Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:8][CH2:9][CH2:10]Br.O1CCOCC1>C(N(CC)CC)C>[N:5]1[N:6]2[CH2:8][CH2:9][CH2:10][NH:1][C:2]2=[CH:3][CH:4]=1
Reactant: BrCCCBr
Reactant: Nc1ccn[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: c1cc2n(n1)CCCN2
Temperature: 25 °C

Procedure:
5-Aminopyrazole (10 g) and 1,3-dibromopropane (13.4 ml) were added to 1,4-dioxane (20 ml) under stirring at ambient temperature. Triethylamine (40.1 ml) was added thereto. The mixture was refluxed under stirring for 4 hours. The reaction mixture was cooled to 0°-5° C. in an ice-bath and stirred for 30 minutes. An insoluble material was filtered off, and the filtrate was evaporated under reduced pressure to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (5.1 g).
Reaction SMILES: CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.O[CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:33][CH:32]=3)[NH:23][C:22](=[O:46])[C:21]=2[CH:47]=1.[CH2:48]([NH:50][CH2:51][CH2:52][OH:53])[CH3:49]>C(Cl)Cl>[CH2:48]([N:50]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:35][CH:36]=3)[NH:23][C:22](=[O:46])[C:21]=2[CH:47]=1)[CH2:51][CH2:52][OH:53])[CH3:49]
Reactant: CCNCCO
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4cc(CO)ccc4c23)cc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCO)Cc1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
DIEA (0.03 mL, 0.19 mmol) and methanesulfonyl chloride (0.01 mL, 0.09 mmol) were added to a solution of 273 (27 mg, 0.06 mmol) in CH2Cl2 and stirred for 2 h at room temperature. 2-(Ethylamino)ethanol (17 mg, 0.19 mmol) was added, and the reaction mixture was stirred for 1 h. The crude product was purified directly via HP-LC to provide 274 (6 mg, 16% yield) as a solid. LC-MS (M+H=508, obsd.=508).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)[N:6]=[CH:5]2
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2ncc3cc(Br)ccc32)CC1
Temperature: 50 °C
Reaction time: 13 h

Procedure:
A solution of 5-bromoindazole (5.00 g), ethyl trans-4-hydroxycyclohexanecarboxylate (8.73 g), triphenylphosphine (13.3 g) in THF (150 mL) was stirred at 0° C. for 15 minutes. To the reaction solution was added dropwise diethylazodicarboxylate (9.03 g) under nitrogen atmosphere at 0° C., and the mixture was stirred at 50° C. for 13 hours. Then, the solvent was removed out, and ethyl acetate (100 mL) and petroleum ether (30 mL) were added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:80-1:15 as the eluting solvent) to give Compound Q14 (3.50 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1>O>[Cl:21][C:22]1[N:27]=[C:26]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([CH3:11])=[CH:5]3)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc2cc(Oc3ccnc(Cl)n3)ccc2[nH]1
Temperature: 2.5 °C
Reaction time: 6 h
Yield: 107.7 %

Procedure:
To a 50 L three-neck round bottom flask, equipped with a mechanical stirrer, addition funnel and thermometer, were added 2-methyl-1H-indol-5-ol (compound 1, 3 Kg), anhydrous acetonitrile (9 L) and potassium carbonate (4.2 Kg). The reaction mixture was cooled to 0-5° C. with stirring under N2. A solution of 2,4-dichloropyrimidine (Compound 2, 3.05 Kg, in 9 L of acetonitrile) was added to the reaction mixture dropwise while keeping the inner temperature of the reaction in the range from 0 to 5° C. After addition was complete, the reaction mixture was allowed to warm to a temperature ranging from 5 to 10° C. over a period of 4-8 hours. When reaction was completed, the reaction mixture was poured into 54 L of distilled water in a 100 L reactor with stirring, and stirred for another hour at room temperature. The precipitates were collected by filtration and the filter cake was washed with pure water to afford Compound 3 (5.7 Kg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:29][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: NC1CCCC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNC2CCCC2)cc1
Yield: 31.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-((cyclopentylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), cyclopentanamine (0.091 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.025 g (31%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27](O)=[O:28].Cl.[OH:31][C:32]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:33]=1[CH2:34][CH2:35][NH:36][CH2:37]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([N:36]1[CH2:35][CH2:34][C:33]2[C:38](=[CH:39][CH:40]=[CH:41][C:32]=2[OH:31])[CH2:37]1)=[O:28]
Reactant: Oc1cccc2c1CCNC2
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)N3CCc4c(O)cccc4C3)c2cc1OC
Yield: 9.3 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 119 (9.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.80 and 2.90 (2t, 2H), 3.52-4.07 (m, 17H), 4.42 and 4.94 (2s, 2H), 6.29-7.17 (m, 4H), 7.48 and 7.51 (2s, 1H), 7.78 and 7.84 (2s, 2H), 9.50 and 9.52 (2s, 1H); MS (ESI) m/z 532 ([M+H]+).
Reaction SMILES: C([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]1[N:42]=[CH:41][C:40]2[CH:39]=[CH:38][C:37]3[C:43]([C:47]([O:49]CC)=O)=[N:44][N:45]([CH3:46])[C:36]=3[C:35]=2[N:34]=1)=[O:24])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH4+:52].[OH-]>C(O)C>[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]1[N:42]=[CH:41][C:40]2[CH:39]=[CH:38][C:37]3[C:43]([C:47]([NH2:52])=[O:49])=[N:44][N:45]([CH3:46])[C:36]=3[C:35]=2[N:34]=1)=[O:24]
Reactant: CCOC(=O)c1nn(C)c2c1ccc1cnc(Nc3ccccc3NC(=O)[C@@H]3CCCN3C(=O)OCC3c4ccccc4-c4ccccc43)nc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(N)=O)c2ccc3cnc(Nc4ccccc4NC(=O)[C@@H]4CCCN4)nc3c21
Temperature: 65 °C
Reaction time: 12 h
Yield: 47 %

