Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH:9]1[CH2:22][C:23]([O:25][CH3:26])=[O:24]>N1C=CC=CC=1>[OH:3][N:2]=[C:5]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][C:28]=1[F:39])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH:9]1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: NO
Reactant: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CC1CN(CCSc2cccs2)CCC1CCC(=NO)c1c(F)cnc2ccc(OC)cc12
Temperature: 60 °C

Procedure:
0.363 g of hydroxylamine hydrochloride was added in several portions to a mixture of 0.99 g of methyl (3RS,RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate in 10-cm3 of pyridine, with stirring and under an inert atmosphere, and the resulting mixture was heated in the region of 60° C. for 16 hours. After cooling in the region of 20° C., the reaction mixture was concentrated to dryness under reduced pressure (8 kPa) at a temperature in the region of 55° C. The evaporation residue was taken up in 75-cm3 of ethyl acetate and 40-cm3 of distilled water. The organic phase was washed three times with 40-cm3 of distilled water and 40-cm3 of a saturated sodium chloride solution, dried over magnesium sulfate for 30 minutes, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.98 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2-thienylthio)ethyl]piperidine-3-acetate wereobtained in the form of a yellow gum.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH2:11].C(Cl)Cl.C[N+]1([O-])CCOCC1.C(#N)C>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.CCCCCC>[CH3:1][CH2:2][C:3](=[O:12])[CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH2:11]
Reactant: C=CC=CC=CCCC(O)CC
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CC#N
Product: C=CC=CC=CCCC(=O)CC
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.9 %

Procedure:
In argon atmosphere, 6,8,10-undecatrien-3-ol (5) (1.80 g, 10.8 mmol), methylene chloride (45 mL), Molecular Sieves 4A (4.50 g), N-methylmorpholine N-oxide (NMO) (1.90 g, 16.2 mmol) and acetonitrile (5 mL) were added to a 100 mL flask, and further tetrapropylammonium perruthenate (TPAP) (190 mg, 0.541 mmol) was added, followed by stirring at room temperature for 4 h. TPAP (190 mg, 0.541 mmol) was added, followed by stirring for 2 h at room temperature. Then NMO (1.90 g, 16.2 mmol) was added, followed by stirring for 3 h at room temperature. Hexane was added to the reaction mixture which then was filtered, and the filtrate was concentrated under reduced pressure. Thus obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=50:1) to give 6,8,10-undecatrien-3-one (1-1) (476 mg, 2.90 mmol, yield 27%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:15])[C:13](=[O:16])[CH:12]3[CH:8]([CH2:9][CH2:10][CH2:11]3)[N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH:17]1([N:7]2[C:6]3[N:22]=[C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])[N:3]=[CH:4][C:5]=3[N:14]([CH3:15])[C:13](=[O:16])[CH:12]3[CH:8]2[CH2:9][CH2:10][CH2:11]3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN1C(=O)C2CCCC2N(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C1CCCC1C(=O)N2C
Yield: 34.1 %

