Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[C:4]([N:10]1[CH:14]=[C:13]([C:15]#[N:16])[N:12]=[N:11]1)[C:5](OCC)=[O:6].[NH:18]([C:20]1[N:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:21]=1)[NH2:19].FC(F)(F)C(O)=O>O>[O:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:18]3[C:5](=[O:6])[C:4]([N:10]4[CH:14]=[C:13]([C:15]#[N:16])[N:12]=[N:11]4)=[CH:3][NH:19]3)[CH:21]=2)[CH2:27][CH2:28]1
Reactant: NNc1cc(N2CCCOCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCCOCC4)ncn3)c2=O)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (0.9 mmol) of the compound from Example 7A, 178 mg (0.9 mmol) of the compound from Example 14A and 33 ml (49 mg, 0.4 mmol) of trifluoroacetic acid in 3 ml of water is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 80 mg (27% of theory) LC-MS (Method 4): Rt=1.40 min; MS (ESIpos): m/z=354 [M+H]+;
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[C:17]([CH:18]=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:25]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
23.1 g of 9-(naphthalene-2-yl)anthracene was dispersed into 250 ml of DMF (dimethylformamide), and then 14.9 g of NBS (N-bromosuccinimide) in DMF solution (150 ml) was dropped therein. After stirred at room temperature for 7 hours, it was left over a night. 200 ml of water was added thereto, and then the crystal precipitated was separated by filtration. Subsequently it was washed by ethanol adequately, followed by drying, and 28.8 g of 9-bromo-10-(naphthalene-2-yl)anthracene of beige color crystal was obtained (Yield: 99%).
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[Li]CCCC.[CH2:24]=[O:25].[Cl-].[NH4+]>C1COCC1>[OH:25][CH2:24][C:2]#[C:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)CC1
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC#CCO)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(3,3-dibromoprop-2-en-1-yl)piperidine-1-carboxylate from step 1 of this Example (19.5 g, 50.9 mmol) was dissolved in THF (170 mL) and cooled to −78° C. n-BuLi (2.5 Min hexanes, 46.8 mL, 117 mmol) was added slowly, maintaining internal temperature below −65° C. The mixture was stirred for additional 30 min, before paraformaldehyde (4.59 g, 152.7 mmol) was added in one portion. The reaction was stirred at −78° C. for 30 min and warmed to room temperature and allowed to stir at RT for 1 hour. Saturated aqueous ammonium chloride was added, and the aqueous layer was extracted 3 times with ethyl acetate. Column chromatography eluting with 30% acetone/hexanes afforded the product as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:13])=[O:12]
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Br)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
4-Bromo-3-chlorosulfonyl-benzoic acid (2.2, 1.1 g) was dissolved in 20 mL of ethyl acetate and morpholine (Aa, 1.48 mL, 3 eq) was added. The mixture was stirred at room temperature for 2 hours, then extracted with 15 mL of 0.5M HCl. The organic layer was washed with H2O and brine and the solvent evaporated to yield 4-bromo-3-(morpholinosulfonyl)-benzoic acid (2.3.Aa) as an off-white powder (1.13 mg, 88% yield). MS analysis (m−1)=348.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([CH3:25])[C:17]([C:22](Cl)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:25])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: Cc1ccccc1C(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-methylbenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and o-toluoyl chloride in a similar manner as described above to give a gray solid (19% yield). 1H-NMR (DMSO-d6): δ 11.01 (s, 1H), 8.70 (d, 1H), 7.59 (m, 1H), 7.47 (d, 1H), 7.33 (m, 2H), 7.26 (m, 2H), 7.17 (dd, 1H), 5.34 (m, 1H), 2.65 (m, 2H), 2.42 (s, 3H), 2.07 (m, 2H), 1.87 (m, 2H); MS m/z 383 (M−1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][N:22]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CN1C(=O)CCC1.CO>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[CH:3]=[C:4]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:28][CH2:29]1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Nc3ccncn3)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccncn3)c3ncc(C(=O)Nc4ccncc4)n3n2)CC1
Temperature: 120 °C

