Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]#[N:25])=[CH:18][CH:17]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCc2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
A mixture of 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionitrile (0.7 g), sodium azide (0.411 g), ammonium chloride (0.337 g) and N,N-dimethylformamide (15 ml) was stirred for 24 hours at 120° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried, then the solvent was distilled off to leave 5-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl]tetrazole (0.38 g, 48%), which was recrystallized from ethyl acetate--hexane to give colorless prisms, m.p.143°-144° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:34])[C:12](=[O:13])[N:11]([C@@H:14]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10](=[O:26])[N:9]2[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[C:5]1([C@@:8]2([CH3:34])[C:12](=[O:13])[N:11]([C@@H:14]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C:10](=[O:26])[N:9]2[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccc(Br)cc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O
Yield: 80.4 %

Procedure:
1.9 g (3.59 mmol) of 169.3 in 190 ml of ethanol were hydrogenated over 76 mg of 10% palladium/carbon for 2 h. The catalyst was filtered off, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the solution was washed with a 10% strength sodium hydrogen carbonate solution. The phases were separated and the organic phase was dried over sodium sulfate. After filtration, 1.3 g (80%) of 169.4 were obtained.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28]([CH:27]=[CH:26][C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH:11]=[CH:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(C=CCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(COc3ccc(C=CCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
13 mg (0.50 mmol) 95% sodium hydride were given to a solution of 108 mg (0.50 mmol) 4-(4-[1,2,3]triazol-1-yl-but-1-enyl)-phenol in 4.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was collected, washed with water (2×10 ml), methanol (2×10 ml), diethyl ether and dried in vacuum at 40° C. to yield 225 mg (86%) of product.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[CH2:2].[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=2)(=[O:28])=[O:27])[CH:25]=1)=[NH:20])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19](=[NH:20])[C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:30]=[C:31]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH:1]=[CH2:2])[CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: C=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1ccccc1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1

Procedure:
Following the procedure outlined for Examples 41–107, reaction of 2-vinyl-phenylboronic acid (30 mg, 0.20 mmol, Aldrich Chemical Company), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol, Strem Chemicals, Inc., Newburyport, Mass.), Na2CO3 (400 μL, 2M aqueous), and toluene/EtOH mixture (2:1, 1.2 mL) afforded 25 mg (50%) after purification (1:3 EtOAc/hexanes, 2000μ SiO2 plate) of the title compound as a white foam.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].O[Li].O>C1COCC1.O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:30][CH2:31][S:32][CH3:33])=[O:29])=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[CH:9]=2)=[O:15])[CH:17]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a stirred solution of the product of Example 300 (140 mg, 0.29 mmol) in THF (6 mL) was added a solution of LiOH.H2O (37 mg, 88 mmol) in H2O (1 mL) and the resulting solution stirred for 2 hours at ambient temperature. The reaction was concentrated in vacuo and 1 N HCl was added to the residue. The resulting precipitate was filtered and washed with H2O. Lyopholization gave the title compound (87 mg, 59%) as a white powder. 1H NMR (300 MHz, DMSO-d6, 90° C.) δ 9.12 (d, 1H, J=2.4 Hz), 8.74 (dd, 1H, J=4.9, 1.9 Hz), 8.31 (dt, 1H, J=7.9, 1.8 Hz), 7.84 (dd, 1H, J=7.9, 1.8 Hz), 7.63 (s, 1H), 7.61 (d, 1H, J=2.4 Hz), 7.54 (dd, 1H, J=7.9, 4.9 Hz), 7.45 (d, 1H, J=7.9 Hz), 7.23-7.21 (m, 2H), 7.19-7.15 (m, 2H), 4.30-4.26 (m, 1H), 2.28-2.22 (m, 1H), 2.20-2.14 (m, 1H), 2.11 (s, 3H), 1.98 (s, 3H), 1.88-1.81 (m, 1H), 1.75-1.68 (m, 1H), MS m/z 464 (M+1)+, 446. Anal calcd for C25H25N3O4S.HCl.0.5 H2O (509.01): C, 58.99; H, 5.35; N, 8.26. Found: C, 59.38; H, 5.49; N, 7.89.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=3[CH3:40])=[C:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:19]3[C:24]=2[CH:23]=[C:22]([Br:25])[CH:21]=[CH:20]3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:25][C:22]1[CH:21]=[CH:20][N:19]2[C:24]([CH:23]=1)=[C:16]([C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[C:17]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[CH3:40])=[C:18]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(Br)ccn2c1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCNCC2)c2cc(Br)ccn2c1-c1ccccc1
Reaction time: 8 h
Yield: 25.8 %

