Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:23]([O-])=O)[CH:8]=2)[N:3]=1>CCOC(C)=O.[Pd]>[NH2:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1c(C)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2ccc(N)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 146.6 %

Procedure:
A mixture of the product of Step 1 (1.05 g, 3.25 mmol) and 10% Pd/C (0.222 g, 32.5) in EtOAc was degassed under reduced pressure and saturated with H2 gas. The resulting mixture was stirred overnight under H2 balloon at room temperature, filtered through Celite bed and filtrate evaporated to dryness to give product as an yellowish solid (1.46 g, 98%), which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.9 Hz, 1H), 7.43-7.48(m, 3H), 7.27-7.34(m, 2H), 7.10 (dd, J=2.5, 8.9 Hz, 1H), 6.55(d, J=2.5 Hz, 1H), 3.79(broad s, 2H), 2.69(s, 3H), 1.2(s, 9H).
Reaction SMILES: [CH3:1][C:2]([CH:6]1[C:18]2[CH:17]=[C:16]([CH2:19]O)[CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[C:8]([O:22][CH3:23])[CH:9]=[CH:10][C:11]=2[F:21])([CH3:5])[CH:3]=[CH2:4].S(Cl)([Cl:26])=O>C(Cl)Cl>[Cl:26][CH2:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12]3[C:11]([F:21])=[CH:10][CH:9]=[C:8]([O:22][CH3:23])[C:7]=3[CH:6]2[C:2]([CH3:5])([CH3:1])[CH:3]=[CH2:4])=[CH:14][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: C=CC(C)(C)C1c2cc(CO)ccc2-c2c(F)ccc(OC)c21
Solvent: ClCCl
Product: C=CC(C)(C)C1c2cc(CCl)ccc2-c2c(F)ccc(OC)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 21.8 (40 mg, 128 μmol) in DCM (0.8 mL), was added thionyl chloride (30 mg, 256 μmol). The resulting mixture was stirred at room temperature for 1 hour. Solvent was removed in vacuo to give a residue which was used without purification (40 mg, 94%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[C:30]([N:31]=[C:32]=[O:33])=[C:29]([CH3:34])[O:28][N:27]=1>O1CCCC1>[CH3:25][C:26]1[C:30]([NH:31][C:32]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:33])=[C:29]([CH3:34])[O:28][N:27]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2.5 ml) was added 3,5-dimethylisoxazol-4-yl isocyanate (168 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 214 mg (68.6%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28]OS(C)(=O)=O)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:34].[Li+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][Br:34])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(COS(C)(=O)=O)cc3)c2CC1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CBr)cc3)c2CC1
Reaction time: 8 h

Procedure:
Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-(4-methanesulfonyloxymethyl -benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous acetone (3 mL), treat with anhydrous lithium bromide (335 mg, 3.89 mmol) and continue stirring overnight. Add water, extract the reaction mixture three times with ethyl ether, wash with brine, dry over anhydrous MgSO4, and concentrate in vacuo to obtain the desired intermediate that was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[CH2:23]([C@@H:30]1[CH2:32][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:32][C@H:30]([OH:31])[CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(C[C@@H]2CO2)cc1
Product: O=C1C(=O)c2ccc(F)cc2C2=C1SCC1(CCN(C[C@H](O)Cc3ccccc3)CC1)O2

Procedure:
Compound 219 was synthesized using 9-fluorospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=76-77° C.; 400 MHz 1H NMR (CDCl3) δ: 8.08 (dd, J=8.6, 5.9 Hz, 1H), 7.37 (dd, J=9.4, 2.7 Hz, 1H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 3H), 7.14 (td, J=8.2, 2.7 Hz, 1H), 4.04-3.95 (m, 1H), 2.98-2.82 (m, 2H), 2.93 (s, 2H), 2.79-2.66 (m, 3H), 2.54-2.37 (m, 3H), 2.16-2.08 (m, 2H), 1.97-1.80 (m, 2H); LCMS: 454 [M+H].
Reaction SMILES: C[O:2][C:3]1C=C(C2C=CC3N=CN=CC=3N=2)C=C[C:8]=1OC.[NH2:21][C:22]1[N:23]=[C:24]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH:43]2[C:48](=[O:57])[NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)[C:25]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=3)[CH:29]=[CH:28][C:26]=2[N:27]=1.N.CNC>>[C:3]([NH:21][C:22]1[N:23]=[C:24]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH:43]2[C:48](=[O:57])[NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)[C:25]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=3)[CH:29]=[CH:28][C:26]=2[N:27]=1)(=[O:2])[CH3:8]
Reactant: COc1ccc(-c2ccc3nc(N)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Reactant: COc1ccc(-c2ccc3ncncc3n2)cc1OC
Agent: CNC
Agent: N
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC

