Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1.[Li+].CC([N-]C(C)C)C.C[O:20][B:21](OC)[O:22]C.Cl>C1COCC1>[CH3:1][N:2]1[C:6]([B:21]([OH:22])[OH:20])=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1
Reactant: COB(OC)OC
Reactant: Cn1ccc(C(F)(F)F)n1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1B(O)O
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-3-trifluoromethylpyrazol (2 g) in 10 ml THF is cooled under an inert gas atmosphere to −78° C. A 2 M solution of LDA (9.75 ml) is added dropwise. The mixture is stirred to 10° C. for 1 h and cooled to −75° C. Trimethylborate (5.8 ml) is added and after stirring for 1 h at −75° C. the mixture is stirred overnight at ambient temperature. The resulting reaction solution is added to 10% hydrochloric acid (15 ml). The water phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with water and a saturated sodium chloride solution. The organic phase is dried and evaporated and the residue is crystallized from water. After drying, one obtains the title compound as nearly colorless crystals (1.12 g) of mp. 138° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH:26][C:27]([CH2:29][CH2:30][CH2:31][CH2:32][C@H:33]1[C@@H:41]2[C@@H:36]([NH:37][C:38]([NH:40]2)=[O:39])[CH2:35][S:34]1)=O.ON1C(=O)CC[C:44]1=O>CN(C=O)C>[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:44])[C:11]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)(=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][C@H:33]1[C@@H:41]2[C@@H:36]([NH:37][C:38]([NH:40]2)=[O:39])[CH2:35][S:34]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: NCc1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)[nH]2)cc1
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(CNC(=O)CCCC[C@@H]3SC[C@@H]4NC(=O)N[C@@H]43)cc2)nc(-c2ccccc2)c1-c1ccncc1

Procedure:
To a solution containing 2-(4-Aminomethylphenyl)-4-phenyl-5-(4-pyridyl)-imidazole (1 equivalent) in DMF was added N-hydroxysuccinimide biotin (1.2 eq). Follwing normal workup and chromatography the title compound was obtained: CIMS (NH3, m/z): 523 (M++H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4][N:3]=1.O.[NH2:16][NH2:17].C(N(CC)CC)C.C1COCC1>O>[CH2:8]([C:7]1[C:2]([NH:16][NH2:17])=[N:3][CH:4]=[N:5][C:6]=1[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)[CH3:9]
Reactant: NN
Reactant: CCc1c(Cl)ncnc1-c1ccco1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1c(NN)ncnc1-c1ccco1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 4-chloro-5-ethyl-6-(furan-2-yl)-pyrimidine (3.0 g), hydrazine monohydrate (3.0 g), triethylamine (3.0 g), and THF (20 ml) was stirred under reflux for 2 hours. To the mixture, hydrazine monohydrate (1 g) was added, and stirred under reflux for 3 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 2.85 g of [5-ethyl-6-(furan-2-yl)-pyrimidin-4-yl]-hydrazine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:14])=[C:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[O:27][CH3:28].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>O>[CH:15]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=2[O:27][CH3:28])[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]=1[OH:14])([CH3:17])[CH3:16]
Reactant: CC(C)c1cc(C(=O)CBr)cc(C(C)C)c1O
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1OCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6.00 g (18.3 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone and 2.78 g (18.3 mmol) of 4-hydroxy-3-methoxy-benzaldehyde in 20 ml of ethyl acetate 5.00 g (36.7 mmol) of potassium carbonate is added and the mixture is stirred for 18 hours at room temperature. After addition of water and adjusting the pH to 5-6 by adding 32% HCl, the mixture is extracted with ethyl acetate. The combined extracts are washed with water, dried and evaporated to give compound 102. 1H-NMR (300 MHz, CDCl3), δ (ppm): 7.79 (s, 2H), 7.46-7.45 (d, 1H), 7.41-7.38 (dd, 1H), 6.90-6.87 (d, 1H), 5.43 (s, 2H), 3.97 (s, 3H), 3.24-3.15 (sept., 2H), 1.32-1.29 (d, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br.Br[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:2]([NH:1][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1cc(Cl)ccc1S
Reactant: BrCc1cccnc1
Agent: Br
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1cccnc1)c1cc2ccccc2o1

