Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([NH:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1.CN(C)C=O.CCOC(C)=O>[O:19]=[C:18]1[CH2:17][CH2:16][CH2:15][N:14]1[C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21]
Reactant: CC(C)(C)OC(=O)[C@H](NCCCC(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CCCC1=O
Yield: 86.1 %

Procedure:
The product of example 128B (307 mg, 1.05 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (602 mg, 3.14 mmol) in pyridine (5 mL) and dimethylformamide (5 mL) was stirred at ambient temperature for 16 hours. The mixture was diluted with EtOAc and washed with H2O and brine. The organic was dried (MgSO4), filtered and concentrated. Purification by chromatography (silica gel, 60% EtOAc in Hexanes) afforded 249 mg (86%) of the title compound. MS (ESI) m/z 276 (M+H)+.
Reaction SMILES: C(C1C=C(O)C(=CC=1)O)(C)(C)C.S(Cl)([Cl:15])=O.CN(C)C=O.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:33])(=O)=[O:31])=[CH:26][CH:25]=1.[Na+]>O>[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([Cl:15])(=[O:33])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: C=Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)Cl)cc1

Procedure:
Into a reaction vessel fitted with a cooling pipe, a stirrer, a thermometer and a nitrogen feed pipe, 2.0 parts of 4-tert-butylcatechol, 565 parts of thionyl chloride and 400 parts of dehydrated N,N-dimethylformamide were fed, and then stirred under ice cooling. To the solution obtained, while this was kept at 0° C. or below, 150 parts of formula-(18) sodium p-styrenesulfonate was dividedly added thereto. After its addition, the reaction solution was stirred for 24 hours while keeping the liquid temperature. After the reaction was completed, the reaction solution was poured into 1,500 parts of water to carry out extraction with toluene, and the organic layer formed was washed with ion-exchanged water. This organic layer was then dried with sodium sulfuric anhydride, followed by evaporation of the solvent under reduced pressure to obtain 128 parts (quantitative) of formula-(19) p-styrenesulfonic acid chloride.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([O:14][CH3:15])[CH:5]=1>C(O)(=O)C>[Br:1][C:9]1[C:4]([F:3])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([NH:10][C:11](=[O:13])[CH3:12])[CH:8]=1
Reactant: COc1cc(F)ccc1NC(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc(F)c(Br)cc1NC(C)=O
Reaction time: 3 h

Procedure:
Bromine (1.8 ml, 34 mmol) was added dropwise to a solution of the product of Step 1 (5.69 g, 31 mmol) in acetic acid (100 ml). After 18 hours at room temperature additional bromine (0.3 ml) was added and the solution stirred for a further 3 hours. The solution was partitioned between water and ethyl acetate and the layers separated. The organic phase was then washed with aqueous sodium thiosulfate solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound. MS (ES+) m/e 262/264 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 4 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of cholesterol (19.3 g, 50.0 mmol) in anhydrous CH2Cl2 (250 mL) was cooled to 4° C. by ice-water bath. To this solution, triethylamine (13.9 mL, 100.0 mmol) was added, followed by the dropwise addition of methanesulfonyl chloride (4.3 mL, 55 mmol) in anhydrous CH2Cl2 (50 mL). The reaction was maintained at 4° C. and stirred for 3 h. When the cholesterol was consumed as analyzed by TLC (hexanes/ethyl acetate, 5:1), the solvent was removed in vacuo. The resulting residue was redissolved in CH2Cl2 (15 mL), the product was precipitated by addition of MeOH (150 mL), and the product collected by vacuum filtration. The solid was washed with MeOH (30 mL) and dried under vacuum to yield the product (23.0 g, 99.0%) as a white solid, mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ 5.41 (s, 1H), 4.56-4.45 (m, 1H), 3.00 (s, 3H), 2.57-2.43 (m, 2H), 2.04-0.81 (m, 38H), 0.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.6, 123.7, 81.9, 56.5, 56.0, 49.9, 42.2, 39.6, 39.4, 39.1, 38.7, 36.8, 36.3, 36.1, 35.7, 31.8, 31.7, 28.9, 28.1, 27.9, 24.2, 23.8, 22.8, 22.5, 20.9, 19.1, 18.6, 11.8; IR (film) ν max 3029, 2944, 2908, 2861, 1468, 1440, 1415, 1353, 1330, 1173 cm−1; ESI+ m/z ((MNa)+ 487.3237, C28H48O3SNa requires 487.3222).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.CCN(P1(N(CC2C=CC=CC=2)CCCN1C)=NC(C)(C)C)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C1COCC1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:31])[CH2:29][CH3:30])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1Cc1ccccc1
Solvent: C1CCOC1
Solvent: C=Cc1ccccc1
Product: CCC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
According to the procedure described in Example 67, the title compound was prepared by using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol), propionyl chloride (87 uL, 1 mmol, Aldrich), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, polymer bound (BEMP resin), (0.34 g, 0.75 mmol) in THF (5 mL). Purification by silica gel chromatography (1:4 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 445 (M+1). Mp: 196.9–197.6° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[CH2:27]([NH:26][S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:35])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Lithium hydroxide monohydrate (0.031 g, 0.70 mmol) was added to a solution of [4-(4-benzylsulfamoyl-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.090 g, 0.18 mmol) in a 3:1 mixture of THF—H2O mixture (12 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave [4-(4-benzylsulfamoyl-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid (0.080 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.38-12.59 (m, 1 H), 8.34 (t, J=6.40 Hz, 1 H), 7.97 (d, J=8.20 Hz, 1 H), 7.88-7.93 (m, 3 H), 7.50 (dd, J=8.60, 2.40 Hz, 1 H), 7.40 (d, J=8.31 Hz, 2 H), 7.17-7.32 (m, 5 H), 7.03 (d, J=1.47 Hz, 1 H), 4.18 (d, J=5.87 Hz, 2 H), 3.86 (s, 2 H), 2.04 (s, 3 H). MS calcd. for C26H21ClNO4S [(M−H)−] 478, obsd. 478.2.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2](=[O:8])/[CH:10]=[CH:9]/[O:11][CH2:12][CH3:13])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C=COCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CCO/C=C/C(=O)C(=O)OCC
Temperature: 55 °C
Yield: 69.7 %

