Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(O[N:51]1N=N[C:53]2C=CC=[CH:57][C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:51][CH:52]([CH3:57])[CH3:53])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and isopropylamine (7.03 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16.4 mg, 48.5%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:11]([C:13]2[CH:14]=[C:15]([Cl:22])[CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH:42]1[CH2:44][CH2:43]1>C(#N)C>[C:1]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:41][CH:42]3[CH2:44][CH2:43]3)[CH:26]=2)[C:11]([C:13]2[CH:14]=[C:15]([Cl:22])[CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCC1CC1
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(O)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OCC3CC3)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
122 mg of 5-chloro-1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-[2-(3-hydroxy-phenyl)-ethyl]-amide (0.25 mmol) and 52 mg potassium carbonate (0.375 mmol) were suspended in 5 ml acetonitrile and treated with 0.027 ml bromomethyl-cyclopropane (0.275 mmol). The mixture was stirred for 24 h in an oil-bath heated to 80° C. After cooling down, the mixture was poured on water/EtOAc, and after separation the aqueous phase was extracted with EtOAc. The combined organic phases were then washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silicagel, heptane/EtOAc 9:1) leading to 66 mg of 5-chloro-1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-[2-(3-cyclopropylmethoxy-phenyl)-ethyl]-amide as a colorless viscous oil. MS (ISP) 515.5 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].Cl[S:9]([OH:12])(=[O:11])=[O:10]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[S:9](=[O:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)Cl
Solvent: Cc1ccccn1
Solvent: ClCCl
Product: O=S(=O)=O
Reaction time: 0.5 h

Procedure:
In a 50 ml 3-neck RBF equipped with a magnetic stir bar, thermocouple probe, addition funnel, nitrogen inlet adapter, and a rubber septum, charged dichloromethane (anh) (2.5 ml) and 2-picoline (1.46 ml, 14.7 mmol). This picoline solution was chilled in an ice/NaCl bath to −2° C. Then a solution of chlorosulfonic acid (0.478 ml, 7.14 mmol) in dichloromethane (anh) (2.5 ml) was added slowly, with temp being maintained below 5° C. (addition time=30 min). The resulting orange solution was stirred for 30 minutes before being added to the sulfation reaction at room temperature as described in this Example, step 2 (below).
Reaction SMILES: C([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH:18][NH:19][C:20]([CH:22]2[CH2:28][CH2:27][CH:26]3[CH2:29][N:23]2[C:24](=[O:35])[N:25]3[O:30][S:31]([OH:34])(=[O:33])=[O:32])=[O:21])=[O:17])=[CH:12][CH:11]=1)C(=O)[O-])(C)(C)C.[NH+]1C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:5][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:18][NH:19][C:20]([CH:22]2[CH2:28][CH2:27][CH:26]3[CH2:29][N:23]2[C:24](=[O:35])[N:25]3[O:30][S:31]([OH:34])(=[O:33])=[O:32])=[O:21])=[O:17])=[CH:14][CH:15]=1
Reactant: CC(C)(C)N(Cc1ccc(C(=O)NNC(=O)C2CCC3CN2C(=O)N3OS(=O)(=O)O)cc1)C(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(C(=O)NNC(=O)C2CCC3CN2C(=O)N3OS(=O)(=O)O)cc1
Yield: 48.7 %

Procedure:
All the amount of the pyridine salt was deprotected with trifluoroacetic acid, and purified by DIAION HP21 (MITSUBISHI CHEMICAL) to afford 100.3 mg of the title compound (yield 48.7%).
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[CH2:4][CH2:3]1)[N:12]=[C:11]([CH3:15])[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]3=[O:24].[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Ca+2]>CC(N(C)C)=O>[CH3:15][C:11]1[N:10]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9](=[O:24])[C:8]2[C:13](=[CH:14][C:5]3[CH2:4][CH2:3][CH:2]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C:30]([NH:32][C@H:33]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:31])=[CH:46][CH:47]=4)[C:6]=3[CH:7]=2)[N:12]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Br)CC3
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC2CCc3cc4nc(C)n(COC(=O)C(C)(C)C)c(=O)c4cc32)cc1)C(=O)OCC
Temperature: 110 °C