Procedure:
Following General Procedure A and B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 3-bromomethyl-pyridine hydrobromide, and benzofuran-2-sulfonyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
In ethanol(50 ml) was dissolved 1-(4-nitrobenzyl)piperidine (6.41 g), and 10% dried palladium on carbon (0.33 g)was added to the mixture. Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 24 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was recrystallized from hexane to give 1-(4-aminobenzyl)piperidine (1.01 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[C:4]([CH3:20])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH:46]1[CH2:53][CH:52]2[N:54]([CH3:55])[CH:48]([CH2:49][CH2:50][CH2:51]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:55][N:54]1[CH:48]2[CH2:49][CH2:50][CH2:51][CH:52]1[CH2:53][CH:46]([NH:45][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[CH3:20])=[N:12][C:11]=13)=[O:19])[CH2:47]2
Reactant: Cc1cc(Cl)ccc1-c1nc2c(C(=O)O)cccc2o1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
A mixture of 2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxylic acid (59 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (79 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (72 mg, 0.26 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.11 mL, 0.82 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (2×20 mL), brine (2×20 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative TLC (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chloro-2-methylphenyl)benzoxazole-4-carboxamide (19 mg, 22%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.01 (br s, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.71 (dd, J=8.1, 0.9 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.43-7.36 (m, 2H), 4.67-4.60 (m, 1H), 3.25-3.15 (m, 2H), 2.88 (s, 3H), 2.70-2.55 (m, 2H), 2.48 (s, 3H), 2.10-2.00 (m, 3H), 1.65-1.40 (m, 3H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 424 (M+H); HPLC 98.4% (AUC), tR=13.82 min.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:34])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Product: O=C(CCc1ccc(Oc2ccccc2)cc1)Nc1cccc2c1cnn2CCN1CCCC1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine and 3-(4-phenoxy-phenyl)-propionic acid were processed according as described in Example 3 to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.84 (m, 2 H), 2.00 (m, 2 H), 2.64 (t, J=7.64 Hz, 2 H), 2.93 (t, J=7.64 Hz, 2 H), 3.06 (m, 2 H), 3.52 (m, 2 H), 3.71 (m, 2 H), 4.74 (t, J=6.08 Hz, 2 H), 6.95 (m, 4 H), 7.11 (m, 1 H), 7.28 (m, 2 H), 7.36 (m, 2 H), 7.49 (m, 1 H), 7.67 (m, 1 H), 8.13 (m, 2 H), 9.95 (s, 1 H); MS (DCI/NH3) m/z 455 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:33])[C:29](Br)([CH3:31])[CH3:30])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:33])[C:29]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]([CH3:24])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:31])[CH3:30])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCCCn1c(C)c(-c2ccc(F)cc2)c2cc(O)ccc21
Product: CCCCCCn1c(C)c(-c2ccc(F)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-fluoro-phenyl)-1-hexyl-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[CH3:43][O:44][C@@H:45]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:46](OCC#N)=[O:47].N1C=CN=C1.C(O)(C(F)(F)F)=O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.O>[CH3:43][O:44][C@H:45]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:46]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:47]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CO[C@@H](Cc1ccccc1)C(=O)OCC#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H](Cc1ccccc1)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: 0.5 h
Yield: 16.5 %

Procedure:
((2R,3S,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h, 0.32 g, 0.50 mmol) and (S)-cyanomethyl 2-methoxy-3-phenylpropanoate (Compound 7b, 0.44 g, 2.01 mmol) were added to a solution of imidazole (3.40 g, 50.00 mmol) and N,N,N-trimethylhexadecan-1-aminium chloride (3.20 g, 10.00 mmol) dissolved in water (30 ml), and the mixture was stirred at room temperature for 30 minutes. TFA (1.0 ml) was added to the reaction solution, followed by concentration. The resulting residue was purified by preparative HPLC (0.05% aqueous TFA solution:acetonitrile=84:16→60:40) to afford the title compound (66 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([N:13]=[N+]=[N-])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[H][H]>CO.[Re]>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH2:13])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: COC(=O)C(CSc1ccccc1)N=[N+]=[N-]
Agent: [Re]
Agent: Cl
Solvent: CO
Product: COC(=O)C(N)CSc1ccccc1
Yield: 80.1 %

