Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.[O:13]1[CH:20]([CH3:21])[CH:14]1[C:15]([O:17]CC)=[O:16].Cl>ClCCl.C(OCC)C>[OH:13][CH:14]([CH:20]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:21])[C:15]([OH:17])=[O:16]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)C1OC1C
Agent: C[Mg]Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(c1c[nH]c2ccccc12)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.3 %

Procedure:
Indole (5.86 g) was dissolved in dichloromethane (50 ml) and to the solution was added dropwise 2.89 M solution of methyl magnesium bromide in diethyl ether (40 ml) over a period of 45 minutes at room temperature. After the dropwise addition was completed, the mixture was stirred for 45 minutes at room temperature. Under cooling at −10° C., a solution of ethyl (2RS,3SR)-2,3-epoxybutanoate (6.51 g) in dichloromethane (50 ml) was added dropwise over a period of 20 minutes. The mixture was stirred for 1 hour at −10 ° C. To the mixture was added 1 N aqueous solution of hydrochloric acid (150 ml). The organic layer was removed, and the aqueous layer was extracted with dichloromethane (50 ml). The organic layers were combined, and concentrated under reduced pressure. The residue was dissolved by adding ethanol (56 ml) and water (24 ml). To the solution was added 1 N aqueous solution of sodium hydroxide (50 ml) under ice cooling. The mixture was stirred for 3.5 hours under ice cooling and 12 hours at room temperature. To the mixture was added 1 N aqueous solution of sodium hydroxide (25 ml), and the mixture was stirred for 1 hour at room temperature. The ethanol was distilled off under reduced pressure, and aqueous layer was washed twice with ethyl acetate (70 ml). The aqueous layer was acidified by adding conc. hydrochloric acid (10 ml). The mixture was extracted twice with ethyl acetate (100 ml). The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate. To the ethyl acetate layer was added activated carbon (1 g) and mixture was stirred. After filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from water to give (2RS,3SR)-2-hydroxy-3-(indol-3-yl)butyric acid (7.27 g) as pale brown solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][NH:20][CH2:21][C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH3:3].N1C=CC=CC=1.Cl.[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[S:43](Cl)(=[O:45])=[O:44].[OH-].[Na+]>ClCCl>[CH2:28]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][N:20]([CH2:21][C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[S:43]([C:39]3[NH:38][CH:42]=[CH:41][N:40]=3)(=[O:45])=[O:44])[CH:15]=2)[CH2:10]1)[CH2:29][CH3:30]
Reactant: O=S(=O)(Cl)c1ncc[nH]1
Reactant: CCCN(CCC)CCCCN1CCc2cc(CNCc3nccn3C)ccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(CCC)CCCCN1CCc2cc(CN(Cc3nccn3C)S(=O)(=O)c3ncc[nH]3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
In a solution of the compound 23-a (100 mg) and pyridine (59 mL) in dichloromethane (3 mL), the compound 36 (74 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture, an aqueous 1N sodium hydroxide solution (15 mL) was added. The aqueous layer was extracted twice with dichloromethane (30 mL). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol:triethylamine=10:1:0→10:1:0.5) to obtain the title compound (119 mg) having the following physical properties.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:14][C:13]=3[CH3:25])[NH:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:18][C:17]1[CH:16]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:14]=[C:13]([CH3:25])[C:12]=1[C:10]1[NH:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:27]=[CH:26][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(-c3c(C)cc(N4CCOCC4)cc3C)[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)cc(C)c1-c1nc2ccc(C(=O)O)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1.83 g of the crude 2-(2,6-Dimethyl-4-morpholin-4-yl-phenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester in 20 ml of THF, 20 ml of water and 400 mg of LiOH were added and it was stirred at room temperature overnight. The reaction mixture was diluted with 100 ml of water and neutralized by 6N HCl. The resulting precipitates were collected by filtration and dried to afford the title compound. LCMS retention T=0.75 min. m/z=352.1. Method 10.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH:20]=[O:21])[CH:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>C(Cl)Cl.CO>[NH2:26][C:24]1[CH:23]=[CH:22][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:25]=1
Reactant: O=CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(Oc2ccnc3cc(-c4cnn(CCO)c4)sc23)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
To a solution of 146 (3 g, 7.53 mmol) in DCM (100 mL) and MeOH (100 mL) was added NaBH4 (0.57 g, 15.06 mmol) and the reaction mixture was stirred at 0° C. for 20 min. The mixture was quenched with saturated NH4Cl solution then extracted with DCM. The extract was collected, dried over anhydrous Na2SO4, filtered, concentrated and the residue was purified by flash column chromatography (eluent 10% MeOH in EtOAc) to afford title compound 156 (1 g, 36% yield) as white solid. MS (m/z)=371.40 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22](=[O:47])[C@H:23]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:24][C:25](=[O:39])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[NH2:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:47])[C@H:23]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[NH:24][C:25](=[O:39])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[NH:27][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)NCCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-β-alanine was coupled with N-[3-[(benzyloxy)carbonyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester to give N-[3-[(benzyloxy)carbonyl]-N-[N-(t-butoxycarbonyl)-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 124°-125° C.