Procedure:
Ethyl 8-{2-[((S)—N-FMOC-pyrrolidine-2-carbonyl)-amino]-phenylamino}-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (200 mg, 0.29 mmol) was suspended in 20 mL of ethanol and 20 mL of NH4OH 30% mixture. The mixture was maintained at 65° C. under stirring for 12 h in a closed bottle. The solvent was then evaporated to dryness, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 94/6) to afford 60 mg (47% yield) of the title compound.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=O)C.Br[CH2:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16]>>[CH:15]([O:14][CH2:13][CH2:12][O:10][CH:7]1[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1)([CH3:17])[CH3:16]
Reactant: CC(C)OCCBr
Reactant: CC(=O)N1CCC(O)CC1
Product: CC(C)OCCOC1CCNCC1

Procedure:
This compound was prepared similarly to Example A from N-acetyl-4-hydroxypiperidine and 1-bromo-2-isopropoxyethane. The compound was characterized by spectroscopic techniques.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=1>C1COCC1.O=O>[Br:5][CH2:2][CH2:27][C:28]1[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCO)cc1
Reactant: BrC(Br)(Br)Br
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
7.16 g (21.59 mmol) of tetrabromomethane and 5.66 g (21.59 mmol) of triphenylphosphine are dissolved in 70 ml of THF with exclusion of oxygen and stirred at room temperature for 30 minutes. Then 3.2 g (14.4 mmol) of tert-butyl 4-(2-hydroxyethyl)benzoate, dissolved in 30 ml of THF, are added dropwise, and the reaction mixture is stirred at room temperature for 12 hours. After conversion is complete, the mixture is evaporated to dryness and the resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 3.9 g (13.7 mmol, 87% yield) of the title compound are obtained as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][C@H:39]([CH3:43])[CH2:38]1)=[O:36]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:41][CH2:42][N:37]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:38][C@H:39]5[CH3:43])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: COCC(=O)N1CCN[C@H](C)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)[C@H](C)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-2-(R)-methyl-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Methoxy-1-(3-(R)-methyl-piperazin-1-yl)-ethanone following General Procedure C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[S:15][C:7]2=[N:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]2[CH2:5][CH2:4]1.[H-].[Na+].[CH:18](Br)=[CH:19][C:20](=[CH2:22])[CH3:21].O>O1CCCC1>[CH:18]([O:1][CH2:2][CH:3]1[S:15][C:7]2=[N:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]2[CH2:5][CH2:4]1)=[CH:19][C:20](=[CH2:21])[CH3:22]
Reactant: OCC1CCn2c(nc3ccccc32)S1
Reactant: C=C(C)C=CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C=COCC1CCn2c(nc3ccccc32)S1
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a solution of one gram of 3,4-dihydro-2-hydroxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in dry tetrahydrofuran (20 ml) was treated with 0.5 g of 50% sodium hydride containing mineral oil at 0° C. under stirring. The mixture was stirred for 1 hr, then one gram of isoprenylbromide was added, and the stirring was continued for three hours at room temperature. The reaction mixture was condensed under reduced pressure. The residue was added with water and then extracted with chloroform, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.42 g (yield: 30%) of the intended product, m.p. 56°-60° C.; IR νmaxKBr cm-1 : 3100-2850, 1600, 1420; Anal. Calcd. for C16H20N2OS: C, 66.63; H, 6.99; N, 9.71; S, 11.12; Found: C, 66.64; H, 6.92; N, 9.94; S, 10.89.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[CH:22]([O-])([O-])OCC.[BH4-].[Na+]>C(O)C>[F:21][C:11]1[CH:10]=[C:9]([CH:7]([C:5]2[N:6]=[C:2]([NH:1][CH3:22])[O:3][CH:4]=2)[CH3:8])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1coc(N)n1
Reactant: CCOC([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of 2-amino-4-(1-(2-fluoro-4-biphenylyl) ethyl)oxazole (1.66 g, 5.88 mmol) and ethyl orthoformate (20 ml) was refluxed for 5 hr and the reaction mixture was evaporated under reduced pressure to a residue. To the residue in ethanol (50 ml) was added sodium borohydride (0.27 g, 7.14 mmol) under cooling, then the mixture was stirred at room temperature for 2 hr. After evaporation, the residue was extracted with ethyl acetate and the extracts were washed with water, dried and then evaporated under reduced pressure to a residue, which was chromatographed and recrystallized to afford 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminooxazole (0.66 g, 40% yield): mp 133.5°-135.0° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]=[O:14])=[C:8]([CH3:15])[CH:7]=1.[CH2:17](O)[CH2:18][OH:19].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:13]2[O:19][CH2:18][CH2:17][O:14]2)=[C:8]([CH3:15])[CH:7]=1
Reactant: OCCO
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCc1cc(C)c(C2OCCO2)c(C)c1