Procedure:
A mixture of 0.580 g (0.0018 mole) of (rac)-6-chloro-4-cyclopentyl-9-methyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraazabenzo[f]azulen-10-one (VII-68), 0.372 g (0.0022 mole) of 4-amino-3-methoxybenzoic acid, 36.97 mL of ethanol and 0.468 mL of hydrochloric acid was heated at reflux overnight. Additional ethanol and hydrochloric acid were added and the mixture heated at reflux overnight. The mixture was then cooled, made basic to dissolve solids by the addition of sodium hydroxide solution, transferred to a separatory funnel with ethyl acetate. The aqueous layer was washed twice with ethyl acetate, and then acidified by the addition of 1 M hydrochloric acid. The acidified aqueous layer was extracted twice with ethyl acetate and these extracts were combined, washed successively with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.277 g of (rac)-4-(4-cyclopentyl-9-methyl-10-oxo-1,2,3,3a,4,9,10,10a-octahydro-4,5,7,9-tetraaza-benzo[f]azulen-6-ylamino)-3-methoxy-benzoic acid, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[C:45]([F:47])[CH:46]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH:26]2[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]2)=[CH:20][C:19]=1[NH:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:17].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH2:27][CH:26]([CH2:25][NH:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]5[CH:44]=[C:45]([F:47])[CH:46]=[C:2]([F:1])[CH:3]=5)[CH:7]=4)[NH:11][N:10]=3)=[O:17])=[C:19]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:20]=2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(CNc2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc(NCC2CNC2)cc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
tert-butyl 3-({[4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-(tetrahydro-2H-pyran-4-ylamino)phenyl]amino}methyl)azetidine-1-carboxylate (738 mg, 1.1 mmol) was dissolved in DCM (12 mL) and TFA (3 mL) was added. The resulting reaction solution was stirred for 3 hours at room temperature. The mixture was diluted with DCM and extracted with 10% aqueous NH3. Aqueous phase was extracted several time with DCM. Collected organic phases were washed with brine, dried over sodium sulfate and evaporated to dryness. Column chromatography purification on silica gel using dichloromethane/methanol/NH3 5N in MeOH 70:30:1 as the eluant, afforded 150 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN(C)C=O.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]([C:26]([OH:28])=[O:27])[C:19]2=[O:29].C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[O:29]=[C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([NH:15][C:7]([CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[NH:6]3)=[O:9])[CH:17]=2)[NH:22][CH:21]=[C:20]1[C:26]([OH:28])=[O:27]
Reactant: Nc1ccc2[nH]cc(C(=O)O)c(=O)c2c1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(C(=O)Nc2ccc3[nH]cc(C(=O)O)c(=O)c3c2)N1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 1.94 g (15 mmol) of 5-oxo-L-proline, 1.1 ml (15 mol) dimethylformamide, and 30 ml of dichloromethane is stirred 0°-5° for 1 hour. A mixture of 2.04 g (10 mmol) of 6-amino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, [J. Pharm. Sci., 11, 1051 (1963)] 4.2 ml (30 mmol) of triethylamine, 3.8 ml (30 mmol) of chlorotrimethylsilane, and 75 ml of dichloromethane is stirred at room temperature for 40 minutes and then is cooled at 0°. The cold acid chloride solution is added to the cold silylated quinoline and is stirred at 5° for 4 hours and overnight at room temperature. The reaction mixture is evaporated and the residue is treated with water to give 1.81 g of 1,4-dihydro-4-oxo-6-[[(5-oxo-2-pyrrolidinyl)carbonyl]-amino]-3-quinolinecarboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[Cl:12]N1C(=O)CCC1=O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:12][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: Fc1ccc2cnccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc2cnccc2c1Cl
Temperature: 50 °C
Yield: 58.4 %

Procedure:
7.0 g (38.1 mmol) of 6-fluoroisoquinoline (3) were dissolved in 60 mL of concentrated sulfuric acid. At 0° C. 10.18 g of N-chloro succinimide were added. After 1 h another 5.2 g of N-chloro succiminide were added and the solution was heated to 50° C. Two more portions of 5.2 g N-chloro succinimide were added successively and stirring was continued at 50° C. until the reaction was complete. The reaction mixture was cooled to room temperature, was poured on ice and adjusted to pH 10 by addition of sodium hydroxide. The precipitate was filtered off, dissolved in dichloromethane and washed with aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, evaporated and the crude product was purified by preparative HPLC to yield 4.04 g of 5-chloro-6-fluoro-isoquinoline (7) as trifluoroacetate. Rt=0.97 min (Method A). Detected mass: 182.0/184.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:16].[CH3:17][O:18][CH2:19]Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:16][CH2:17][O:18][CH3:19]
Reactant: COCCl
Reactant: Oc1c(Br)c(C(F)(F)F)cc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1c(Br)c(C(F)(F)F)cc2ccccc12
Yield: 91 %

Procedure:
2-Bromo-3-(trifluoromethyl)-1-naphthalenol (179) (0.23 g, 0.79 mmol) was treated with chloromethyl methyl ether in the presence of diisopropylethylamine in THF to give 0.24 g (91%) of the title compound (180) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 3H), 5.29 (s, 2H), 7.59-7.65 (m, 1H), 7.65-7.71 (m, 1H), 7.91 (d, J=8.1 Hz, 1H), 8.05 (s, 1H), 8.22 (d, J=8.4 Hz, 1H). LCMS (ESI): m/z 335 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[CH:5]2.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=3)=[N:13][N:12]=[C:7]1[CH:6]=[CH:5]2
Reactant: NNc1ccc2cc(I)ccc2n1
Reactant: O=Cc1ccccn1
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: Ic1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (6-Iodo-quinolin-2-yl)-hydrazine (2.99 g, 10.5 mmol) suspended in CH2Cl2 (30 mL) was added 2-pyridinecarboxaldehyde (1.2 mL, 12.6 mmol). The reaction was stirred at room temperature for 2 hours, followed by the addition of iodobenzene diacetate (3.39 g, 10.5 mmol). The reaction was stirred overnight at room temperature, during which time a precipitate formed. The mixture was concentrated to half the volume, and the precipitate was filtered and washed with minimal CH2Cl2 to give the desired product, 5k. The filtrate was concentrated and suspended in EtOH. After stirring overnight at room temperature, the mixture was filtered and rinsed with EtOH to obtain additional product, 5k.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[CH3:19][C:20]1[S:24][C:23]([C:25]([N:27]2[CH2:32][C:31]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[O:30][CH2:29][CH2:28]2)=[O:26])=[CH:22][CH:21]=1.C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:35]1[CH2:36][CH2:37][C:31]2([O:30][CH2:29][CH2:28][N:27]([C:25]([C:23]3[S:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[O:26])[CH2:32]2)[CH2:33][CH2:34]1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: OCCc1cccc(CBr)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)s1
Reaction time: 1 h