Reaction SMILES: [CH2:1]([C@@:8]1([O:41][C@H:40]([CH2:42][OH:43])[C@@H:38]([OH:39])[C@H:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@@H:22]([C:35](=[O:37])[NH2:36])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:20])[CH3:18])=[O:15])[C@H:10]1[NH:44][C:45](=[O:47])[CH3:46])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48]1([C:54](Cl)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>N1C=CC=CC=1>[CH2:1]([C@@:8]1([O:41][C@H:40]([CH2:42][O:43][C:54]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C@@H:38]([OH:39])[C@H:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@@H:22]([C:35](=[O:37])[NH2:36])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:20])[CH3:18])=[O:15])[C@H:10]1[NH:44][C:45](=[O:47])[CH3:46])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)N[C@@H]1[C@@H](OCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)[C@H](O)[C@@H](CO)O[C@@]1(O)Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1[C@@H](OCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@@]1(O)Cc1ccccc1
Yield: 82 %

Procedure:
A solution of 0.66 g of benzyl (benzyl 2-acetamido-2-deoxy-α-D-glucopyranosid-3-O-yl)acetyl-L-alanyl-D-isoglutaminate (12A, n = 2, X1 = L-alanyl, R2 = CH3) and 0.56 g of triphenylmethyl chloride in 10 ml of pyridine is stirred at 22° C for 5 days and is then evaporated to dryness in vacuo. The residue is partitioned between 30 ml of chloroform and 30 ml of water, the chloroform phase is extracted twice more with 30 ml of water, dried over magnesium sulfate, concentrated in vacuo and the residue is triturated with 50 ml of ether. The resulting solid is collected by filtration, washed with ether and dried giving 0.74 g of benzyl (benzyl 2-acetamido-2-deoxy-6-O-triphenylmethyl-α-D-glucopyranosid-3-O-yl)acetyl-L-alanyl-D-isoglutaminate (12B, n = 2, X1 = L-alanyl, R2 = CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCOCCO
Solvent: c1ccncc1
Product: CC(=O)OCCOCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of 2-{2-[(3-nitroquinolin4-yl)ammo]ethoxy}ethanol (55.5 g, 0.2 mol), acetic anhydride (37.6 mL, 0.4 mol), and pyridine (250 mL) was heated at reflux for 30 minutes. The solution was allowed to cool to ambient temperature and was concentrated under reduced pressure to remove about 50-75% of the pyridine. The residual solution was poured into water to precipitate the product as an oil which solidified upon stirring. The solid was isolated by filtration, washed with water, and dried. The crude product was recrystallized from 2-propanol (200 mL) to provide 55.6 g of 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl acetate as a bright yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\C#N)/[C:10]([NH:12][CH:13]([C:17]2[CH:47]=[CH:46][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][NH:30][C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][C@H:36]3[C@@H:43]4[C@@H:39]([NH:40][C:41](=[O:44])[NH:42]4)[CH2:38][S:37]3)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.BrC1N=C(/C=C/C(NC(C2C=CC(OCCOCCOCCN(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=CC=2)CCC)=O)C=CC=1>>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[C:10]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][NH:30][C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][C@H:36]3[C@@H:43]4[C@@H:39]([NH:40][C:41](=[O:44])[NH:42]4)[CH2:38][S:37]3)=[CH:46][CH:47]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCNC(=O)CCCC[C@@H]2SC[C@@H]3NC(=O)N[C@@H]32)cc1
Agent: CCCC(NC(=O)/C=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Product: CCCC(NC(=O)/C=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCNC(=O)CCCC[C@@H]2SC[C@@H]3NC(=O)N[C@@H]32)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 48 except that acrylamide 50 was used instead of cyanoacrylamide 47. This produced the crude product which was purified by flash silica gel column chromatography, eluting with 7:93 methanol/dichloromethane, to give 51 (50 mg, quantitative) as a clear oil: MS (ES+) m/z 731.2 (M+H)+.