Procedure:
A mixture of 6-bromo-2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (21 g), prepared as described in section (6) of Example 1, diethyl p-aminobenzoyl-L-glutamate (52.5 g), prepared as described in the Journal of Medicinal Chemistry, 1985, 28, 1428, calcium carbonate (27.5 g) and DMA (200 ml) was stirred and heated to 110° C. for 30 minutes. The mixture was cooled to ambient temperature. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially a 1:1 mixture of hexane and ethyl acetate as eluant and then a 1:3 mixture of hexane and ethyl acetate as eluant. There was thus obtained a gum which on trituration under diethyl ether gave diethyl N-{(p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]-benzoyl}-L-glutamate (13.5 g), m.p. 156° C.;
Reaction SMILES: CS(O[CH2:6][C@H:7]([CH3:15])[CH2:8][CH2:9]OS(C)(=O)=O)(=O)=O.[NH2:16][C@@H:17]([CH3:20])[CH2:18][OH:19]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+].O>[CH3:15][C@@H:7]1[CH2:8][CH2:9][N:16]([C@@H:17]([CH3:20])[CH2:18][OH:19])[CH2:6]1
Reactant: C[C@H](N)CO
Reactant: C[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CCN([C@@H](C)CO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.8 %

Procedure:
(R)-2-Methylbutane-1,4-diyl dimethanesulfonate (37.5 g, 0.144 mol, from step 2 of Intermediate 11) was added to neat (S)-2-aminopropan-1-ol (54.8 g, 0.730 mol). The mixture was stirred in a room temperature water bath to minimize the exotherm. After 24 h, the reaction was diluted with DCM (150 mL), sat'd K2CO3 solution (150 mL), and just enough water (60 mL) to dissolve the resulting ppt. The organic layer was separated, and the aqueous layer was extracted with DCM (150 mL). The organic layers were combined, dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give (S)-2-((R)-3-methylpyrrolidin-1-yl)propan-1-ol (17.9 g) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 4.33 (t, 1H), 3.48 (m, 1H), 3.18 (m, 1H), 2.79 (dd, 1H), 2.58 (m, 1H), 2.48 (m, 1H), 2.26 (m, 1H), 2.08 (m, 1H), 2.01 (dd, 1H), 1.88 (m, 1H), 1.20 (m, 1H), 0.98 (d, 3H), 0.96 (d, 3H); LCMS: 144.3 (M+H)+.
Reaction SMILES: C([NH:11][C@H:12]([C:14]([N:16]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[C:28]([OH:33])(=[O:32])[C:29]([CH3:31])=[O:30]>C(O)C.[Pd]>[C:28]([OH:33])(=[O:32])[C:29]([CH3:31])=[O:30].[C:28]([CH:29]([NH:11][C@H:12]([C:14]([N:16]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH3:13])[CH3:31])([OH:33])=[O:32]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)O)Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)C(=O)O
Solvent: CCO
Product: CC(N[C@@H](C)C(=O)N(CC(=O)O)Cc1ccccc1)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of N-carbobenzyloxy-L-alanyl-N-benzyl glycine (5.8 g, 15.6 mmol) and pyruvic acid (3.5 g, 39.1 mmol) in 200 ml absolute ethanol was added 10% palladium on carbon (0.5 g). The mixture was hydrogenated at 50 psi for 4 hours. The solution was filtered and concentrated in vacuo at room temperature. The residue was dissolved in H2O and ethyl acetate. The aqueous layer was washed twice with ethyl acetate and once with ether and lyophilized to provide the crystalline product, m.p. 105°-108° C.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][N:2]=2)=[O:13])[CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1nccc2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](NC(=O)c2nccc3ccccc23)CC1
Temperature: 50 °C

Procedure:
A solution of isoquinoline-1-carboxylic acid (346 mg, 2 mmol), and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.523 mL, 3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (20 mL). The organic solution was washed with water (3×15 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 429 mg (80%) of 405:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:24]5[CH2:29][C@@H:28]6[CH2:30][C@H:25]5[CH2:26][N:27]6[C:31](OC(C)(C)C)=O)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C=O>C(O)=O.O.C(=O)(O)[O-].[Na+]>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:38])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:24]5[CH2:29][C@@H:28]6[CH2:30][C@H:25]5[CH2:26][N:27]6[CH3:31])[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)cc2c1=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3C[C@@H]4C[C@H]3CN4C)cc2c1=O
Yield: 54.8 %

