Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](#[N:29])[CH3:28].CO>C(OCC)(=O)C>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]3[CH2:8][CH2:7][CH2:6][CH2:11][CH2:28][CH2:27]3)=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc2c(-c3ccc(OCCCN4CCCCCC4)cc3)csc2c1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, hexamethyleneimine, potassium carbonate and acetonitrile essentially as described above in Example 118 except that the column chromatography is performed with a graded solvent mixture from 100% ethyl acetate to 10% methanol in ethyl acetate. Purity by LC/MS=100%, [M+H]+=366.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C)C(=O)C.[CH2:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[S:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:36](=[S:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6]1
Reactant: NCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCCCCC(=S)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCC(=S)NCCN1CCOCC1

Procedure:
2.6 Grams of N-(2-aminoethyl)morpholine and 30 ml of N,N-dimethylacetamide were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the resulting solution was slowly added dropwise 7.5 g of 11-decylthioundecanoic acid chloride. After completion of the addition, the temperature of the solution was returned to room temperature, followed by further stirring for 2 hours. The reaction mixture was diluted with 300 ml of benzene, and washed with 5% aqueous sodium bicarbonate solution, pure water and saturated aqueous sodium chloride solution in succession. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain a crystal. The crystal was recrystallized from n-hexane to obtain 7.3 g of the desired product. m.p. 80° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2.N1C=CN=C1.C(Cl)Cl.[CH3:22][C:23]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O>[Si:26]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2)([C:23]([CH3:25])([CH3:24])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc2cccc(O)c2n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A solution of 8-hydroxyquinoline-2-carbaldehyde (10.00 g, 57.75 mmol) and imidazole (8.649 g, 127.0 mmol) in DCM (290 mL, 57.75 mmol) was cooled to 0° C. on an ice bath. TBDMS-Cl (9.574 g, 63.52 mmol) was added and the reaction stirred overnight at ambient temperature. Water was added and the reaction transferred to a separatory funnel. The aqueous phase was extracted 3 times with DCM, the organics combined, followed by washes with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated to residue under reduced pressure. The residue was purified by flash column chromatography, eluting with 25% EtOAc/Hexanes to give the product (12.2 g, 74% yield). MS APCI (+) m/z 288.1 (M+1) detected.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([NH:28][S:29]([CH:32]=[CH2:33])(=[O:31])=[O:30])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].Br[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][C:21]([NH:28][S:29](/[CH:32]=[CH:33]/[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)(=[O:31])=[O:30])([CH3:20])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Reactant: Brc1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccs1
Temperature: 140 °C
Yield: 21.2 %

Procedure:
Palladium acetate (169 mg, 0.75 mmol) and triphenylphosphine (420 mg, 1.6 mmol) were added to a solution of ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (10 g, 45.7 mmol) and 2-bromo-thiophene (3.74 mL, 39.1 mmol) in N,N-dimethylformamide (75 mL). Triethylamine (14.7 mL, 105.5 mmol) was added and the mixture was flushed with nitrogen and heated at 140° C. for 16 hours. The mixture was cooled to room temperature and 1N HCl (250 mL) was added in one portion. The mixture was extracted with ethyl acetate (3×200 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a solid. The solid was purified by dry flash chromatography (SiO2, heptane to 1:1 heptane: ethyl acetate). The fractions were combined to afford (E)-2-thiophen-2-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (2.5 g, 21% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.CCCCC>[C:13]1([S:19]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([Br:1])=[C:3]3[CH:10]=[CH:9]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Yield: 72.5 %