Procedure:
Reference: Dujardin, G; Rossignol, S.; Brown, E. Synthesis, 1998, 763-770. Add ethyl chlorooxoacetate (67 mL, 600 mmol) to a solution of palladium acetate (1.35 g, 6 mmol), ethyl vinyl ether (315 mL, 3.3 mol), and triethylamine (125 mL, 900 mmol) at ambient temperature. Heat to 55° C. for 24 hours, cool to room temperature, then partition the reaction mixture between diethyl ether and water. Concentrate under reduced pressure the organic layer to obtain (E)-4-ethoxy-2-oxo-but-3-enoic acid ethyl ester (72 g, 70%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J=13.2 Hz, 1H), 6.15 (d, J=13.2 Hz, 1H), 4.29 (q, J=7.6 Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 1.34 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([OH:26])=O)=[CH:18]3)=[N:12][CH:13]=1)=[O:6].[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH2:40][N:41]3[CH2:46][CH2:45]C[CH2:43][CH2:42]3)=[CH:39][C:34]=2[O:33][CH2:32]1.Cl.C([N:50]=C=NCCCN(C)C)C.O>C1COCC1>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH2:40][N:41]3[CH2:42][CH2:43][N:50]([C:24]([C:19]4[NH:20][C:21]5[C:17]([CH:18]=4)=[CH:16][C:15]([O:14][C:11]4[N:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]6[CH:27]=[CH:28][C:29]([Cl:30])=[C:2]([Cl:1])[CH:3]=6)=[CH:9][CH:10]=4)=[CH:23][CH:22]=5)=[O:26])[CH2:45][CH2:46]3)=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: CCN=C=NCCCN(C)C
Reactant: c1cc2c(cc1CN1CCCCC1)OCO2
Reactant: O=C(Nc1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2)nc1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccc3[nH]c(C(=O)N4CCN(Cc5ccc6c(c5)OCO6)CC4)cc3c2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.9 %