Procedure:
2-acetamido-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine was synthesized from 2-chloro-4-(4-[3-methylphenyl)amino]carbonyl]piperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyrido[3,2-d]pyrimidine. In a first step, 2-amino-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine was synthesized according to the procedure mentioned for examples 15, using ammonia (instead of dimethylamine). Subsequent acetylation yielded the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CS(C)=O>[CH3:8][N:5]1[CH:6]=[CH:7][C:2]([NH:13][C:14]2[CH:15]=[C:16]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)=[C:3]([N+:10]([O-:12])=[O:11])[C:4]1=[O:9]
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Reactant: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cn1ccc(Nc2cccc(-c3ccccc3C#N)c2)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Yield: 97.3 %

Procedure:
4-Chloro-1-methyl-3-nitro-1H-pyridin-2-one (0.71 g, 3.8 mmol) and 3′-aminobiphenyl-2-carbonitrile (0.73 g, 3.8 mmol) were dissolved in triethylamine (5.25 ml, 37.8 mmol) and DMSO (5 ml) and heated at 90° C. for 18 h. The mixture was allowed to cool to ambient temperature then poured onto water (150 ml). The aqueous phase was extracted with ethyl acetate (2×150 ml), the combined organics were washed with water (3×75 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown solid. The solid was triturated with diethyl ether (20 ml), filtered and left to air dry, to give 3′-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-ylamino)biphenyl-2-carbonitrile (1.28 g, 98%) as a brown solid: δ (400 MHz, CDCl3) 3.50 (3H, s), 6.24 (1H, d, J 8), 7.26 (1H, d, J 8), 7.34 (1H, d, J 8), 7.48 (2H, dd, J 4 and 2), 7.51-7.59 (2H, m), 7.60 (1H, t, J 8), 7.68-7.72 (1H, m), 7.81 (1H, dd, J 8 and 1), 10.47 (1H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O.[CH2:23](COC)OC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]=[C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:5]=1[O:4][CH3:3])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COCCOC
Reactant: COC(=O)c1ccc(OC)c(OC2CCCCC2=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=C1CCCCC1Oc1cc(C(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
43.8 g of methyltriphenylphosphonium bromide in 300 ml of abs. dimethoxyethane are treated in portions under nitrogen with 3.6 g of sodium hydride (80% in paraffin). The mixture is stirred at RT for 1 h and a solution of 30 g of methyl 4-methoxy-3-(2-oxocyclohexyloxy)benzoate is then slowly added dropwise. The mixture is stirred at RT overnight and then worked up analogously to Example B5. 21 g of the title compound are obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1ncc(Cl)cc1B(O)O
Solvent: CN(C)C=O
Product: COc1ncc(Cl)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 5-chloro-2-methoxypyridine-3-boronic acid (CAS RN 943153-22-8) and using DMF as reaction solvent. Off-white solid (28%). MS (ESI): m/z=490.0 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18]([O:20]C)=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3.S(=O)(=O)(O)O>CO.C1COCC1.[OH-].[Li+]>[F:22][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3([O:17][C:8]=2[C:7]([C:18]([OH:20])=[O:19])=[CH:6][CH:5]=1)[CH2:16][CH2:15][S:14][CH2:13][CH2:12]3
Reactant: COC(=O)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OC(F)F)c2c1OC1(CCSCC1)O2
Temperature: 25 °C