Procedure:
To a stirred solution of 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester, (2.2 g, 10 mmol) and ethane-1,2-diol (1.86 g, 30 mmol) in toluene (50 mL) was added p-TsOH.H2O (38 mg, 0.2 mmol) and the solution was refluxed using a Dean-Stark apparatus overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (5:1) as eluent to give 3-(4-[1,3]dioxolan-2-yl-3,5-dimethylphenyl)-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][OH:27])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH:26]=[O:27])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CO)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)s1
Reaction time: 20 h
Yield: 40.6 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((5-hydroxymethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.085 g, 0.19 mmol) in DMF (6 mL) was added pyridinium dichromate (PDC) (0.25 g, 0.65 mmol) at ambient temperature. After stirring for 20 hours, water was added and the reaction mixture was extracted with methylene chloride. The combined extracts were dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography on silica to afford 0.035 g of N-(4-chlorophenyl)-2-[((5-formyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a pale yellow solid; NMR (DMSO-d6) 11.3 (s, 1), 10.8(s, 1), 9.9 (s, 1),8.3 (d, 1), 8.1 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (d, 1), 7.4 (d, 2) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:26]>C(Cl)Cl>[F:26][C:10](=[O:11])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccsc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To (R)-2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)acetic acid in CH2Cl2 cooled to −10° C. was added pyridine and cyanuric fluoride. The solution was stirred for 1 hour at −10° C., quenched with ice and extracted with CH2Cl2 and ice cold water, dried (Na2SO4), filtered and evaporated to give (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.CN(C)C1C=CC=CC=1.[Cl:40][C:41]([Cl:46])([Cl:45])[C:42](Cl)=[O:43]>ClCCl>[Cl:40][C:41]([Cl:46])([Cl:45])[C:42]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:43]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2,2′-dimethyl-biphenyl-4-yl)-methanone of Step C (12.4 g, 31.6 mmol) and N,N-dimethylaniline (6.4 mL, 50.5 mmol) in dry dichloromethane (90 mL) at 0° C. under nitrogen, was added trichloroacetyl chloride (5.3 mL, 47.5 mmol). The reaction was then allowed to warm slowly to room temperature while stirring overnight. The reaction mixture then was washed with 2N hydrochloric acid (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark foam. Purification by filtration through a plug of silica gel (60 g) eluting with dichloromethane afforded the title compound (15.9 g, 94%) as a light orange solid, m.p. 212-214° C. MS [(+)ESI, m/z]: 537 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH2:16][SH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[C:18]([NH:9][CH:10]([CH2:16][SH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Cl
Reactant: CCOC(=O)C(N)CS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NC(CS)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.5 mL) was added to a suspension of ethyl 2-amino-3-mercaptopropanoate hydrochloride (5 g) in DCM (50 mL). The resulting mixture was cooled in an ice/salt bath and butyryl chloride (3.3 mL) was added dropwise. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous phase was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a white solid. Yield 3 g.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:19]([O:21]CC3C=CC([N+]([O-])=O)=CC=3)=[O:20])=[C:8]([C:11]3[N:12]4[CH:18]=[N:17][CH:16]=[C:13]4[S:14][CH:15]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:19]([OH:21])=[O:20])=[C:8]([C:11]3[N:12]4[CH:18]=[N:17][CH:16]=[C:13]4[S:14][CH:15]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4cncn34)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3csc4cncn34)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.8 %

Procedure:
To a solution of 4.70 g of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 10 ml of THF and 10 ml of {fraction (1/15)} M phosphate buffer was added 240 mg of 10% Pd-C. The reactor was purged with hydrogen, and the reaction mixture was stirred at room temperature for 3 hours. The catalyst was collected by filtration and washed with water. The filtrate was washed with ethyl acetate, and the aqueous layer was purified by column chromatography on DIAION HP-20 to give 27.5 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:33].[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of (R)-tert-butyl 5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (30 mg, 0.066 mmol) in DCM was treated with 4N HCl in dioxane (0.5 mL). The reaction was stirred at about room temperature overnight. The reaction was concentrated and triturated with ether (×2) to yield (R)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]dihydrochloride (21 mg, 73%). LCMS (APCI+) m/z 355, 357 [M+H]+; Rt=2.09 min.