Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:16])[S:13][C:14]=2[CH3:15])[CH:5]=1.[C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH3:19].[Li]>>[C:22]([O:21][C:18](=[O:20])[CH2:19][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12]([CH3:16])[S:13][C:14]=2[CH3:15])[CH:5]=1)=[O:17])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cccc(-c2nc(C)sc2C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: Cc1nc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)s1

Procedure:
A sample of 3-(2,5-dimethyl-thiazol-4-yl)-benzoic acid methyl ester (0.99 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give 3-[3-(2,5-dimethyl-thiazol-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (1.12 g) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[C:7]1([N:6]2[C:2]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[N:3][N:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)C[C@H](Nc1nnnn1-c1ccccc1)C(=O)O
Yield: 36.8 %

Procedure:
A suspension of 5-chloro-1-phenyl-1H-tetrazole (2.80 g, 15.5 mmol), L-leucine (3.36 g, 25.6 mmol) and potassium carbonate (6.43 g, 46.5 mmol) in isopropanol (20 mL) was heated to reflux for 3 h. The mixture was cooled and partitioned between ethyl acetate and 1 M HCl. The organic phase was washed with brine and concentrated. Purification by flash chromatography on silicic acid (50% ethyl acetate/hexanes) provided 1.57 g of N-(1-phenyl-1H-tetraazol-5-yl)-L-leucine.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C@@H:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C[N:17](C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.[Cl:37][C:38]1[C:39](=[S:47](=[O:49])=[O:48])[CH2:40][C:41](=[CH:45][CH:46]=1)[C:42](O)=[O:43]>>[NH2:17][S:47]([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:38]=1[Cl:37])[C:42]([NH:14][C@H:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:43])(=[O:49])=[O:48]
Reactant: CN1CCC[C@H]1[C@@H](N)c1ccccc1
Reactant: O=C(O)C1=CC=C(Cl)C(=S(=O)=O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: CN1CCC[C@H]1[C@@H](NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Yield: 46.7 %

Procedure:
According to the procedure described in Example 2, starting with 0.12 g (0.63 mmol) of [(S)-[(2S)-(1-methyl-2-pyrrolidinyl)]phenylmethyl]amine, 0.12 g (0.63 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, 0.085 g (0.63 mmol) of hydroxybenzotriazole and 0.14 g (0.63 mmol) of 4-chloro-3-sulfonylbenzoic acid, and after work-up and purification by chromatography on silica gel with a gradient of dichloromethane and methanol, 0.12 g of 3-(aminosulfonyl)-4-chloro-N-[(S)-[(2S)-1-methyl-2-pyrrolidinyl](phenyl)methyl]benzamide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:14]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[N:15]2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.CO.NN>C(OCC)(=O)C.[Ni].O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([N:14]2[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]2)[CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCCC(c1ccc(C(=O)OC)cc1)n1ccc([N+](=O)[O-])n1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC(c1ccc(C(=O)OC)cc1)n1ccc(N)n1
Yield: 94.1 %

Procedure:
The 4-[1-(3-nitro-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (127 mg, 0.42 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. While stirring, a 50% slurry of raney nickel in water (500 μL) was added followed by hydrazine (150 μL). Immediate effervescence was observed. The reaction continued to stir and bubble for 30 min. The reaction was passed through a plug of celite and concentrated in vacuo to afford 4-[1-(3-amino-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (108 mg, 94%) as a clear oil: ESI-LRMS m/e calcd for C15H19N3O2 [M+] 273.15, found 274.29 [M+H+], 547.43 [2M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH:11](Br)Br.Cl.C(=O)([O-])[O-:16].[Na+].[Na+]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH:11]=[O:16]
Reactant: O=C(O)c1ccc(Br)c(C(Br)Br)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: O=Cc1cc(C(=O)O)ccc1Br
Temperature: 70 °C