Procedure:
A solution of tert-butyl(1S,4S)-5-(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.30 g) and 38% aqueous formaldehyde (0.42 ml) in formic acid (5 ml) was stirred at 90° C. for 16 hours. The reaction mixture was diluted with water and sodium bicarbonate added, evacuated to dryness. The residue was partitioned between methylene chloride and saturated NaHCO3 solution. The organic phase was washed with water and dried (magnesium sulphate). The residue was purified by column chromatography on an ion exchange column (isolute SCX-2 column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methylene chloride and then a 49:1 mixture of methanol and aqueous ammonia solution to give the title compound (0.137 g); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.96 (m, 1H), 2.14 (s, 3H), 2.32 (s, 3H), 2.57 (d, 1H), 2.87 (m, 2H), 3.29 (d, 1H), 3.45 (m, 1H), 3.56 (s, 1H), 4.50 (d, 1H), 7.13 (d, 1H), 7.26 (m, 1H), 7.52 (d, 1H), 7.61 (d, 1H), 7.81 (m, 1H), 7.90 (m, 1H), 7.99 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 430.
Reaction SMILES: [CH3:1][C@@H:2]([N:9]1[C:13](=[O:14])[CH2:12][C@@H:11]([C:15](O)=[O:16])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CSC.B>O1CCCC1>[OH:16][CH2:15][C@H:11]1[CH2:10][N:9]([C@@H:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])[C:13](=[O:14])[CH2:12]1
Reactant: C[C@H](c1ccccc1)N1C[C@H](C(=O)O)CC1=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@H](c1ccccc1)N1C[C@H](CO)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5 g (1′R,3R)-1-(1′Phenylethyl)-5-oxo-3-pyrrolidine carboxylic acid was dissolved in 50 mL tetrahydrofuran, then the solution was cooled to 0° C. 16.5 mL borane dimethyl sulfide (2 M in tetrahydrofuran) was added dropwise over 30 min and the reaction solution was slowly warmed to 25° C. and stirred for a further 2 h at 25° C. The reaction mixture was concentrated, diluted in dichloromethane and washed with sodium bicarbonate solution. The water phase was extracted with dichloromethane (×2) and the combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: Cl.C[O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])[NH2:6].C(N(C(C)C)CC)(C)C.COC1C=CC(N=NC(N[C@H](C(O)=O)CC2C=CC=CC=2)=O)=CC=1>CN(C)C=O>[NH2:6][C@H:5]([C:4]([OH:14])=[O:3])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13]
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Agent: COc1ccc(N=NC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCCC[C@H](N)C(=O)O
Reaction time: 0.08 h

Procedure:
Operating mode: 1 equivalent of arginine methyl ester hydrochloride was taken up in dimethylformamide (3 ml/mmol). 1.1 equivalent of DIAE (diisopropyl ethylamine), 1 equivalent of N-(4-methoxyphenylazoformyl)-L-phenylalanine then 1.1 equivalent of TBTU (O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) were added. The necessary quantity of DIAE was added to obtain a pH of 7-8. After 5 min, it was evaporated to dryness and purified by chromatography (orange crystals).
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=O.[Li+].[OH-]>C1COCC1.O.CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:15]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:25][CH2:24]3)[C:12](=[O:23])[NH:13][CH2:14]2)=[CH:17][CH:18]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C1NCN(c2ccc(Cl)cc2)C12CCNCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.7 %

Procedure:
To a mixture of 1.5 g (2.97 mmol) 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(4-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one in 4.5 ml THF, 4.5 ml water and 4.5 ml methanol were added 0.85 g (35.6 mmol) powdered LiOH. The reaction mixture was stirred at ambient temperature for 48 hours. The solvent was removed in vacuo. The residue was stirred in water. The resulting solid was filtered, washed with water and dried to provide the title compound (0.55 g) as a colorless solid; MS (ISP): 266.1 MH+.
Reaction SMILES: [N+:1]([C:4]1[CH:51]=[CH:50][C:7]([CH2:8][O:9][C:10](=[O:49])/[C:11](/[N:22]2[CH:25]([S:26]S(C3C=CC(C)=CC=3)(=O)=O)[CH:24]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:23]2=[O:48])=[C:12](\N(C2CCCCC2)C)/[CH3:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.C(OCC)(=[O:61])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(#N)C.C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:11]2[N:22]3[C:23](=[O:48])[C@@H:24]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C@H:25]3[S:26][CH2:13][C:12]=2[OH:61])=[O:49])=[CH:50][CH:51]=1)([O-:3])=[O:2]
Reactant: C/C(=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1)N(C)C1CCCCC1
Reactant: CCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CC#N
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 148 mg (0.2 mmol) of a mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-(N-methylcyclohexylamino)-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester, in 3 ml of dry acetonitrile, is heated under nitrogen for about 4 hours at 80° C. until no further starting material can be detected by thin layer chromatography (silica gel: toluene/ethyl acetate, 1:1). The heating bath is removed, 38 mg (0.2 mmol) of p-toluenesulphonic acid and about 0.2 ml of water are added to the reaction mixture and the mixture is stirred for a further 2 hours at room temperature. The reaction mixture is diluted with benzene, washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is triturated at 0° C. with diethyl ether and gives pale yellow 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester. IR spectrum (methylene chloride): characteristic bands at 2.95; 3.3; 5.6; 5.75 (sh); 5.9; 5.95 (sh); 6.55, 7.45, 8.15 and 8.3μ; NMR spectrum (deuterochloroform): δ in ppm: 3.4 (zH, q, J=17 Hz); 4.57 (2H, s); 5.06 (1H, d; J=5 Hz); 5.35 (2H, q, J=14 Hz); 5.7 (1H dd, J=5, 10 Hz); 6.8-8.4 (10H, c) and 11.4 (1H, br.s.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:18][C:17]3[C:19]([O:26][CH3:27])=[CH:20][CH:21]=[C:22]([C:23](O)=[O:24])[C:16]=3[N:15]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:62][S:63]([C:66]1[CH:73]=[CH:72][C:69]([CH2:70][NH2:71])=[CH:68][CH:67]=1)(=[O:65])=[O:64]>CN(C=O)C.[Cl-].[Na+].O>[CH3:62][S:63]([C:66]1[CH:73]=[CH:72][C:69]([CH2:70][NH:71][C:23]([C:22]2[C:16]3[NH:15][C:14]([NH:13][C:11]([C:3]4[N:2]=[CH:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[N:18][C:17]=3[C:19]([O:26][CH3:27])=[CH:20][CH:21]=2)=[O:24])=[CH:68][CH:67]=1)(=[O:64])=[O:65]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: COc1ccc(C(=O)O)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12
Yield: 26.4 %