Procedure:
4-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 1 Eq.) was dissolved in dry THF and cooled in an ice-bath. NaH (60% dispersion in mineral oil, 305 mg, 1.2 Eq.) was added portionwise. The resultant mixture was stirred at 0 ° C. for 45 minutes and benzene sulfonyl chloride (1.076 g, 1.2 Eq.) was added slowly dropwise. The resultant mixture was stirred at 0 ° C. for a further 75 minutes and then the solvent was removed in vacuo. The residue was partitioned in EtOAc/sat. NH4Cl and extracted with EtOAc (3×50 mL). The combined organics were washed with sat. aq. Na2CO3 (1×20 mL), brine (1×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (20% EtOAc/80% hexanes), followed by recrystallization from EtOAc/hexanes. The product was filtered and then washed with pentane obtaining the title compound as a white powder (1.24 g, 73% yield); 1H NMR (DMSO D6) 6.8(1H, d), 7.6-7.66(3H, m), 7.72-7.76(1H, m), 8.0(1H, d), 8.1(2H, m), 8.24-8.26(1H, m); LC/MS M+1; (obs.)339.1; LC/MS M−1 (obs.) 337.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[C:26](O)=[O:27])(=[O:19])=[O:18])[CH2:13][CH2:12]1.Cl.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCOCC1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:30]([O:37][NH:38][C:26]([C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)(=[O:18])=[O:19])=[O:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NOCc1ccccc1)[C@H]1CCCCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (0.46 g, 1.12 mmol) [prepared as described Step 2 above] in methylene chloride (10 ml) was added O-benzylhydroxylamine hydrochloride salt (0.54 g, 3.36 mmol), followed by 4-dimethylaminopyridine (0.15 g, 1.23 mmol), 4-methylmorpholine (0.38 ml, 3.47 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.43 g, 2.24 mmol). The reaction was stirred at RT for 2 h, diluted with methylene chloride (50 ml) and washed with 1M HCl. The organic layer was washed with brine, dried over MgSO4, and concentrated to give N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (95%) as a clear oil. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[C:5](=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[NH:6][C:7](=[O:17])[CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:25].[Na+].CC(C)=O>O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[C:5](=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[NH:6][C:7](=[O:17])[CH2:8][S:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:25]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)CSCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)CS(=O)Cc1ccccc1

Procedure:
2 g (5.7 mmol) of N-(benzylthio)acetyl-4-chloro-anthranilic acid methyl ester and 3.66 g (17.1 mmol) of sodium metaperiodate are dissolved in 12 ml of water and 48 ml of acetone and the resulting solution is stirred at reflux for 6 hours. The reaction mixture is allowed to cool, filtered and concentrated by evaporation. Chromatography of the crude product on silica gel with hexane/ethyl acetate yields N-(benzylsulfinyl)acetyl-4-chloro-anthranilic acid methyl ester in the form of a yellow oil interspersed with crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([C:2]4[NH:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)[CH:11]=3)[CH2:18][CH2:19]2)=[O:24])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1

Procedure:
Synthesised as described in Method X-Step c starting from 1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-4-carboxylic acid (0.1 g, 0.28 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.06 g, 0.34 mmol). (72%)
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH:6]([NH2:9])([CH3:8])[CH3:7]>>[CH:6]([NH:9][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])([CH3:8])[CH3:7]
Reactant: CC(C)N
Reactant: OCC1CO1
Product: CC(C)NCC(O)CO
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 37 g (0.5 mole) of glycidol and 35.4 g (0.6 mole) of isopropylamine was stirred at 25° overnight. Excess isopropylamine was evaporated in vacuo and the mixture was distilled to give 53 g of product: b.p. 80° C./0.1 mm Hg. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C6H15O2N.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:7]([C:10]1[CH:11]=[C:12]([C:15]([NH:17][N:18]([CH2:34][C@@H:35]([OH:39])[C:36]([OH:38])=[O:37])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][CH:21]=2)=[O:16])[NH:13][N:14]=1)(=[O:9])[CH3:8].C1COCC1>>[C:7]([C:10]1[CH:11]=[C:12]([C:15]([NH:17][N:18]([CH2:34][C@@H:35]([O:39][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:36]([OH:38])=[O:37])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[F:33])=[CH:22][CH:21]=2)=[O:16])[NH:13][N:14]=1)(=[O:9])[CH3:8]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](OC(=O)C(C)C)C(=O)O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
Isobutyryl chloride (23.4 μL, 221.1 μmol) and (R)-3-[N′-(5-acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (10.5 mg, 22.1 μmol) were combined in THF (108 μL, 1.3 mmol), and stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC to yield the title compound (4.9 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C26H26ClFN4O6, 545.15. found 545.1.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16](O)=[O:17].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[C:25]([O:24][C:22]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16](=[O:17])[NH:13][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][N:10]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1nccc(-c2ccccc2)n1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nccc(-c2ccccc2)n1