Procedure:
4-Bromo-3-(dibromomethyl)benzoic acid (3.7 g) was added to a solution of aqueous sodium carbonate (16 g in 100 ml) and the mixture heated at 70° C. for 12 hrs. The pH of the cooled reaction was adjusted to pH5 using hydrochloric acid (2N) and the mixture extracted with ethyl acetate, to give, after evaporation of the solvent in vacuo, 4-bromo-3-formylbenzoic acid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[CH:2]1[N:1]=[CH:5][N:4]2[CH:9]=[C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)[CH:7]=[CH:6][C:3]=12
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2nccn2c1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4cncn4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using imidazo[1,2-a]pyridine-6-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (ddd, J=8.1, 4.8, 1.0 Hz, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.78-7.92 (m, 2H), 8.21 (s, 1H), 8.46 (dt, J=8.2, 1.8 Hz, 1H), 8.83 (dd, J=4.7, 1.7 Hz, 1H), 9.27 (dd, J=2.2, 0.8 Hz, 1H), 9.69 (dd, J=1.7, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH2:25]>O1CCCC1>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[OH:1]
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (1.68 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 2,4-difluorobenzenamine (1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: N1C(C)=CC=CC=1C.[SH:9][CH:10]([CH3:14])[CH:11]([OH:13])[CH3:12].FC(F)(F)S(O[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[C:24]([Si:21]([CH3:23])([CH3:22])[O:13][CH:11]([CH3:12])[CH:10]([SH:9])[CH3:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(O)C(C)S
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(S)C(C)O[Si](C)(C)C(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2,6-lutidine (163 μl) was added to a solution of 3-mercapto-2-butanol (68 mg) in DCM (5 ml) and the mixture was cooled down to −20° C. Tert-butyldimethylsilyl trifluoromethanesulfonate (163 μl) was slowly added and it was stirred 1 h at −20° C. Another 163 μl of the silyl reagent was added and the mixture was allowed to warm to RT and stirred one might at RT. The mixture was evaporated off and used without purification and characterization.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([C:25](=[O:37])[NH:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=4)[CH:23]=[CH:24][C:18]=3[N:17]=2)=[C:11]([Cl:38])[CH:10]=1)(C)(C)C>Cl.O1CCOCC1>[Cl:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][C:6]([OH:39])=[O:5])[CH:10]=[C:11]([Cl:38])[C:12]=1[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25](=[O:37])[NH:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[CH:23]=[CH:24][C:18]=2[N:17]=1.[ClH:15]
Reactant: CC(C)(C)OC(=O)CCc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1

Procedure:
A solution of 3-(3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl)-propionic acid tert butyl ester (440 mg, 0.8 mmol) in 4 M HCl in dioxane (25 mL) was stirred at ambient temperature 6 h. The solution was evaporated to half volume and diluted with diethyl ether to give 3-(3,5-dichloro-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl)-propionic acid as an HCl salt. 1H-NMR (DMSO-d6, 400 MHz): δ 11.91 (s, 1H), 8.67 (d, J=9.09 Hz, 1H), 8.61 (s, 1H), 8.35 (d, J=9.09 Hz, 1H), 8.05-8.14 (m, 4H), 7.87 (t, J=7.77 Hz, 2H), 7.62-7.67 (m, 4H), 2.94 (t, J=7.33 Hz, 2H), 2.68 (t, J=7.39 Hz, 2H). MS (ESI) m/z 505.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH:28](O)=[O:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH:28]=[O:29])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: O=CO
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Product: O=CN1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1

Procedure:
A solution of the amine from example 4 (300 mg, 0.79 mmol) in formic acid (15 ml) was stirred at 80° C. for 3 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and sodium bicarbonate solution. The layers were separated, and the organic phase was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[C:20]([O:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)OCCc1c(-c2ccccc2)nc(N)n2ncnc12