Procedure:
0.91 gram (3.84 mmoles) of the 2-azido-3-phenylmercapto-propionic acid methyl ester obtained in Example 2 in 8 ml of methanol was treated with 0.28 gram (7.68 mmoles) of hydrogen chloride, 1 mole % of rhenium VII sulfide based on the azido compound employed was added and the mixture hydrogenated in an autoclave at a hydrogen pressure of 60 bar at 25° C. for 3.5 hours. After the end of the reaction the catalyst was filtered off with suction, the solvent remained under reduced pressure and the residue treated with 20 ml of acetone. After addition of 20 ml of diethyl ether for complete precipitation, the precipitate was filtered off with suction, then washed with diethyl ether and dried at 40° C. for 12 hours under reduced pressure. There were obtained 0.65 gram (68% of theory) of 2-amino-3-phenylmercapto-propionic acid methyl ester.HCl with a melting point of 123° to 125° C.
Reaction SMILES: ClCC([O:5][CH:6]([CH2:41][O:42]C(=O)CCl)[CH2:7][NH:8][C:9](=[O:40])[C:10]1[C:31]([I:32])=[C:30]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])[C:29]([I:38])=[C:12]([C:13]([NH:15][CH2:16][CH:17]([O:24]C(=O)CCl)[CH2:18][O:19]C(=O)CCl)=[O:14])[C:11]=1[I:39])=O.[OH-].[Na+].O.Cl>CN(C)C(=O)C>[OH:5][CH:6]([CH2:41][OH:42])[CH2:7][NH:8][C:9](=[O:40])[C:10]1[C:31]([I:32])=[C:30]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])[C:29]([I:38])=[C:12]([C:13]([NH:15][CH2:16][CH:17]([OH:24])[CH2:18][OH:19])=[O:14])[C:11]=1[I:39]
Reactant: O=C(CCl)Nc1c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Yield: 88.4 %

Procedure:
N,N′-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide in N,N-dimethylacetamide, from Example 1, was hydrolyzed by adding 156 mL of 10N sodium hydroxide solution (1.56 moles). Water (100 mL) was then added to the mixture to give a homogeneous solution. 1N Hydrochloric acid(59 mL, 0.59 moles) was added to precipitate the N,N′-bis (2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. The precipitate was collected and washed with water. The wet product was dried at 60° C. in a vacuum oven to give 81.69 g of product, 88.4% yield. The material was 100% pure by HPLC analysis.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:43])[NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][O:38][CH3:39])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(OCC)C>ClCCl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:41]=[CH:40][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][O:38][CH3:39])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:42])[CH:8]=2)=[O:43])[CH2:3][CH2:2]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To 338 (0.19 g, 0.31 mmol) in dichloromethane (40 mL) was added TFA (3 mL). The solution was stirred for 6 h, then concentrated. The residue was partitioned between 98:2 dichloromethane/methanol mixture and 1M NaOH(aq), washed with brine, dried over MgSO4, filtered and concentrated. The resulting oil was triturated with diethyl ether and ethyl acetate providing 339 (0.13 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1H: 8.80 (s, 1H); 8.57 (s, 1H); 8.51 (d, J=5.5, 1H); 8.31 (s, 1H); 8.23 (d, J=8.0, 1H); 7.89 (dd, J=8.0, 1.5, 1H); 7.73 (dd, J=13.5, 2.2, 1H); 7.38 (t, J=9.0, 1H); 7.20 (d, J=8.2, 1H); 6.66-6.62 (m, 2H); 3.78 (s, 2H); 3.41 (t, J=5.7, 2H); 3.24 (s, 3H); 2.65 (d, J=5.7, 2H); 2.57-2.51 (m, 1H); 0.66-0.62 (m, 2H); 0.44-0.41 (m, 2H). MS (m/z): 508.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16]1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:19]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[O:20])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)C2CCC2)C1

Procedure:
Acylation of (R)-piperidin-3-yl-carbamic acid tert-butyl ester (300 mg) with cyclobutyl carbonylchloride (0.342 ml) was performed according to the method described for example 20c. The residue was concentrated in vacuo and used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH3:13])=[C:4]([CH2:14][O:15][CH3:16])[CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23]>C1COCC1>[CH3:16][O:15][CH2:14][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: COCc1cc(Br)ccc1N1CCCC1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1cc(C(=O)O)ccc1N1CCCC1C
Reaction time: 3 h

Procedure:
To a solution of 1-[4-Bromo-2-(methoxymethyl)phenyl]-2-methylpyrrolidine (16.5 g, 58 mmol) in anhydrous THF (160 mL) was added n-butyl lithium in drops at −78° C. After 3 hours at −78° C., the reaction mixture was poured onto crushed dry-ice (100 g). Once the excess carbon dioxide was escaped, the reaction mixture was evaporated, and then acidified with 1.5 N HCl. The precipitate was filtered off and washed with pet ether to afford title compound as a solid. LC/MS, M+(ESI): 249.9. 1H NMR (DMSO-d6, 400 MHz) δ 12.4 (1H, brs), 7.84 (1H, s), 7.70 (1H, d), 6.85 (1H, d), 4.32-4.42 (2H, m), 3.59-3.87 (1H, m), 3.56 (1H, m), 3.29 (3H, s), 3.13 (1H, m), 2.14 (1H, m), 1.89 (1H, m), 1.74 (1H, m), 1.55 (1H, m), 0.99 (3H, d).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.O=S(Cl)[Cl:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([Cl:15])=[O:12])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c[nH]c2ccccc12