Procedure:
A solution of 6-chloro-N-(pyridin-4-yl)-8-(pyrimidin-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (12 mg, 0.033 mmol) in NMP (1 mL) was treated with (trans)-cyclohexane-1,4-diamine (37.4 mg, 0.327 mmol) and heated to 120° C. for 4 hours. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 30 min gradient, monitored at 220 nm). The product (retention time=19.202 minutes) was isolated and lyophilized to dryness to afford 6-((trans-4-aminocyclohexyl)amino)-N-4-pyridinyl-8-(4-pyrimidinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (2.1 mg, 8.59%). 1H NMR (500 MHz, DMSO) δ ppm 8.87 (1H, s), 8.65-8.74 (3H, m), 8.51 (1H, d, J=10.45 Hz), 8.25 (2H, d, J=6.60 Hz), 8.21 (2H, s), 7.25 (1H, d, J=6.05 Hz), 3.82-3.93 (1H, m), 3.16-3.24 (1H, m), 2.39 (2H, d, J=14.57 Hz), 2.11-2.22 (3H, m), 1.45-1.68 (4H, m). HPLC Rt=1.888 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=445.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[N:28]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][N:30]=[N:29]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:20][C:14]1[CH:13]=[C:12]2[C:17](=[C:16]([F:18])[C:15]=1[N:35]1[CH2:36][CH2:37][CH:33]([N:28]3[CH:32]=[CH:31][N:30]=[N:29]3)[CH2:34]1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:9]=[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2=[O:21]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of ethyl 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate (180 mg, 0.5 mmol), 3-(1,2,3-triazol-1-yl)-pyrrolidine hydrochloride (259 mg, 1.4 mmol) and DBU (384 mg, 2.5 mmol) in acetonitrile (20 ml) was heated at 75° C for 3 h, cooled to r.t. and stirred for another 15 h. The separated solid was filtered, successively washed with acetonitrile and ether. The white crystalline solid thus obtained was dried in vac-oven at 40° C. Yield: 135 mg, 56.7%. 1H NMR (CDCl3) δ: 1.35 (t, 3H), 2.50 (m, 2H), 3.70 (m, 1H), 3.85 (m, 2H), 4.10 (m, 1H), 4.35 (q, 2H), 5.25 (m, 1H), 7.20 (m, 2H), 7.40 (m, 2H), 7.63 (d, 1H), 7.72 (d, 1H), 7.90 (dd, 1H), 8.25 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][Si:12]([CH3:18])([CH3:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].N1C=CC=CC=1.[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])#[N:26]>C(Cl)Cl>[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][Si:12]([CH3:17])([CH3:18])[C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])=[O:31])#[N:26]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2cccc(C#N)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a mixture of 2-nitro-4-(dimethyl-t-butylsiloxy)aniline (10.01 g, 37.30 mmol) and CH2Cl2 (400 mL) at 0° C was added pyridine (3.4 mL, 42.0 mmol) followed by the 3-cyanobenzoyl chloride (8.65 g, 52.2 mmol). The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with CH2Cl2 (800 mL) and washed with sat. aq. NH4Cl (2×200 mL). The organic layer was MgSO4 dried, filtered, and concentrated. The residue was chromatographed (20% EtOAc/hexanes) to give the title compound as a solid (13.94 g, 94%); IR(CHCl3): 2932, 1689, 1508, 1289, 863 cm−1; NMR(300 MHz, CDCl3): δ0.27 (s, 6H), 1.02 (s, 9H), 7.27 (s, 1H), 7.70 (m, 2H), 7.90 (d, J=7.8, 1H), 8.16 (d, J=1.2, 1H), 8.30 (s, 1H), 8.79 (d, J=9.3, 1H), 11.15 (br s, 1H); MS(FD): 397.0.
Reaction SMILES: Cl[C:2]1([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=2[O:25][CH3:26])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[C:3]1=[O:15].[N-:27]=[N+:28]=[N-:29].[Na+].[I-].[Na+].O>CC(C)=O>[N:27]([C:2]1([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][C:17]=2[O:25][CH3:26])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[C:3]1=[O:15])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(C)C)ccc1C1(Cl)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(C)C)ccc1C1(N=[N+]=[N-])C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 49.3 %