Procedure:
The title compound, m.p. 89°-91°, was prepared by the method of Example 2 using 5.1 g (0.02 mole) of the product compound of Example 1 and 3.25 g (0.02 mole) of octanoyl chloride, except that the solution was not divided before purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][C:30](Br)=[O:31].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C1COCC1.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:30](=[O:31])[CH2:29][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[S:14][C:10]=1[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:9]
Reactant: Cc1cccc(C(=O)c2sc(N)nc2-c2ccco2)n1
Reactant: O=C(Br)CBr
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)c2sc(NC(=O)CN3CCOCC3)nc2-c2ccco2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Compound 286 (150 mg, 0.526 mmol) and triethylamine (0.367 mL, 2.63 mmol) were dissolved in THF (4 mL), and bromoacetyl bromide (0.206 mL 2.37 mmol) was added thereto at 0° C., followed by stirring for 1 hour at room temperature. Further, a solution (2 mL) of morpholine (0.689 mL, 7.89 mmol) and triethylamine (1.10 mL, 7.89 mmol) in THF was added thereto at 0° C., followed by stirring for 1 hour at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography to afford the entitled Compound 287 (150 mg, 69%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25](O)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:37][C:38]1[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][O:34][CH2:33]4)[CH:30]=3)[C:25]([NH:37][C:38]3[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][N:39]=3)=[O:26])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@H]3CCOC3)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.133 mL, 1.0 mmol) was added to a suspension of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid (350 mg, 0.94 mmol) in DCM (10 mL) and stirred at RT for 30 min. 2-Amino-5-methylpyrazine (196 mg, 1.82 mmol) and pyridine (0.148 mL, 1.82 mmol) were added and the reaction stirred at RT for 2 hours. The solvent was removed in vacuo and water (30 mL) added. The mixture was extracted with ethyl acetate (3×20 mL), washed with 2N hydrochloric acid (20 mL), water (10 mL), saturated aqueous sodium bicarbonate solution (20 mL), water (10 mL) and brine (20 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by chromatography, eluting with 0-10% methanol in DCM, to give the desired product as a colourless oil (150 mg). 1H NMR δ (CDCl3): 2.12-2.18 (1H, m), 2.22-2.29 (1H, m), 2.31-2.40 (2H, m), 2.56 (3H, s), 3.89-4.03 (4H, m), 4.25 (2H, t), 4.71 (2H, t), 4.97-5.00 (1H, m), 6.76 (1H, t), 7.15 (1H, t), 7.25 (1H, d), 7.38-7.40 (1H, m), 8.12 (1H, s), 8.14 (1H, d), 8.32 (1H, s), 8.34 (1H, d), 9.52 (1H, d); m/z 476 (M+H)+, 474 (M−H)−
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCCCCCC.[C:43]([O:49][CH2:50][CH3:51])(=[O:48])[CH2:44]C(O)=O>C1COCC1>[Si:1]([O:18][C@H:19]([CH3:23])[C:20](=[O:22])[CH2:44][C:43]([O:49][CH2:50][CH3:51])=[O:48])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: CCOC(=O)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCOC(=O)CC(=O)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2R)-2-{[tert-Butyl(diphenyl)silyl]oxy}propanoic acid (the product from step i, 7.85 g) in THF (300 ml) was added CDI (4.26 g) and the reaction was stirred at room temperature for approximately 15 mins. In a separate flask (71.7 ml) of a 1M heptane solution was added to a solution of ethyl hydrogen malonate (9.47 g) in THF (300 ml) at 0° C. This solution was then allowed to warm to RT. The acyl imidazole solution was then transferred to the flask which contained the magnesium salt and the reaction was monitored for the next 2 d. When the reaction was complete it was quenched by the addition of 250 ml of sat. aq NH4Cl solution. The reaction mixture was then extracted with Et2O (3×200 ml). The combined organics were dried (MgSO4), filtered and reduced to yield a clear oil which was purified by column chromatography on silica gel 4% EtOAc/96% iso-hexane. This gave the subtitle compound as a colourless oil. Yield: 2.0 g
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][CH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16]CC3C=CC=CC=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)C.C([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])(OCC1C=CC=CC=1)=O>>[NH2:35][C@H:36]([C:38]([N:6]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH2:5][C:4]([OH:3])=[O:24])=[O:39])[CH3:37]
Reactant: CCOC(=O)CNC1CCc2cc(OCc3ccccc3)ccc21
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: C[C@H](N)C(=O)N(CC(=O)O)C1CCc2cc(O)ccc21
Yield: 60.8 %