Procedure:
33 mg (0.1 mmol) of 2-[(isoquinoline-3-carbonyl)-amino]-7-methoxy-1H-benzoimidazole-4-carboxylic acid and 100 mg (0.25 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.4 mL of DIEA and reacted with 32 mg (0.15 mmol) of 4-methanesulfonyl-benzylamine hydrochloride as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 14 mg (26%) of isoquinoline-3-carboxylic acid [7-(4-methanesulfonyl-benzylcarbamoyl)-4-methoxy-1H-benzoimidazol-2-yl]-amide. LCMS: 530 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[S:16][CH2:17][C:18]([C:21]([CH2:25][CH3:26])([CH3:24])[CH2:22][CH3:23])=[N:19][N:20]=1.O>ClCCl.N1C=CC=CC=1>[CH2:22]([C:21]([C:18]1[CH2:17][S:16][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:20][N:19]=1)([CH3:24])[CH2:25][CH3:26])[CH3:23]
Reactant: CCC(C)(CC)C1=NN=C(N)SC1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCC(C)(CC)C1=NN=C(NC(=O)c2c(OC)cccc2OC)SC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 4.1 %

Procedure:
Two grams of 2,6-dimethoxybenzoyl chloride dissolved in about 3 ml dichloromethane was added dropwise to a stirring solution of 1.99 g of 2-amino-5-(1-ethyl-1-methylpropyl)-6H-1,3,4-thiadiazine in 10 ml of pyridine. The mixture was stirred at room temperature for approximately 72 hours and poured into water. The product was extracted into ether and washed with water. The ether phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The resulting oil was chromatographed over silica gel eluting with a 1:4 (v:v) mixture of ethyl acetate/toluene. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 0.15 g of N-[5-(1-ethyl-1-methylpropyl)-6H-1,3,4-thiadiazin-2-yl]-2,6-dimethoxybenzamide. mp=134°-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:10]3[CH:11]([OH:23])[CH2:12][CH2:13][CH2:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Oc1ccc(Br)cc1C1C=CCCC1
Solvent: c1ccccc1
Product: OC1CCCc2c1oc1ccc(Br)cc21

Procedure:
A solution of the phenol and MCPBA in benzene is refluxed overnight. A solid is precipitated out and filtered. The filtrate is concentrated under vacuum and chromatographed (10% EtOAc in hexanes) to give 8-bromo-1,2,3,4-tetrahydro-dibenzofuran-4-ol 108 as clear oil, 0.66 g, 39%.
Reaction SMILES: O[C@@H:2]([C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 38.3 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3S*)-3-hydroxy-4,4-dimethyl-2-(5-phenyl-pentoxy-carbonylamino)-pentanoic acid (0.346 g, 0.98 mmol) in dry CH2Cl2 (45 mL), at 0° C., Et3N (0.41 mL, 2.95 mmol) and subsequently TBTU (0.38 g, 1.20 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 90:10 to 70:30) to afford the pure title compound (0.125 g, 38%), as white solid. MS (ESI) m/z: 351 [M−NH4]+; (ESI) m/z: 332 [M−H]−. 1H NMR (DMSO-d6) δ 0.93 (s, 9H), 1.34 (h, J=6.37, 7.16 Hz, 2H), 1.53-1.65 (m, 4H), 2.57 (t, J=7.69 Hz, 2H), 4.02 (q, J=6.25 Hz, 2H), 4.36 (d, J=6.24 Hz, 1H), 5.56 (dd, J=6.32, 8.47 Hz, 1H), 7.07-7.34 (m, 5H), 8.38 (d, J=8.48 Hz, 1H).