Procedure:
2-chloro-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (1.23 g, 3.2 mmol) was completely dissolved in acetone (30 ml). This solution was added with sodium azide (0.47 g, 7.2 mmol), sodium iodide (0.59 g, 3.9 mmol), water (6 ml), followed by heating 12 hrs under reflux. The reaction mixture was concentrated, and extracted with ethylacetate, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (Brown syrup, 600 mg, 48%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH2:31])[NH:27][C:26](=[O:32])[CH2:25]2>>[NH2:31][C:30]1[CH:29]=[C:28]2[C:24]([C:25](=[CH:19][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:7](=[O:18])[C:6]=4[C:2]=3[CH3:1])[C:26](=[O:32])[NH:27]2)=[CH:23][C:22]=1[F:21]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(N)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 54 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-amino-1,3-dihydro-indol-2-one as starting materials to give 2-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (22 mg, 54%) as a red solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([O:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]4[CH:25]=[CH:26][CH:27]=[C:16]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH2:32]([OH:35])[CH2:33][CH3:34].[H-].[Na+]>C(#N)C>[CH2:32]([O:35][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3([O:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]4[CH:25]=[CH:26][CH:27]=[C:16]34)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:28]([F:30])([F:29])[F:31])[CH2:33][CH3:34]
Reactant: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Reactant: CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCCOc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1C(F)(F)F
Temperature: 70 °C

Procedure:
(4-Fluoro-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (22 mg, 0.051 mmol), nPrOH (12 μL, 0.15 mmol), and NaH (60%, 6.1 mg, 0.15 mmol) were combined in acetonitrile (1 mL) and the reaction mixture was heated at 70° C. for 1 h. The reaction mixture was filtered and purified by reverse phase HPLC to provide (4-propoxy-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 470.2, found 471.2 (M−1)−; Retention time: 2.83 minutes (4 min run).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([CH2:9][CH3:10])[C:6](Cl)=[O:7].[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH2:9]([CH:5]1[CH2:4][C:3]2[C:11](=[CH:12][CH:13]=[CH:14][C:2]=2[CH3:1])[C:6]1=[O:7])[CH3:10]
Reactant: CCC(Cc1ccccc1C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCC1Cc2c(C)cccc2C1=O
Temperature: 80 °C

Procedure:
101.7 g (0.48 mol) of 2-(2-methyl-benzyl)-butyryl chloride (e2) were added dropwise to 191 g (1.43 mol) of AlCl3 in 600 ml of toluene, and the mixture was heated at 80° C. for about 3.5 hours. The reaction mixture was poured onto 1 l of ice/concentrated HCl, and the phases were separated. The aqueous phase was extracted 4 times with 250 ml of toluene each time, and the combined organic phases were washed with saturated aqueous NaHCO3 solution and NaCl solution and dried over MgSO4. The solvent was removed in vacuo and the residue was distilled (78° C./0.2 mmHg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH:19](=[N+:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: C(c1ccccc1)=[N+]1CCCCC1
Agent: [Cl-]
Product: c1ccc(COc2ccc3[nH]cc(C(c4ccccc4)N4CCCCC4)c3c2)cc1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-benzyloxy-1H-indole and 1-benzylidene-piperidinium chloride.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25]>>[O:25]=[C:24]1[NH:23][CH:29]([CH:12]([CH3:11])[C:14]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[C:4]([CH3:3])[CH:13]=3)=[CH:22][CH:21]=2)=[O:15])[C:27](=[O:28])[NH:26]1
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Reactant: O=C1CNC(=O)N1
Agent: Cl
Product: Cc1cc(COc2ccc(NC(=O)C(C)C3NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 13 %

Procedure:
2-(4-hydantoinyl)propionic acid (50 mg, 0.30 mmol) and 4-[(2-methyl-4-quinolinyl)methoxy]-aniline bis-HCl salt (101 mg, 0.30 mmol) were coupled using general coupling method A to give 20 mg (13%) of the product hydantoin. MS found: (M+H)+=419.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:12])(=[O:11])[C:8]([CH3:10])=[CH2:9].[C:13](=[O:21])([O:17][CH2:18][CH2:19]Cl)[O:14][CH2:15][CH3:16].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:13](=[O:21])([O:17][CH:18]([O:11][C:7](=[O:12])[C:8]([CH3:10])=[CH2:9])[CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)OCCCl
Reactant: C=C(C)C(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OC(C)OC(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.5 %