Reaction SMILES: CC1[N:3]([C:8]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH:18]=3)[N:10]([CH3:20])[N:9]=2)C(C)=CC=1.NO.Cl.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C.O>[CH3:20][N:10]1[C:11]([C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH:18]=2)=[CH:12][C:8]([NH2:3])=[N:9]1
Reactant: Cc1ccc(C)n1-c1cc(C2=CCN(C)CC2)n(C)n1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CC=C(c2cc(N)nn2C)CC1
Temperature: 110 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
To a mixture of 4-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazol-5-yl]-1-methyl-1,2,3,6-tetrahydropyridine (1.06 g) and hydrochloric acid hydroxylamine (2.73 g) in ethanol (10 mL) and water (1 mL) was added triethylamine (1.10 mL), followed by stirring at 110° C. for 5 hours. After leaving to be cooled, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; chloroform:methanol=100:0-98:2) to obtain 1-methyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-3-amine (574 mg) as a pale brown solid.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:19][N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:12]1[C:11]2[CH:10]=[CH:9][C:8]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[C:3]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:4]=2
Reactant: CC(C)C(=O)Cl
Reactant: CN(C)CCCn1c2ccccc2c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)C(=O)c1ccc2c(c1)c1cc(C(=O)C(C)C)ccc1n2CCCN(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 48.1 %

Procedure:
Compound 30 (0.25 g, 1.0 mmol) was dissolved in nitrobenzene (5 mL). AlCl3 (0.6 g, 4.5 mmol) and then isobutyroyl chloride (0.6 mL, 5.7 mmol) were added in portions. The reaction mixture was stirred for 40 min (LC/MS monitoring). The obtained mixture was poured into ice/water mixture and extracted with CHCl3. The combined extracts were evaporated, and the residue was purified by chromatography in a short thick silica gel column (eluent: CHCl3/MeOH 99:1→90:10) to afford 0.189 g (47%) of the product. 1H NMR (DMSO-d6): δ 1.20 (12H, d, J=6.7 Hz); 1.90-1.97 (2H, m); 2.11 (6H, s); 2.18 (2H, t, J=6.7 Hz); 3.91 (2H, septet, J=6.7 Hz), 4.50 (2H, t, J=6.6 Hz); 7.76 (2H, d, J=8.7 Hz); 8.14 (2H, dd, J=8.7 Hz, J=1.5 Hz); 9.11 (2H, d, J=1.5 Hz). ELSD: 100%, ESI-MS: m/z 392 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)[CH3:34].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N)C.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][S:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1)[CH3:34]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (32.7 mg, 0.171 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (26.1 mg, 0.171 mmol), and DMF (Volume: 0.5 mL) were stirred together to give a yellow solution. Ethanamine hydrochloride (9.28 mg, 0.114 mmol) and 4-methylmorpholine (0.065 mL, 0.593 mmol) were added. The reaction was stirred at room temperature for 4 hours. The crude reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered off and dried in vacuum to afford the title compound (12.0 mg, 22.6%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 7.79 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.53 (s, 1H), 6.85-7.00 (m, 3H), 5.96 (br. s., 1H), 5.06 (d, J=13.4 Hz, 1H), 4.43 (dd, J=10.5, 3.4 Hz, 1H), 3.39-3.54 (m, 4H), 3.30 (br. s., 4H), 3.15 (td, J=12.9, 2.3 Hz, 1H), 3.00 (br. s., 1H), 2.87 (d, J=10.4 Hz, 2H), 2.60 (br. s., 4H), 2.42 (d, J=1.5 Hz, 1H), 1.25 (t, J=7.2 Hz, 3H). [M+H] calc'd for C, 24; H, 30; N, 6; O, 2; S, 467; found, 467. MP: 288.9° C.