Procedure:
2-(3-(Bromomethyl)phenyl)ethanol (example 6, step a) (0.136 g) was added to a stirred solution of (5-methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.250 g) and triethylamine (0.278 mL) in MeCN (5 mL). After 1 h, the reaction mixture was concentrated and applied to a silica gel column eluting with ethyl acetate:triethylamine, 95:5 to give the subtitled compound. Yield 0.24 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BrH:18]>C(OCC)(=O)C.C(O)(=O)C.[Cu](Br)Br>[Br:18][CH:9]([S:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:17]
Reactant: O=C(CSc1ccccc1)c1ccccc1F
Reactant: Br
Agent: Br[Cu]Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1F)C(Br)Sc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 1-(2-fluorophenyl)-2-(phenylthio)ethanone (413 mg) in ethyl acetate (6 mL) were added copper (II) bromide (419 mg) and a 47% solution (2 drops) of hydrogen bromide in acetic acid and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield 503 mg, yield 92%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:14]=1.[H-].[Na+].S(OC)(O[CH3:30])(=O)=O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:30][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:14]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(C=CC#N)c2)c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(C)oc(=O)c1C(=O)C=Cc1cccc(C=CC#N)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 30.6 %

Procedure:
To a mixture of 20 ml of hexamethylphosphoramide and 3.50 g of 4-hydroxy-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one was added 0.46 g of sodium hydride (60% oily) at about 0° C., and a temperature was raised to 50° C., followed by stirring for 1 hour and 10 minutes. Then, 3.22 g of dimethyl sulfate was added thereto, and the mixture was stirred at 50° C. for 4 hours. Thereafter, the reaction mixture was added to ice water, and the mixture was extracted with ethyl acetate. The organic layer washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.12 g of 4-methoxy-3-[3-[3-(2-cyanoethenyl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a)] as a pale yellow crystal.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5]1([N:11]2[C:15]([CH3:17])([CH3:16])[CH2:14][NH:13][C:12]2=[O:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N1C=CC=CC=1>C(Cl)Cl>[CH:5]1([N:11]2[C:15]([CH3:16])([CH3:17])[CH2:14][N:13]([C:1]([Cl:4])=[O:2])[C:12]2=[O:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC1(C)CNC(=O)N1C1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CN(C(=O)Cl)C(=O)N1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A 0° C. solution of phosgene (15% in toluene, 1.854 mL, 2.60 mmol) in DCM (10 mL) was treated drop-wise with a solution of 1-cyclohexyl-5,5-dimethylimidazolidin-2-one (0.34 g, 1.732 mmol) and pyridine (0.28 mL) in DCM (5 mL), stirred at 0° C. for 0.5 h, then concentrated to dryness to afford crude 3-cyclohexyl-4,4-dimethyl-2-oxoimidazolidine-1-carbonyl chloride (0.45 g, 100%) which was used without further purification.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15](=[O:29])[C@@H:16]1[CH2:20][C@@H:19]([OH:21])[CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[OH:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1CNCC2.CCN(CC)CC.[NH4+].[Cl-]>CN(C=O)C>[OH:30][C:31]1[CH:40]=[CH:35][CH:34]=[C:33]2[C:32]=1[CH2:9][N:8]([C:1]([O:21][C@H:19]1[CH2:18][N:17]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C@H:16]([C:15]([O:14][CH3:13])=[O:29])[CH2:20]1)=[O:2])[CH2:12][CH2:11]2
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Oc1cccc2c1CNCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(O)c3C2)CN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 69 %