Procedure:
A solution of the compound of step 3 (70 mg, 115 μmol) in DCM (4 ml) and TFA (2 ml) was stirred at room temperature for 2 h. The solvents were evaporated and the resulting solid was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. The obtained solid was dissolved in a small quantity of MOH, mixed with 0.1 N hydrochloric acid and the mixture lyophilized overnight to give 15 mg of the title compound in the form of [7-bromo-2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone hydrochloride with the following characteristics:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=3)[CH:9]=[CH:8]2)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[CH2:31][CH:32]=O)[NH:27][C:26](=[O:34])[CH2:25][CH2:24]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[CH2:31][CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[CH:14]=4)[CH:9]=[CH:8]3)[CH2:5][CH2:6]1)[NH:27][C:26](=[O:34])[CH2:25][CH2:24]2
Reactant: NC(=O)c1ccc2ccn(C3CCNCC3)c2c1
Reactant: COc1cc2c(cc1CC=O)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
100 mg of 1-(piperidin-4-yl)-1H-indole-6-carboxamide and 87 mg of (6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)acetaldehyde were suspended in 5 ml of methylene chloride. Thereafter, 0.05 ml of acetic acid and 0.13 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) and by NH silica gel column chromatography (chloroform-methanol), and then reprecipitated from ethyl acetate, so as to obtain 18 mg of the subject compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=3)[CH:10]([CH2:27][CH2:28][S:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:9]2=[O:37])=[CH:4][CH:3]=1>C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=3)[CH:10]([CH2:27][CH2:28][S:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:9]2=[O:37])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C2C(CCSc3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Solvent: O=CO
Product: O=C(O)COc1ccc(C2C(CCSc3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Yield: 102 %

Procedure:
A solution of 1-(4-fluorophenyl)-3-[2-(4-fluorophenylthio)ethyl]-4-[4-(t-butoxycarbonylmethoxy)phenyl]azetidin-2-one (Method 16; 0.880 g, 1.67 mmol) in formic acid (5 ml) was stirred at room temperature for 19 hours. The solvent was removed under reduced pressure and the residue was dissolved in DCM (25 ml). The organic layer was washed twice with water (1×10 ml and 1×5 ml) and once with brine (5 ml), dried over magnesium sulphate and concentrated. This gave the title compound as a colourless oil (0.800 g; ˜quantitative yield). NMR (CD3COOD, 400 MHz) 2.10-2.30 (m, 2H), 3.10 (dt, 2H), 3.30-3.40 (m, 1H), 4.75 (s, 2H), 4.80 (d, 1H), 6.95-7.05 (m, 6H), 7.25-7.40 (m, 6H); m/z: 470.2.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:20][C:21]1[N:22]=[CH:23][N:24]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=1>>[CH2:13]([C:6]1[S:5][C:4]2[NH:1][C:2](=[S:3])[N:29]([CH2:28][CH2:27][CH2:26][N:24]3[CH:25]=[C:21]([CH3:20])[N:22]=[CH:23]3)[C:9](=[O:11])[C:8]=2[CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Cc2ccccc2)sc1N=C=S
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc(Cc4ccccc4)cc3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-benzylthiophene-3-carboxylate (0.102 g. 0.35 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (0.049 g, 0.35 mmol) as described above.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31](=[O:49])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:40](N2C=CN=C2)=[O:41])=[CH:34][C:33]=1[O:47][CH3:48]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:49])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])=[CH:34][C:33]=1[O:47][CH3:48]
Reactant: COC(=O)c1ccc(CNC(=O)n2ccnc2)cc1OC
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (49.2 mg, 0.116 mmol) and 4-{[(imidazole-1-carbonyl)-amino]-methyl}-2-methoxy-benzoic acid methyl ester (224.3 mg, 0.775 mmol) in CH2Cl2 (8 mL) was stirred rt for 16 hrs. The reaction mixture was then purified by flash column to give rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (61.9 mg, 82.8%). HRMS (ES+) m/z Calcd for C33H33Cl2F2N3O4: 644.1889; Found: 644.1888
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=2)=[C:7]([CH2:23][N:24](C(OCC2C=CC=CC=2)=O)[CH2:25][CH3:26])[CH:6]=1)C>CO>[CH2:21]([O:20][C:18]([CH2:17][C:15]1[CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:37])=[O:3])=[CH:6][C:7]=2[CH2:23][NH:24][CH2:25][CH3:26])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C(=O)OCC)cc2CN(CC)C(=O)OCc2ccccc2)c1
Solvent: CO
Product: CCNCc1cc(C(=O)O)ccc1-c1cncc(CC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[(N-Benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-(5-ethoxycarbonylmethyl-pyridin-3-yl)-benzoic acid ethyl ester (0.5 g, 1 mmol) was dissolved in MeOH (20 mL), and the solution was purged with N2 for 10 minutes. 10% Palladium on carbon (0.2 g) was added, and the reaction was stirred under an atmosphere on H2 at room temperature for 3 hours. Additional 10% palladium on carbon (0.1 g) was added, and the reaction was stirred under H2 overnight. The mixture was purged with N2 and filtered over Celite. After washing with MeOH, the filtrate was concentrated to give 4-(5-ethoxycarbonylmethyl-pyridin-3-yl)-3-ethylaminomethyl-benzoic acid.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8]([C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:7]=[C:2]1[NH:3][C:4](=[O:6])[C:5](=[CH:8][C:10]2[CH:22]=[CH:21][C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[S:1]1
Reactant: O=Cc1ccc(OCCCC(=O)O)cc1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CCCOc1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 32.3 %

