:24])(=[O:27])=[O:26])[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1nccc(-c2cccc(CNCCc3ccncc3)c2)n1
Product: CS(=O)(=O)N(CCc1ccncc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 20 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:15]1[O:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=1)=[O:5]
Reactant: COC(=O)c1ccco1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)c2ccccc2C)o1
Yield: 90.4 %

Procedure:
A mixture of 2-methylbenzoyl chloride (prepared as described by Frankland and Ashton, Trans. Chem. Soc. 1899, 75, 494; 77 g.), methyl 2-furoate (83 g.), anhydrous ferric chloride (1.5 g.) and carbon tetrachloride (125 ml.) was heated under reflux on a steam bath for 7.5 hours and then distilled to give methyl 5-(2-methylbenzoyl)-2-furoate (110 g.) in the form of a colourless oil, b.p. 170° C./0.2 mm.Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12](C(OC(C)(C)C)=O)[CH3:13])=[CH:8][C:7]=1[CH3:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][C:7]=1[CH3:21]
Reactant: COC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
A solution of crude [4-(tert-butoxycarbonyl-methyl-amino)-2-methyl-phenoxy]-acetic acid methyl ester (25.8 g, 77 mmol) in CH2Cl2 (600 ml) was treated at 0° C. with TFA (198 ml) and stirred at RT for 30 min. The reaction was evaporated, treated with chilled aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 16.2 g of crude (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester. Purification by flash chromatography with a gradient of n-heptane:EtOAc 9:1 to 4:1 yielded 12.7 g of (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester as an orange oil, MS: 210 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:54][C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])[CH2:12][CH2:13][NH:14][C:15](=[O:53])[CH2:16][N:17]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24][N:23]([CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:22][CH2:21][N:20]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:19][CH2:18]2)=[O:10])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.[C:73]1(=[O:82])[N:77]([CH2:78][CH2:79][NH2:80])[C:76](=[O:81])[CH:75]=[CH:74]1.Cl>CC#N>[O:82]=[C:73]1[CH:74]=[CH:75][C:76](=[O:81])[N:77]1[CH2:78][CH2:79][NH:80][C:59](=[O:60])[CH2:58][NH:57][C:55](=[O:56])[CH2:54][N:11]([C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:12][CH2:13][NH:14][C:15](=[O:53])[CH2:16][N:17]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:36])[CH2:25][CH2:24][N:23]([CH2:37][C:38]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:44])[CH2:22][CH2:21][N:20]([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCCN(CC(=O)NCC(=O)O)C(=O)Cc2ccc(O)cc2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: NCCN1C(=O)C=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)NCCN(CC(=O)NCC(=O)NCCN2C(=O)C=CC2=O)C(=O)Cc2ccc(O)cc2)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 50-mL round bottom flask loaded with 2-(2-(2-(4-hydroxyphenyl)-N-(2-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)ethyl)acetamido)acetamido)acetic acid 3 (0.113 g, 0.131 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.038 g, 0.198 mmol, 1.5 eq.) and 2-maleimidoethylamine.HCl (0.035 g, 0.198 mmol, 1.5 eq.). The mixture was dissolved in 10 mL of CH3CN and stirred for 12 hours at room temperature. After solvent removal in vacuo, purification was achieved by preparative reverse-phase HPLC (gradient from 100% 0.1% formic acid in water to 50% 0.1% formic acid in water/50% CH3CN) to give 4. 1H-NMR (300 MHz, CDCl3) δ 9.02 (m, 1H), 8.07 (m, 1H), 7.01 (m, 2H), 6.79 (m, 2H), 6.65 (s, 1H), 4.23-2.80 (m, 34H), 1.45 (s, 27H); 13C-NMR (75 MHz, CDCl3) δ 173.67, 173.43, 171.04, 170.33, 170.26, 170.08, 169.94, 169.86, 168.64, 156.55, 156.47, 134.16, 130.33, 130.06, 125.57, 125.09, 115.95, 115.84, 81.93, 81.87, 81.81, 81.70, 56.63, 56.08, 55.90, 53.12, 52.01, 50.95, 49.79, 49.41, 49.39, 47.22, 43.44, 43.07, 39.58, 39.15, 38.25, 38.10, 37.74, 37.34, 28.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][C:26]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH3:15])=[O:27])=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc([N+](=O)[O-])cc1)CC2

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methyl-isoquinoline (35.2 g, 0.17 m) in methylene chloride (50 ml) under nitrogen at ambient temperature was added p-nitrophenylacetic acid (31.4 g, 0.17 m) and then portionwise dicyclohexylcarbodiimide (37.0 g, 0.18 m) and the mixture stirred for 3 hr. The precipitated solid was removed by filtration and the filtrate evaporated to an oily residue. The residue was treated with 500 ml methanol and the solid precipitate collected by filtration to give, after drying, N-(4-nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as a yellow solid, 66.0 g (100+% yield). The product contains a small amount of dicyclohexylurea.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][Cl:30])[CH:7]=[CH:6][CH:5]=3)[C:16]=12
Reactant: O=C(Cl)CCl
Reactant: CC(C)n1nc(-c2cccc(N)c2)c2c(N)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2cccc(NC(=O)CCl)c2)c2c(N)ncnc21
Reaction time: 1 h
Yield: 13 %

Procedure:
A solution of THF (20 mL), compound 22 (200 mg, 0.75 mmol) and DIPEA (143 μL, 0.821 mmol) was cooled to 0° C. Chloroacetylchloride (54 μL, 0.67 mmol) was added and the reaction was allowed to proceed for 1 hour and afterwards concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and washed with saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (30.4 mg, 13% yield): 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.41 (s, 1H), 7.95 (s, 1H), 7.67 (d, J=7.6, 1H), 7.53 (t, J=7.9, 1H), 7.41 (d, J=7.7, 1H), 5.11 (hept, J=6.7, 1H), 4.30 (s, 2H), 1.51 (d, J=6.7, 6H); 13C NMR (100 MHz, DMSO) δ 165.06, 154.82, 151.89, 150.90, 144.68, 139.03, 132.62, 128.28, 123.81, 120.02, 119.24, 96.92, 48.84, 43.55, 21.77; [M+H]+ calculated for C16H17ClN6O 345.1, found 345.4.