Procedure:
4-Phenyl-pyrimidin-2-ylamine (200 mg, 1 mmol), Boc-L-Pro-OH (327 mg, 1.3 mmol) and TFFH (Fluoro-N,N,N′-tetramethylformamidinium hexafluorophosphate; 463 mg, 1.3 mmol) were stirred as a solution in DCM (10 mL) containing triethyl amine (300 mL, 2 mmol). Purification by silica gel chromatography gave the title compound. m/z 369.1 (MH+).
Reaction SMILES: CI.[C:3]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[OH:12])(=[O:5])[CH3:4].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:3]([C:6]1[CH:7]=[C:8]([NH:13][C:14](=[O:16])[CH3:15])[CH:9]=[CH:10][C:11]=1[O:12][CH3:17])(=[O:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(NC(C)=O)cc1C(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
Methyl iodide (3.42 ml, 7.81 g, 55 mmol) was added to a stirred mixture of N-(3-acetyl-4-hydroxyphenyl)acetamide (J.Org.Chem. 1995, 60, 4324-4330) (9.65 g, 50 mmol) and potassium carbonate (13.82 g, 100 mmol) in dimethylformamide (50 ml). The mixture was stirred at room temperature for 72 hours, then the solvent was evaporated under reduced pressure. Water (100 ml) was added and the mixture was extracted with ethyl acetate (6×100 ml). The combined organic fractions were dried (MgSO4) and evaporated under reduced pressure to give N-(3-acetyl-4-methoxyphenyl)acetamide as a tan solid (10.34 g, 100%), 1H NMR (d6 -DMSO) δ 9.91 (1H, br. s), 7.76 (2H, m), 7.12 (1H, d, J=9.6 Hz), 3.86 (3H, s), 2.52 (3H, s), and 2.01 (3H, s). m/e (CI+) 208 (MH+).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:6][C@H:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[C:2]=[O:3].[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[CH:15]([OH:21])[CH2:14]2>>[C:7]1([C@@H:5]2[CH2:6][C@H:4]2[NH:1][C:2](=[O:3])[O:21][CH:15]2[CH:16]3[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]3)[CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC1CN2CCC1CC2
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Product: O=C(N[C@@H]1C[C@H]1c1ccccc1)OC1CN2CCC1CC2
Yield: 28 %

Procedure:
Using general procedure A, (+/−)((1S,2R)-2-isocyanatocyclopropyl)benzene (117 uL, 0.780 mmol) and quinuclidin-3-ol gave (+/−) quinuclidin-3-yl(1R,2S)-2-phenylcyclopropylcarbamate (63 mg, 28%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 5.43 (br s, 1H), 4.77 (br s, 1H), 3.23 (dd, J=9.0, 14.0 Hz, 1H), 2.97-2.65 (m, 6H), 2.15-1.12 (m, 8H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.1, 140.7, 140.2, 128.5, 126.8, 126.3, 71.5, 55.7, 47.5, 46.6, 32.7, 25.6, 25.2, 24.5, 19.5, 16.2 ppm. Purity: >99.9% UPLCMS (210 nm); retention time 0.67 min; (M+1) 287.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22](O)=[O:23])[O:8][C@H:7]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[C:6]=2[CH:35]=1.C(N1C=CN=C1)([N:38]1C=CN=C1)=O.C(=O)(O)[O-].[NH4+]>CN(C)C=O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][N:15]([CH3:17])[CH3:16])[C:10](=[O:20])[C@@H:9]([CH2:21][C:22]([NH2:38])=[O:23])[O:8][C@H:7]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[C:6]=2[CH:35]=1
Reactant: CN(C)CC(C)(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)CC(C)(C)CN1C(=O)[C@@H](CC(N)=O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
Trans-7-chloro-5-(1 -naphthyl)-1 -(2,2-dimethyl-3-dimethylamino-propyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (1.16 g, 2.35 mmol) and 1,1'-carbonyldiimidazole (1.91 g, 11.8 mmol) were dissolved in dimethylformamide (75 ml). Stirring for 1 h at room temperature was followed by addition of ammonium bicarbonate (1.86 g, 23.5 mmol) in one portion to the reaction mixture, which was stirred for further 18 hours at room temperature. The solvent was concentrated under reduced pressure and the residue flash chromatographed directly (dichloromethane/methanol/aqueous ammonia 99:1:0.1 to 98:2:0.2). The solid was taken up in dichloromethane and a stoichiometric amount of 1N HCl in ether was added. Removal of the solvent provided a solid which was dissolved in ethanol and precipitated with ether to give the title compound (0.42 g, 36%) as a colorless solid.
Reaction SMILES: [C:1]([CH:4]([CH2:8][C:9]12[CH2:23][CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=31)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)C(O)=O)([OH:3])=[O:2].[Br:24]Br>CCOCC.C1(C)C(C)=CC=CC=1>[Br:24][CH:4]([CH2:8][C:9]12[CH2:23][CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=31)[C:15]1[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:1]([OH:3])=[O:2]
Reactant: BrBr
Reactant: O=C(O)C(CC12CC(c3ccccc31)c1ccccc12)C(=O)O
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: O=C(O)C(Br)CC12CC(c3ccccc31)c1ccccc12