Procedure:
5-[5-(3,4-Dichlorobenzoylamino)pyridin-2-yloxy]-1H-indole-2-carboxylic acid (0.250 g, 0.565 mmol) was dissolved in THF (20 mL). To the solution were added 1-benzo[1,3]dioxol-5-ylmethylpiperadine (0.125 g, 0.565 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.119 g, 0.622 mmol), and the resulting solution was stirred for 15 hours at room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to yield 0.360 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[CH3:37][NH:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:43][CH:40]([CH2:41][OH:42])[CH2:39][N:38]([CH3:37])[C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:35])([F:34])[F:36])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: CNCC(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC(O)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (1.2 g, 2.44 mmol) and 3-methylamino-1,2-propanediol (0.32 g, 3.04 mmol) in N,N-dimethyl formamide (10 mL) was added 1-hydroxybenzotriazole (0.36 g, 2.66 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.52 g, 2.71 mmol) followed by N,N-diisopropylethyl amine (0.64 mL, 3.67 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown foam. Purification by flash chromatography using a solvent system of 5% methanol in chloroform gave a white foam, which was crystallized from ethyl acetate to provide 1.15 g of title product as a white solid, m.p. 169-172° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][C:25]([CH2:33][CH3:34])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:24][C:25]([CH2:33][CH3:34])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)oc1CC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)oc1CC
Yield: 71.7 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.21 g, 1.2 mmol), thionyl chloride (5 mL), ethyl 2-(4-aminophenyl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (99b) (0.2 g, 0.77 mmol) and pyridine (5 mL), to obtain 0.23 g of the title compound as a light pink solid (72%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:38])[NH:32][C:33]3[N:34]=[N:35][NH:36][N:37]=3)=[CH:27][CH:26]=2)[C:12](=[O:23])[NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(O[C:50]1[C:55]([F:56])=[C:54]([F:57])[C:53]([F:58])=[C:52]([F:59])[C:51]=1[F:60])=O>CN(C=O)C>[F:56][C:55]1[C:50]([O:18][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([NH:13][C:12]([N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)[CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:38])[NH:32][C:33]4[N:34]=[N:35][NH:36][N:37]=4)=[CH:27][CH:26]=3)=[O:23])[CH:15]=2)=[C:51]([F:60])[C:52]([F:59])=[C:53]([F:58])[C:54]=1[F:57]
Reactant: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)O)c2)cc1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C(=O)Nc2cccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the above resin bound 3-{3-(4-tert-butylphenyl)-3-[4-(2H-tetrazol-5-ylcarbamoyl)benzyl]ureido}benzoic acid was added a solution of pyridine (500 μL) in DMF (5 mL) followed by pentafluorophenyl trifluoroacetate (850 μL). The mixture was shaken for 4 hours at 25° C., filtered and washed with DMF (2×10 mL), affording the resin bound title compound.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:17])[CH2:15][OH:16].CO.C[O-].[Na+]>CCOCC>[CH2:1]([NH:13][C:15](=[O:16])[CH2:14][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)CO
Reactant: CCCCCCCCCCCCN
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)CO
Yield: 74.9 %

Procedure:
181.4 g (1.0 mol) of dodecylamine, 104.1 g (1.0 mol) of ethyl glycolate and 7.5 g (40 mmol) of a methanol solution containing 28% sodium methylate were fed into a 500-ml four-necked flask equipped with a stirrer and a thermometer. The obtained mixture was stirred under a stream of nitrogen gas, and the temperature thereof was elevated to 100° C. At this temperature, the reaction mixture was stirred for 2 hr while distilling off formed methanol. The obtained reaction mixture was dissolved in 500 ml of ether at room temperature. The ether solution thus obtained was transferred to a separatory funnel, and washed with water. The ether phase was separated, and concentrated. The solid remaining after concentration was dried in a reduced pressure to thereby obtain 182.3 g of white powdery N-dodecylglycolamide (yield: 74.9%). The hydroxyl value of this N-dodecylglycolamide was 229.4 (calculated value: 230.5).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C(OCC)=O)NN=1)(C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH:50]([C:51]([O:53][CH3:54])=[O:52])[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46](B(O)O)[CH:47]=2)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:13]([O:12][C:10]([C:8]1[N:7]([C:46]2[CH:47]=[C:48]3[C:43](=[CH:44][CH:45]=2)[CH2:42][N:41]([C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])[CH:50]([C:51]([O:53][CH3:54])=[O:52])[CH2:49]3)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1Cc2cc(B(O)O)ccc2CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1cc(C(=O)OCc2ccccc2)[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1Cc2cc(-n3nc(C(C)(C)C)cc3C(=O)OCc3ccccc3)ccc2CN1C(=O)OC(C)(C)C
Yield: 81 %