Procedure:
Methyl 7-Difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylate(437 mg) was dissolved in a mixture of Methanol(5 mL) and THF(5 mL) and 1M aqueous Lithium hydroxide(3.9 mL) was added. The ester was cleaved after 1 hour at 50° C. The solution was cooled to room temperature and acidified with 2N sulfuric acid (1.95 mL) and the product was extracted into EtOAc. 7-Difluoromethoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid was obtained after removal of solvents under reduced pressure.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[C:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(NC(C)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-acetyl-p-phenylenediamine
Reaction SMILES: [CH3:1][C:2]([OH:33])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl>[OH:33][C:2]([CH3:1])([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)[CH2:3][CH2:4][O:5][S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH3:51])=[CH:42][CH:43]=1)(=[O:49])=[O:48]
Reactant: CC(O)(CCO)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCC(CCc4ccc(OC(F)(F)F)cc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
3-Methyl-4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butane-1,3-diol (1.68 g, 3.6 mmol), dichloromethane (17 ml), triethylamine (1.00 ml, 7.2 mmol) and p-toluenesulfonyl chloride (0.82 g, 4.3 mmol) were mixed and ice-cooled. 1,1,3,3,-Tetramethylpropanediamine (0.12 ml, 0.7 mmol) was added thereto and stirred at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0, 50:50) to afford the title compound as a colorless powder (2.03 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:15]
Reactant: O=C([O-])[O-]
Reactant: Brc1ccccc1OC[C@H]1CCCN1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCC[C@@H]1COc1ccccc1Br
Yield: 38.6 %

Procedure:
(2R)-2-[(2-Bromophenoxy)methyl]pyrrolidine (1.84 g), potassium carbonate (1.09 g) and methyl iodide (0.49 ml) were stirred in dimethylformamide (10 ml) for 2 h at room temperature. The mixture was concentrated in vacuo and water added (50 ml). The mixture was extracted with diethyl ether (3×30 ml). The organic portions were combined and washed with water (2×20 ml), brine (2×20 ml) and dried (MgSO4) and concentrated in vacuo yielding the title compound as a pale orange oil (0.75 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=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:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: COc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
6-Bromo-N-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and p-anisidine (94 mg, 0.76 mmol) in a similar manner as described in Example 13 to give 41 mg (29%) of a light brown solid. 1H-NMR (DMSO-d6): δ 811.05 (s, 1H), 7.54 (s, 1H), 7.22 (d, 1H), 7.11 (d, 1H), 6.73-6.66 (m, 4H), 5.48 (d, 1H), 4.70-4.65 (m, 1H), 3.63 (s, 3H), 2.66-2.53 (m, 2H), 1.98-1.89 (m, 2H), 1.79-1.71 (m, 2H); MS m/z (M−1) 369, 371.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]([C:20]([OH:22])=[O:21])[N:18]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:17]3[S:16][CH:15]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:42][C:43]([Cl:47])([Cl:46])[CH2:44]O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:42][C:43]([Cl:47])([Cl:46])[CH2:44][O:21][C:20]([CH:19]1[N:18]2[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=[C:14]1[CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22]
Reactant: COc1ccc(CC2=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc12
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CC2=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)c2ccccc12