Procedure:
Indole 3-carboxylic acid, (2.0 g) was dissolved in 5 ml of SOCl2. The mixture was heated to reflux for 30 minutes. Removal of excess of SOCl2 under vacuum provided intermediate 9, indole 3-carbonyl chloride, which was carried to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])([CH2:7][OH:8])[C:4](=[O:17])[O:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[O:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])([CH2:7][O:8][S:20]([CH3:19])(=[O:22])=[O:21])[C:4](=[O:17])[O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC(=O)C(CO)(c2ccc(Cl)cc2Cl)O1
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(COS(C)(=O)=O)(c2ccc(Cl)cc2Cl)O1
Temperature: 0 °C

Procedure:
63.5 g (0.22 mole) of 2,2-dimethyl-4-(2,4-dichlorophenyl)-4-hydroxymethyl-1,3-dioxolan-5-one are dissolved in 400 ml of pyridine and to this solution are added 28.9 g of methanesulfonyl chloride at 0° to 5° C. The resultant suspension is stirred for 2 hours at the same temperature, then poured into ice-water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated to dryness. The residual resin is crystallised by addition of a small amount of diethyl ether/hexane and the product is isolated by filtration. Melting point: 98°-100° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[S:7][C:8]([CH:12]=O)=[C:9]([Cl:11])[N:10]=1.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O.CC1C=CC(S(O)(=O)=O)=CC=1>[Cl:5][C:6]1[S:7][C:8]([CH:12]2[O:4][CH2:1][CH2:2][O:3]2)=[C:9]([Cl:11])[N:10]=1
Reactant: OCCO
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc(Cl)c(C2OCCO2)s1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
In a round bottom flask equipped with a Dean-Stark trap was charged ethylene glycol (2.3 mL, 41.1 mmol), 2,4-dichloro-1,3-thiazole-5-carbaldehyde (2.5 g, 13.7 mmol), and toluene (35 mL). To this solution was added 4-methylbenzene-1-sulfonic acid hydrate (210 mg, 1.1 mmol). The reaction mixture was stirred at reflux overnight. After cooling to room temperature, the solution was poured in 10% sodium carbonate solution (50 mL). The mixture was extracted with EtOAc (2×35 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 2,4-dichloro-5-(1,3-dioxolan-2-yl)-1,3-thiazole (2.9 g, 93% yield). The product was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)#[N:2].O.NN.C(Cl)Cl.[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][NH2:7])#[N:2]
Reactant: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: N#Cc1cccc(CN)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of the N-(3-cyanobenzyl)phthalimide (2.70 g, 10.4 mmol) and hydrazine hydrate (2.5 mL, 51 mmol) in MeOH (50 mL) was heated to reflux for 1 h. After cooling at room temperature, CH2Cl2 and aq. 1N NaOH were added. The CH2Cl2 layer was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give an oil (1.10 g), which was pure enough for the next reaction. MS 133 (M+H) and 116 (M−NH2)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C(Cl)=O)=CC=1.[CH3:42][CH2:43][O:44][C:45]([C:47]1[CH:48]=[CH:49][C:50]([NH2:53])=[CH:51][CH:52]=1)=[O:46]>C1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:45]([O:44][CH2:43][CH3:42])=[O:46])=[CH:52][CH:51]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: O=C(Cl)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of 23.55 g. of bis(p-chlorophenyl)acetic acid in 250 ml. of benzene is added dropwise 33.1 g. of sulfonyl chloride. The mixture is refluxed 5 hours, the solvent is evaporated, and the residue is evaporated from three 250 ml. portions of benzene, giving 26.06 g. of bis(p-chlorophenyl)acetyl chloride as an oil. To this oil is added a solution of 27.7 g. of benzocaine. The mixture is stirred overnight, filtered, washed with 200 ml. each of 10% hydrochloric acid, saturated sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and evaporated. The residue is crystallized twice from 200 ml. of ethanol, giving 25.76 g. of the desired product as colorless needles, m.p. 171°-172° C.