Procedure:
To a solution of benzyl 3-t-butyl-1H-pyrazole-5-carboxylate (0.100 g, 0.387 mmol, synthesized by trans-esterification of commercially available ethyl 3-t-butyl-1H-pyrazole-5-carboxylate), 2-(t-butoxycarbonyl)-3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (0.195 g, 0.581 mmol, made analogously to Example A56) and pyridine (0.092 g, 1.16 mmol) in methylene chloride (4 mL) was added copper(II)-acetate (0.105 g, 0.581 mmol) and the resulting mixture was stirred at Rt for 1d. The mixture was directly loaded on a silica gel column, chromatographed and concentrated to yield 2-t-butyl 3-methyl 6-(5-(benzyloxycarbonyl)-3-t-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2,3 (1H)-dicarboxylate (171 mg, 81% yield) as a colorless foam. MS expected 548.3 found 548.3. To this material (0.136 g, 0.248 mmol) in EtOAc (5 mL) was added palladium on charcoal (10%, 0.013 g, 0.012 mmol) and the mixture was stirred under an atmosphere of H2 overnight. The mixture was filtered and the filtrate was concentrated to yield 1-(2-(t-butoxycarbonyl)-3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazole-5-carboxylic acid (114 mg, 100%) as a colorless foam. MS expected 458.2 found 458.3.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=O)[CH2:10][CH2:9]1)=O)(C)C.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]([C:32]2[S:36][C:35]([CH2:37][N:38]3[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]3)=[CH:34][CH:33]=2)[CH:29]=[CH:30][CH:31]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:51][C@@H:40]1[NH:41][CH2:42][CH2:43][N:38]([CH2:37][C:35]2[S:36][C:32]([C:28]3[CH:27]=[C:26]([CH2:25][NH:24][C:18](=[O:20])[C:17]4[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:16]=4)[CH:31]=[CH:30][CH:29]=3)=[CH:33][CH:34]=2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Reactant: C[C@H]1CN(Cc2ccc(-c3cccc(CN)c3)s2)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc(-c3cccc(CNC(=O)c4cccc(CC5CCNCC5)c4)c3)s2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (319 mg, 1.0 mmol) in CHCl3 (5.0 mL) was added 1,1-dimethylethyl (2S)-4-({5-[3-(aminomethyl)phenyl]-2-thienyl)methyl)-2-methyl-1-piperazinecarboxylate (401 mg, 1.0 mmol), TEA (0.26 ml, 2 mmol), EDC (288 mg, 1.5 mmol) and HOBt (150 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 2 h, followed by addition of 1 mL of saturated Na2CO3. The organic layer was dried over Na2SO4, and filtered. The filtrate was mixed with 1 mL of TFA, and stirred at room temperature for 1 h. After removal of the solvent, the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (261 mg, 52%). LC/MS: m/z, 502 (M+H), 1.31 min.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.Br[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].C([N:27]1CCOCC1)C.C>C(O)(C)C.N>[N+:22]([C:21]1[C:13]([NH:27][C:6]2[CH:5]=[N:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=3)[N:7]=2)=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])([O-:24])=[O:23]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: Nc1cccc2nccnc12
Reactant: CCN1CCOCC1
Agent: N
Solvent: CC(C)O
Product: O=C(O)c1cccc([N+](=O)[O-])c1Nc1cnc2ccccc2n1
Temperature: 67.5 °C
Yield: 42 %

Procedure:
A mixture of 5-aminoquinoxaline (1.0 g, 6.89 mmol), 2-bromo-3-nitrobenzoic acid (4.0 g, 13.78 mmol), Cu/CuI (catalytic) and N-ethylmorpholine (5 mL) in isopropanol (5 mL) was heated at 65-70° C. overnight. The mixture was then dissolved in aqueous ammonia, treated with charcoal/Celite, and filtered. The filtrate was acidified with conc. HCl, and the resulting precipitate was collected while the mixture was still warm and washed with water (to remove unreacted 2-bromo-3-nitrobenzoic acid). It was then dried and chromatographed on silica gel, eluting with CH2Cl2/MeOH (19:1), to give 3-nitro-(quinoxalinylamino)benzoic acid (0.9 g, 42%): mp (MeOH) 232-237° C.; 1H NMR [(CD3)2SO] δ 6.92-6.97 (m, 1 H, ArH), 7.30 (t, J=8.0 Hz, 1 H, ArH), 7.62-7.66 (m, 2 H, 2xArH), 8.23 (dd, J=8.2, 1.6 Hz, 1 H, ArH), 8.29 (dd, J=7.8, 1.6 Hz, 1 H, ArH), 8.97 (d, J=1.7 Hz, 1 H, H-2′ or H-3′), 9.03 (d, J=1.9 Hz, 1 H, H-2′ or H-3′), 10.73 (br s, 1 H, NH), 13.8 (br s, 1 H, CO2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])C=1B(O)O.[CH3:22]OCCOC.O>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])=[C:2]([CH3:22])[CH:7]=1
Reactant: COc1cccc(F)c1B(O)O
Reactant: Cc1ccc(Cl)cc1Br
Reactant: COCCOC
Solvent: O
Product: COc1cccc(F)c1-c1ccc(Cl)cc1C

Procedure:
Treatment of 2-bromo-4-chlorotoluene (20 mL, 0.15 mol) with 2-fluoro-6-methoxybenzene boronic acid (10.0 g, 58.8 mmol) in DME-water (5:1, 300 mL) according to the procedure described for Example 69, Step 1 provided 21.0 g of 4-chloro-2′-fluoro-6′-methoxy-2-methylbiphenyl as a colorless oil.