Procedure:
A solution of 10.9 g of 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid in 300 ml of methylene chloride is treated with 1.80 ml of pyridine, then successively with 2.50 ml of 2,2,2-trichloroethanol in 20 ml of methylene chloride and 4.95 g of dicyclohexylcarbodiimide in 40 ml of methylene chloride. The addition of the reagents is carried out at room temperature and while stirring. The reaction mixture is stirred for 20 hours at room temperature, freed from dicyclohexylurea by means of filtration and the filtrate is evaporated under reduced pressure. The residue is taken up in ethyl acetate and mixed with an aqueous dipotassium hydrogen phosphate buffer solution (pH 7.5). The aqueous portion is separated, washed several times with ethyl acetate and the pH adjusted to 2.5 with 20% aqueous phosphoric acid. After repeated extraction with ethyl acetate, the organic extracts from the aqueous phase having pH 2.5 are combined, washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on 450 g of silica gel, elution being carried out with methylene chloride containing 5% of methyl acetate, fractions of 500 ml being taken. The residue of the fractions 12-13 is crystallised from ethyl acetate and yields the 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid 2,2,2-trichloroethylester, which melts at 145-147°; [α]D20 = + 271° ± 1° (c = 0,918 in chloroform); ultraviolet absorption spectrum (in methanol): λmax = 210 mμ (ε = 67000), 232 mμ (ε = 41200), 298 mμ (ε = 9990) and 322 mμ (ε = 4960); infrared absorption spectrum (in mineral oil): characteristic bands at 2,90μ, 5,62μ, 5,68μ, 6,02μ, 6,27μ and 6,60μ; thin-layer chromatogram (silica gel): Rf = 0.27 (system: toluene/ethyl acetate 4:1) and Rf = 0.38 (system: toluene/acetone 9:1).
Reaction SMILES: COC(=O)[NH:4][C@:5]1([C:9](=[O:27])[NH:10][C:11]2[S:12][C:13]([CH3:26])=[C:14]([CH3:25])[C:15]=2[C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:7][C@@H:6]1[CH3:8].N1CCCCC1.C(O)(=O)C>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:15]3[C:14]([CH3:25])=[C:13]([CH3:26])[S:12][C:11]=3[NH:10][C:9](=[O:27])[C@:5]3([CH2:7][C@@H:6]3[CH3:8])[N:4]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)N[C@]1(C(=O)Nc2sc(C)c(C)c2C(=O)c2ccc(Cl)cc2)C[C@@H]1C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@]1(C[C@@H]1C)C(=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
A round bottomed flask was charged with 9H-fluoren-9-yl)methyl-(1R,2S)-1-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-ylcarbamoyl)-2-methylcyclopropylcarbamate (225 mg, 0.385 mmol) and a stir bar. DMF (16 mL, 0.02 M) was added, followed by piperidine (4 mL, 40.4 mmol), and the solution was stirred at room temperature 15 min. The solution was washed with water, extracted twice with ethyl acetate, washed with brine, and concentrated before being taken up in ethanol (25 mL). Acetic acid (12.5 mL, 218 mmol) was added, and the solution was stirred at 90° C. 3 h before being concentrated with celite and purified by column chromatography to give (1R,2S)-5′-(4-chlorophenyl)-2,6′,7′-trimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one (Compound 218) as a light yellow amorphous solid (96 mg). LRMS (M+H)+: 345 m/z.
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[CH:23][CH:24]=1.S(Cl)(Cl)=O>>[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([N:1]([CH2:8][C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:30])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CNc1ccccc1)OC1CCCCC1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC2CCCCC2)c2ccccc2)c1
Yield: 14.7 %

Procedure:
The procedure is similar to that described in Example 28, but starting with cyclohexyl 2-anilinoacetate (8.6 g), 2-[3-(3-methylphenyl)ureido]acetic acid (7.7 g) and thionyl chloride (2.7 cc). The product obtained is purified by chromatography on silica gel (0.063-0.200 mm; 150 g) contained in a column 3.5 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)], collecting 20-cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in isopropanol, cyclohexyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (2.3 g), m.p. 176° C., is obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([S:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([OH:23])=O)(=[O:18])[CH3:17].[NH2:31][C@H:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35].O.OC1C2N=NNC=2C=CC=1>O1CCCC1>[C:16]([S:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH:31][C@H:32]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)SC(Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This salt is converted to the free acid. Dicyclohexylcarbodiimide in tetrahydrofuran is added to a solution of (S)-2-acetylthio-3-phenylpropionic acid, (L)-leucine, 1,1-dimethylethyl ester, and hydroxybenzotriazole hydrate in tetrahydrofuran at -8° and the reaction mixture is stirred overnight warming to room temperature, and is then worked up according to the procedure of Example 37 to yield (S)-N-[2-(acetylthio)-1-oxo-3-phenylpropyl]-L-leucine, 1,1-dimethylethyl ester as a clear, light yellow, viscous oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Cl[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][O:17][C:15]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
tert-Butyl(3S)-3-aminopyrrolidine-1-carboxylate (0.09 mL, 0.5 mmol) was combined with methyl chloroformate (0.049 mL, 0.64 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated. The residue was purified on silica gel (eluting with 0 to 10% methanol in dichloromethane) to give tert-butyl (3S)-3-[(methoxycarbonyl)amino]pyrrolidine-1-carboxylate, LCMS [M+Na] 267.1. The latter was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the crude product (35 mg, 40%), which was used directly in the next step. LCMS calculated for C6H13N2O2 (M+H)+: m/z=145.1; Found: 145.1.