Procedure:
Thiazolidine-2,4-dione (3.55 g, 27.6 mmol), 4-(4-formylphenoxy)butyric acid (5.74 g, 27.6 mmol), anhydrous sodium acetate (11.3 g, 138 mmol) and acetic acid (100 mL) was refluxed for 16 h. After cooling, the mixture was filtered and washed with acetic acid and water. Drying in vacuo afforded 2.74 g (32%) of 4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenoxy]butyric acid as a solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1C
Yield: 98.4 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.2 g, 98%) as an oily product.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23](O)=[O:24])=[C:17]2[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27].[NH2:35][CH2:36][CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1>O>[NH:40]1[CH:39]=[C:38]([CH2:37][CH2:36][NH:35][C:23]([C:18]2[NH:19][C:20]3[C:16]([C:17]=2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:15][C:14]([Cl:13])=[CH:22][CH:21]=3)=[O:24])[N:42]=[CH:41]1
Reactant: NCCc1c[nH]cn1
Reactant: O=C(O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: O=C(NCCc1c[nH]cn1)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
Carbonyldiimidazole (180 mg, 1.11 mmol) was added to a solution of 5-chloro-3-phenylsulfonylindole-2-carboxylic acid (Example 27, Step A) (336 mg, 0.5 mmol) cooled in an ice bath under an inert atmosphere. After 0.5 hours, histamine (125 mg, 1.12 mmol) was added to the yellow solution. After 5 hours the reaction was diluted with water and the product extracted into ethyl acetate. This organic layer was washed with dilute aq. NaHCO3, dried (Na2SO4), filtered through charcoal and the solvents evaporated. Trituration of this residue with methylene chloride gave the crude product. Crystallization from hot ethyl acetate gave analytically pure product, mp 220°-221.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH2:29][CH3:30])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][C@:65]1([C:70]([NH:72][S:73]([CH:76]2[CH2:78][CH2:77]2)(=[O:75])=[O:74])=[O:71])[CH2:67][C@H:66]1[CH:68]=[CH2:69]>ClCCl>[CH:76]1([S:73]([NH:72][C:70]([C@@:65]2([NH:64][C:18]([C@@H:13]3[CH2:14][C@@H:15]([OH:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C@H:21]([CH2:29][CH3:30])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])=[O:19])[CH2:67][C@H:66]2[CH:68]=[CH2:69])=[O:71])(=[O:75])=[O:74])[CH2:78][CH2:77]1
Reactant: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.3 g, 3.05 mmole) in dichloromethane (50 mL) was added HATU (1.15 g, 3.05 mmole) followed by DIPEA (1.6 mL, 9.13 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide (1.22 g, 3.05 mmole) was added to the reaction mass and the mixture was stirred at room temperature for 1 h. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4; filtered; then concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (6% methanol in chloroform) to get 1.7 g (87%) of tert-butyl (2S,3R)-1-((2S,4R)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidin-1-yl)-3-ethyl-5-methyl-1-oxonon-8-en-2-ylcarbamate as a white solid. MS: MS m/z 639.55 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[O:10])=[C:4]([Cl:22])[CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:25])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[O:10])=[C:4]([Cl:22])[CH:3]=1
Reactant: CI
Reactant: Cn1c(=O)oc2ccc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccc2oc(=O)n(C)c2c1)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
5-[2-(4-Bromo-2-chloro-phenyl)-acetyl]-3-methyl-3H-benzooxazol-2-one (304 mg) was dissolved in DMF (8 mL). The mixture was cooled to 0° C. To this solution was added sodium hydride (60% in mineral oil, 37 mg). The mixture was stirred for 10 minutes at 0° C. and then for 1 hour at r.t. The mixture was cooled to 0° C. and methyl iodide (119 mg) was added dropwise over a period of 10 minutes. Stirring was continued over night at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (238 mg, 76%). MS (neg. ion, m/e)=394.2 [(M−H)−].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][N:11]([CH2:32][CH2:31][C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(ncn2CCC(=O)OC(C)(C)C)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (0.50 g, 1.25 mmol) is dissolved in DMF (8 mL) under N2 and K2CO3 (0.26 g, 1.88 mmol) is added followed by t-butyl acrylate (1.84 mL, 12.54 mmol). The reaction mixture is heated to 90° C. with stirring. After 4 hours, the reaction mixture is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with water (3×) and brine, dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography eluted with 19:1 methylene chloride:ethyl acetate provides 0.41 g (62%) desired product.