Procedure:
By reacting 10 g of (5-benzyloxyindan-1-yl)glycine ethyl ester with 8 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 4, there is obtained 5.2 g of L-alanyl-N-(5-hydroxyindan-1-yl)glycine as colorless amorphous powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[S:26][C:25]3[CH2:24][CH2:23][N:22](CC4C=CC=CC=4Cl)[CH2:21][C:20]=3[CH:19]=2)=[O:17])[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC(Cl)=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:17])[C:18]2[S:26][C:25]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]=3[CH:19]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1cc2c(s1)CCN(Cc1ccccc1Cl)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1cc2c(s1)CCNC2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 1.10 g (2.18 mmol) 4-benzyloxy-1-{2-[5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-yl]-2-oxo-ethyl}-1H-pyridin-2-one (example 38.1a) in 20 mL DCM is added at 0° C. 0.29 mL (2.61 mL) chloro-formic acid 1-chloro-ethyl ester. The reaction mixture is stirred 60 h at RT. Additional 0.29 mL (2.61 mL) chloro-formic acid 1-chloro-ethyl ester is added and the mixture is stirred overnight. Additional 0.29 mL (2.61 mL) chloro-formic acid 1-chloro-ethyl ester is added and the reaction mixture is refluxed overnight. The solvent is removed, to the residue 30 mL of methanol are added and the reaction mixture is refluxed for 30 min. After cooling to RT, the precipitate is collected after cooling the mixture to RT, washed with cold methanol and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[I:16]I.S(Cl)(Cl)(=O)=O.[F:23][C:24]1[CH:43]=[CH:42][C:27]([CH2:28][NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[O:31])=[CH:26][CH:25]=1>CN(C=O)C>[F:23][C:24]1[CH:43]=[CH:42][C:27]([CH2:28][NH:29][C:30](=[O:31])[C:32]2[CH:37]=[CH:36][C:35]([S:38]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]([I:16])=[CH:2]3)(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:26][CH:25]=1
Reactant: II
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(=O)(Cl)Cl
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(I)c3ccccc32)cc1
Reaction time: 0.37 h
Yield: 52.1 %

Procedure:
Dissolve indole (2.93 g 0.025 mole) in 10 ml DMF. Cool the solution in an ice-water bath. Add potassium-t-butoxide (3.08 g, 0.0275 mole) and 10 ml DMF. Stir in an ice-bath for 22 minutes. Add iodine (7.61 g, 0.03 mole) and stir in an ice-bath for 12 minutes. Add the second shot of potassium-t-butoxide (3.08 g, 0.0275 mole) and 10 ml DMF. Add the appropriate sulfonyl chloride, 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride, (9.01 g, 0.0275 mole) and 10 ml DMF. Stir at ambient temperature for 16 hours. Quench the reaction with 100 ml water, and extract with ethyl acetate (3×150 ml). Wash the organics with sodium metabisulfate (10 g in 100 ml water), water (3×200 ml) and saturated brine (1×200 ml). Concentrate the organics and purify over silica gel using 20% ethyl acetate in heptane to obtain 6.96 g (yield=52.2%) of the desired product as an off-white solid: 1H NMR (DMSO): 9.2 (t, 1H), 8.1 (m, 3H), 8.0 (m, 3H), 7.4 (m, 5H), 7.1 (m, 2H), 4.4 (d, 4H). MS (ES−)=532.91 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[N:20]=[C:19]([N:21]([CH3:26])[CH2:22][C:23](O)=[O:24])[C:18]([C:27]#[N:28])=[C:17]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:30]=4)[C:16]=3[C:39]#[N:40])[N:12]=2)=[CH:4][CH:3]=1.[CH3:41][N:42](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[N:20]=[C:19]([N:21]([CH3:26])[CH2:22][C:23]([NH:42][CH3:41])=[O:24])[C:18]([C:27]#[N:28])=[C:17]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:33][CH:34]=4)[C:16]=3[C:39]#[N:40])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)O)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)CN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
100 mg (0.162 mmol) of the compound from Example 34A were initially charged in 2 ml of DMF, cooled to 0° C., and 123 mg (0.324 mmol) of HATU were added. After 20 min, 243 μl (0.486 mmol) of methylamine and 56 ml (0.324 mmol) of N,N-diisopropylethylamine were added, and the mixture was then stirred at RT overnight. Water was added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile+0.15% conc. hydrochloric acid). This gave 37 mg of the desired compound. In addition, more solid precipitated from the aqueous phase overnight; this was filtered off and washed with a little water. This gave another 50 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH:16]=[N:17][NH2:18].CCN(CC)CC>C1COCC1>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH:16]=[N:17][NH:18][C:4]([C:3]1[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: NN=Cc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
To a stirred solution of 2-chloro-nicotinoyl chloride (1.75 g, 10 mmol) in 40 mL THF was added 3-trifluoromethyl-benzylidene-hydrazine (1.88 g, 10 mmol) in 20 mL THF at 0° C., followed by 1.5 mL Et3N. The solution was stirred at room temperature overnight and precipitate was observed. It was filtered and the solid was washed with MeOH, dried to yield the title compound (3.63 g, 90%). 1H NMR (acetone-d6): 11.08 (s, 1H), 8.53 (d, J=4.5 Hz, 2H), 8.27 (s, 1H), 7.72 (m, 3H), 7.57 (m, 2H).