Procedure:
Carbonyldiimidazole (0.176 g, 1.086 mmol) was added to a stirred, room temperature solution of DMF (5 mL) and N-Boc-trans-4-hydroxy-L-proline methyl ester (0.21 g, 0.87 mmol) and the mixture was stirred 45 min. 8-Hydroxy-1,2,3,4-tetrahydroisoquinoline (0.20 g, 0.87 mmol) and Et3N (0.18 g, 1.74 mmol) were added and the resulting solution was heated at 50° C. for 2 h. The reaction mixture was poured into aqueous saturated NH4Cl and extracted with EtOAc, dried over Na2SO4 and concentrated to an oil. The residue was purified by column chromatography on silica gel (gradient elution, 10 to 80% EtOAc in hexanes) to give 1-tert-butyl 2-methyl (2S,4R)-4-{[(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (0.25 g, 0.60 mmol, 69% yield) as a colorless foam after evaporation of solvent. LRMS (ESI) m/z 321.3 [((M-Boc)+H)+; calcd for C16H21N2O5: 321.4].
Reaction SMILES: [C:1]1([C:7]2[O:13][C@H]3[C@H:9]([C:10](=[O:14])[NH:11]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O-:18])(O)=O.[Na+]>C(Cl)Cl.CC(C)=CCO>[C:7]([NH:8][C@@H:9]1[C@@H:10]([O:14][CH2:3][CH:2]=[C:1]([CH3:7])[CH3:6])[NH:11][C:15]1=[O:18])(=[O:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Reactant: O=C([O-])O
Agent: CC(C)=CCO
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)=CCO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
181 mg (0.96 mmol--1.2 equivalents) of anhydrous tin-II chloride (dried by fusing briefly under a high vacuum) were added all at once, at 0° C., to a suspension of 150 mg (0.78 mmol) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one in 1.3 ml of anhydrous methlene chloride and 0.81 ml (7.8 mmols--10 equivalents) of 3-methyl-2-buten-1-ol. The cooling bath was removed and a clear solution was formed after a few minutes. The reaction mixture was stirred for a further 15 minutes at room temperature, poured into dilute NaHCO3 solution and extracted with methylene chloride and the extract was washed with water and dried over MgSO4. After the solvent had been evaporated off in vacuo and the residue had been filtered on 5 g silica gel (toluene:ethyl acetate 3:7), 153 mg (70%) of the title compound were obtained as colorless crystals, melting point: 92° C., RF : 0.38 (toluene:ethyl acetate 3:7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:11]=1)=[O:7].[CH2:32]=[O:33]>C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH3:32])[CH2:21]2)[CH:11]=1)=[O:7].[CH:31]([O-:30])=[O:33]
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)NCCC3CCCNC3)c2)cc1OC
Reactant: C=O
Solvent: O=CO
Product: COc1ccc(C(=O)NCc2cccc(C(=O)NCCC3CCCN(C)C3)c2)cc1OC
Product: O=C[O-]
Temperature: 70 °C
Yield: 28 %

Procedure:
Compound 33 (80 mg, 0.188 mmol), (Example 8), was dissolved in formic acid (0.5 mL) and formaldehyde (0.5 mL, 37% aqueous solution) was added. The resulting mixture was heated at 70° C. overnight. The solvents were evaporated and the product was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound as a formate salt (23 mg, 28% yield), MS analysis electrospray, 440 (M+H).
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[CH3:18][C:19]1([CH3:28])[S:23][C:22](=[O:24])[NH:21][CH:20]1[C:25]([OH:27])=O.[N+]([O-])(O)=O.[N+:33]([O:36][CH2:37][CH2:38][NH2:39])([O-:35])=[O:34]>O1CCCC1>[N+:33]([O:36][CH2:37][CH2:38][NH:39][C:25]([CH:20]1[C:19]([CH3:18])([CH3:28])[S:23][C:22](=[O:24])[NH:21]1)=[O:27])([O-:35])=[O:34]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC1(C)SC(=O)NC1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)SC(=O)NC1C(=O)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
1.38 ml of triethylamine and 0.37 ml of diethyl cyanophosphonate were added, whilst ice-cooling and stirring, to a suspension of 360 mg of 5,5-dimethyl-2-oxothiazolidine-4-carboxylic acid and 417 mg of N-(2-nitrooxyethyl)amine nitrate in 50 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 4 hours, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with ethyl acetate, and the resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residual pale yellow oil was purified by column chromatography through silica gel, using a 50:1 by volume mixture of methylene chloride and methanol as the eluent. The crystals thus obtained were recrystallized from diethyl ether, to give 180 mg of the title compound as colorless crystals, melting at 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH3:72])[C:65]([C@@H:67]1[CH2:71][CH2:70][CH2:69][NH:68]1)=[O:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][C@H:67]1[C:65]([N:64]([CH3:72])[CH3:63])=[O:66])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3C(=O)N(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-dimethylaminocarbonyl-pyrrolidine in DMSO at ambient temperature.