Procedure:
Potassium tert. butoxide (3.70 g, 0.033 mol ) was added to a solution of methacrylic acid (2.84 g, 0.033 mol) in DMF (100 ml). Ethyl chloroethyl carbonate (5.08 g, 0.033 mol) from Example 1q(i) above was added to the resulting suspension. 18-crown-6 (0.61 g, 2.3 mmol) was then added and the reaction mixture was left with stirring at room temperature for 3 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography gave 2.50 g (38%) of the title product. (Adjusted for recovered starting material the yield was 75%).
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[C:30]([CH2:31][NH:32]C(OC(C)(C)C)=O)=[N:29][CH:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:30]1[N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:27]=[CH:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NCc1ncnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)N1S(=O)(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncnc1CN)c1csc(N)n1)C(=O)O
Yield: 62.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (143 mg, 0.181 mmol), DCM (1.81 mL) and TFA (837 μl, 10.9 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (60 mg, 62%) as a white powder. LCMS: Rt=0.28 min, m/z=532.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.23 (d, J=9.1 Hz, 1H), 8.40 (br s, 3H), 8.06 (s, 1H), 7.59-7.27 (m, 2H), 6.84 (s, 1H), 5.37 (dd, J=9.0, 5.5 Hz, 1H), 4.61-4.51 (m, 1H), 4.49-4.34 (m, 3H), 4.25 (dd, J=15.3, 5.8 Hz, 1H), 1.37 (s, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Ca+2]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH3:18])[CH2:13][CH2:14]1)=[O:4]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: Cc1ccccc1N1CCN(C(=O)CCl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Chloroacetyl chloride (4.5 ml, 56.6 mmol) is added dropwise to a solution of 1-o-tolylpiperazine (8.31 [lacuna], 47.2 mmol) and calcium carbonate (14.2 g, 142 mmol) in methyl ethyl ketone (100 ml) cooled to 0° C. The reaction mixture is stirred at this temperature for 1 h 30 and is then filtered through Celite. The Celite is rinsed several times with ethyl acetate and 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulfate, filtered and concentrated to give the expected product in the form of a brown solid.
Reaction SMILES: [Na].[CH:2]([C:4]1[N:5]([CH2:9][C:10]([NH:12][CH:13]2[C:20](=[O:21])[N:19]3[CH:14]2[S:15][CH2:16][C:17]([CH2:25][S:26][C:27]2[N:31]([CH3:32])[N:30]=[N:29][N:28]=2)=[C:18]3[C:22]([OH:24])=[O:23])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:3].[C:33]([O:36][CH2:37]Cl)(=[O:35])[CH3:34]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:36][CH2:37][O:23][C:22]([C:18]1[N:19]2[CH:14]([S:15][CH2:16][C:17]=1[CH2:25][S:26][C:27]1[N:31]([CH3:32])[N:30]=[N:29][N:28]=1)[CH:13]([NH:12][C:10](=[O:11])[CH2:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[CH:2]=[O:3])[C:20]2=[O:21])=[O:24])(=[O:35])[CH3:34]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Reactant: CC(=O)OCCl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCOC(=O)C1=C(CSc2nnnn2C)CSC2C(NC(=O)Cn3cccc3C=O)C(=O)N12
Reaction time: 0.5 h

Procedure:
The sodium salt of 7-[[(2-formyl-1-pyrryl)acetyl]-amino]-3-[[(1-methyltetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3 grams, is added to about 40 ml of dry dimethylformamide (DMF) and stirred for 30 minutes. The 4.0 ml of chloromethyl acetate in 5 ml of DMF was added. This mixture is stirred for about 4 hours at room temperature. This mixture is diluted with ethyl acetate and thoroughly washed with water. The ethyl acetate portion is dried over sodium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].[CH3:29][NH2:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[NH:30][CH3:29])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CN
Product: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and methylamine were reacted by a procedure similar to Example 47 to give 250. MS: (ESI+) 427.2
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:17])=[C:7]([CH3:16])[C:8]([OH:15])=[C:9]([C:12](=O)[CH3:13])[C:10]=1[CH3:11])(=[O:3])[CH3:2].Cl.[NH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[NH:31][C:30]2=[O:35])=[CH:26][CH:25]=1>>[C:1]([O:4][C:5]1[C:6]([CH3:17])=[C:7]([CH3:16])[C:8]([OH:15])=[C:9]([C:12](=[N:19][O:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:28][CH:29]3[S:33][C:32](=[O:34])[NH:31][C:30]3=[O:35])=[CH:36][CH:37]=2)[CH3:13])[C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)Oc1c(C)c(C)c(O)c(C(C)=O)c1C
Agent: Cl
Product: CC(=O)Oc1c(C)c(C)c(O)c(C(C)=NOCCOc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Yield: 44.6 %

Procedure:
Following a procedure similar to that described in Example 46, but using 0.32 g of 5'-acetoxy-2'-hydroxy-3',4',6'-trimethylacetophenone and 0.40 g of 5-[4-(2-aminooxyethoxy)benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)], 0.28 g of the title compound was obtained as an amorphous powder, melting at 60°-75° C. (softening point).