Procedure:
α-Carboxy-β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid was treated with bromine in ether, and the corresponding brominated compound was refluxed in xylene to give α-bromo-β-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid. α-Bromo-β-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid was treated with thionyl chloride and then with N-benzyl-N-hydroxyethylamine to give α-bromo-β-(9,10-dihydro-9,10-methano-9anthryl)propionic acid N-benzyl-N-hydroxyethylamide, I.R., 3400, 3060, 3045, 2860, 1640, 1360, 1158, 1048, 1012, 698 cm-1.
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:3]2[N:8]3[CH:9]=[CH:10][N:11]=[C:7]3[CH:6]=[N:5][N:4]=2)[CH2:15][CH2:14]1
Reactant: CSc1nncc2nccn12
Reactant: CN1CCNCC1
Product: CN1CCN(c2nncc3nccn23)CC1

Procedure:
A 5.0 gm. portion of 5-(methylthio)-imidazo[1,2-d]-as-triazine is combined with 45 ml. of N-methylpiperazine and refluxed for 5 hours. The reaction mixture is evaporated giving a brown oil. This oil is triturated four times with 30 ml. portions of hot benzene. The combined benzene solutions are treated with charcoal, evaporated to 75 ml., retreated with charcoal, cooled and filtered, giving 1.0 gm. of the desired product, m.p. 176°-178° C. This base forms non-toxic acid-addition salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid-addition salts, formed by admixture of the organic free base with an equivalent of an acid, suitably in a neutral solvent, are formed with such acids as sulfuric, phosphoric hydrochloric, sulfamic, citric, lactic, tartaric, acetic, benzoic, gluconic, ascorbic, and related acids. For purposes of this invention, 5-(4-methyl-1-piperazinyl)-imidazo[1,2-d]-as-triazine is equivalent to its non-toxic acid-addition salts.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H:31](CCN1CC(OC2C=CC(Cl)=C(C)C=2)C1)CO>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][C:3]=1[CH3:31]
Reactant: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1
Reactant: Cc1cc(OC2CN(CC[C@H](N)CO)C2)ccc1Cl
Agent: Cl
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)c(C)c3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].[F:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH2:32]Cl)[CH:30]=4)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][N:4]5[C:5](=[O:6])[CH2:7][NH:1][C:2]5=[O:3])[CH:30]=4)[CH2:25][CH2:24]3)[CH2:21][CH2:22]2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(CCl)cc43)CC2)cc1
Reactant: O=C1CNC(=O)N1
Agent: [H-]
Agent: [Na+]
Product: O=C1CNC(=O)N1Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 49.1 %

Procedure:
Hydantoin (130 mg), 60% sodium hydride (54 mg) and 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (400 mg) were treated as in Example 202 to give the title compound (230 mg) as a white powder (yield: 49%).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=1.O>CS(C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:20]2[CH2:7][C@H:21]2[N+:22]([O-:24])=[O:23])=[CH:18][CH:19]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10 min a solution of 1-bromo-4-[(trans)-2-nitrovinyl]benzene (0.53 g, 2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture was stirred at room temperature for 6 h. The reaction was poured over water (10 mL) and extracted with Et2O (3×10 mL); the organic layers were washed with brine (2×15 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual oil was purified by column chromatography on silica gel (5% EtOAc/hexanes) affording 0.15 of 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene [27% yield].