Reaction SMILES: [C:1]([C:3]1[C:16]2[S:15](=[O:18])(=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].Cl>CS(C)=O>[NH:20]1[C:1]([C:3]2[C:16]3[S:15](=[O:17])(=[O:18])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:8](=[O:19])[C:7]=3[CH:6]=[CH:5][CH:4]=2)=[N:2][N:22]=[N:21]1
Reactant: N#Cc1cccc2c1S(=O)(=O)c1ccccc1C2=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2S(=O)(=O)c2c1cccc2-c1nnn[nH]1

Procedure:
4-Cyanothioxanthone-10,10-dioxide (1.35 g), sodium azide (0.39 g) ammonium chloride (0.32 g) and dimethylsulphoxide were heated together at 125°-130° C. for 6.5 hours. The mixture was cooled, poured into dilute hydrochloric acid and the precipitated product filtered off. It was warmed with 1% sodium bicarbonate solution, filtered, and the filtrate acidified with dilute hydrochloric acid. 4-(5-Tetrazolyl)thioxanthone-10,10-dioxide was filtered off and recrystallised from acetic acid, m.p. 271° C. with decomposition.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:33])=[O:32])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20](O)=[O:21])C1C=CC=CC=1.[CH3:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[OH:8][C:9]1[CH:10]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([N:38]2[CH2:39][CH2:40][CH:35]([CH3:34])[CH2:36][CH2:37]2)=[O:21])[CH:23]=[CH:24][C:25]=1[N:26]1[S:27](=[O:33])(=[O:32])[NH:28][C:29](=[O:31])[CH2:30]1
Reactant: O=C(O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Reactant: CC1CCNCC1
Product: CC1CCN(C(=O)Cc2ccccc2Cc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)CC1

Procedure:
The title compound is prepared from {2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-phenyl}-acetic acid and 4-methylpiperidine analogous to Example 314, steps B and C. (M−1)−=456. HPLC retention time=1.07 min (Method A).
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:20][S:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>ClCCl>[CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[C:28]2[C:27]3[C:31](=[C:23]([CH2:22][S:21][CH3:20])[CH:24]=[CH:25][CH:26]=3)[NH:30][CH:29]=2)[CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(F)cc1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(F)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
188 mg (1.13 mmol) of cyclopropyl(4-fluorophenyl)methanol and 0.10 ml (1.35 mmol) of trifluoroacetic acid were added to 200 mg (1.13 mmol) of the compound from Example 8A in 13 ml of dichloromethane. The reaction mixture was stirred at RT for 15 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 267 mg (73% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[C:25](#[N:31])[CH2:26][CH2:27][CH2:28][C:29]#[CH:30]>C(NCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][C:25]#[N:31])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CCCCC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: N#CCCCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 5 (0.35 g), CuI (0.042 g), and Pd(PPh3)2Cl2 (0.012 g) in 10 mL diethylamine is added 5-hexynenitrile (0.085 mL). The reaction is stirred overnight. The reaction is then partitioned between ethyl acetate and water. The organic layer is washed twice with water, dried over MgSO4, filtered, and adsorbed onto silica. A Biotage Flash 40S (eluent 3% MeOH:CH2Cl2) affords the desired product. The product is recrystallized from CH2Cl2 --MeOH/hexanes. A second crop of crystals is obtained by concentration of the filtrate. The total yield of the title compound is 0.21 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:21].[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:29]([Sn:33](Cl)([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH3:32].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:29][CH2:30][CH2:31][CH3:32])[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(I)c2)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(C)c3)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a stirred solution of 4-(4-chloro-3-methyl-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyrimidine (Example E.76) (1.03 g, 2.51 mmol) in THF (20 mL) was added at 0° C. isopropyl-magnesium chloride lithium chloride (1M in THF, 3.05 mL, 3.05 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (1.14 g, 3.5 mmol) was added, the reaction mixture was stirred at room temperature for 15 h, poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on alox (ethylacetate/heptane) to yield the title compound (1.19 g, 83%) as a yellow oil. MS (ISP) 575.3 [(M+H)+].
Reaction SMILES: [C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].N[C@H:15](C1C=CC=CC=1)[CH2:16]C(O)=O.CC#N.O.CC#N>O>[C:1]([NH:4][C@H:5]([C:9]1[CH:8]=[CH:7][CH:6]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: CC(=O)NC1(CC(=O)O)CCCC1
Solvent: CC#N
Solvent: O
Product: CC(=O)N[C@@H](CC(=O)O)c1ccccc1

Procedure:
The title compound is prepared analogously as described for (1-acetylamino-cyclopentyl)-acetic acid from (S)-3-amino-3-phenylpropionic acid. MS (LC-MS): [M+H]+=208.2. tR (HPLC, -Waters Symmetry C18 column, 10-95% CH3CN/H2O/3.5 min, 95% CH3CNIH2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 0.79 min.