Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1cccc(F)c1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1cccc(F)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:24][CH2:23][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:17]1([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:24][CH2:23][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CN2CCc3ncnc(Nc4ccccc4)c3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(Nc2ncnc3c2CNCC3)cc1
Reaction time: 24 h
Yield: 110.5 %

Procedure:
6-Benzyl-5,6,7,8-tetrahydro-N-phenylpyrido[4,3-d]pyrimidin-4-amine (1.5 g, 3.8 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (1.5 g, 20% wt). The mixture was shaken on a Parr Shaker under H2 (g) atmosphere (60 PSI) for 1 day. The mixture was filtered through celite and evaporated to give 0.95 g of material as a yellow solid (quant.), which was used as such for the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[C:21](Br)=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:32]([C:36]#[CH:37])([CH3:35])([CH3:34])[CH3:33]>C1COCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[C:21]([C:37]#[C:36][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cnc(Nc2nc(Cl)cn(Cc3ccccc3)c2=O)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2nc(Cl)cn(Cc3ccccc3)c2=O)c(C#C[Si](C)(C)C)c1
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
Compound 26 (2.0 g, 4.9 mmol), triphenylphosphine (52 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (173 mg, 0.25 mmol), triethylamine (1.03 mL, 7.4 mmol), and TMS-acetylene (1.05 mL, 7.4 mmol) were combined in THF (20 mL) at r.t. under nitrogen. After stirring 10 min, copper iodide (40 mg) was added, and the reaction stirred for 8 h. The reaction was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (2:1:2 hexanes/EtOAc/CH2Cl2) gave 2.0 g (96%) of the title compound as a pale yellow solid. MS (ES) [m+H] calc'd for C21H23ClN4OSi, 423, 425; found 423, 425.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([CH:25]=3)[C:21]([O:23][CH3:24])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28].C1COCC1>C(OCC)(=O)C>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([NH:15][S:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([N:1]=[C:27]=[S:28])=[CH:3][CH:4]=3)[CH:9]=2)(=[O:14])=[O:13])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N)cc3c2)ccc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N=C=S)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To 4.5 g (11.5 mmol) of compound 134 and 9.01 g (50.6 mmol) of 1,1′-thiocarbonyldiimidazole was added 50 mL of THF. The solution was allowed to stir at ambient temperature for 1.5 hours. Then, the reaction was poured into 300 mL of ethyl acetate and extracted with 1N HCl, water, and brine. The organic layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation to yield 4.77 g of compound 135.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:25]>C1(C)C=CC=CC=1>[Cl:25][C:4]1[C:3]2[C:8](=[CH:9][C:10]([I:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(I)cc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1cc(I)cc2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.4 g (1.27 mmol) 5-chloro-7-iodo-3H-quinazolin-4-one, 0.5 ml (3.18 mmol) DIPEA and toluene, 0.3 ml (2.8 mmol) POCl3 is added dropwise and stirred at RT for 1 h, the heated to 90° C. for 1.5 h. After cooling to RT the solvent is evaporated giving rise to crude 4,5-dichloro-7-iodo-quinazoline.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cccc2cc[nH]c12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Add potassium tert-butoxide (1 M in tetrahydrofuran, 14.1 mL, 14.1 mmol) to a solution of methyl triphenylphosphonium bromide (5.05 g, 14.1 mmol) in tetrahydrofuran (80 mL) and stir the reaction mixture for 45 minutes at room temperature. Add a solution of 7-formylindole (1.00 g, 6.89 mmol) in tetrahydrofuran (10 mL) and stirred for 1.5 hours. Dilute the reaction mixture with ethyl acetate (250 mL), wash sequentially with an 8:1 mixture of water and 1 N hydrochloric acid (2×100 mL) and saturated aqueous sodium chloride (100 mL), dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Subject the residue silica gel chromatography. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound as a brown oil.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][CH2:9][C@:10]12[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:24]3[C:16]4=[C:17]([CH2:31][CH2:32][N:14]([C@@H:15]14)[CH2:13][CH2:12][CH2:11]2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=13>O>[CH3:8][CH2:9][C@:10]12[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:24]3[C:16]4=[C:17]([CH2:31][CH2:32][N:14]([C@@H:15]14)[CH2:13][CH2:12][CH2:11]2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=13.[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)O
Agent: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Solvent: O
Product: CC(C)(C)C(=O)[O-]

Procedure:
According to the method of the preceding example, 4 g of the salt are prepared starting from 1.02 g of pivalic acid and 3.36 g of apovincamine. The product has melting point of 110° C., is insoluble in water and soluble in alcohol; the apovincamine content thereof is 73.8%.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].C([Li])CCC.[Cl:15][Si:16]1(Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Cl:15][Si:16]1([CH:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[C:5]([CH3:8])=[C:4]2[CH3:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cl[Si]1(Cl)CCCCC1
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si]2(Cl)CCCCC2)C(C)=C1C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Into a flask containing 100 ml of tetrahydrofuran, 2,3,4,5-tetramethylcyclopenta-2,4-diene (3.67 g, 30 mmol) was added, and then n-butyl lithium (12 ml) was added in droplets thereto at 0° C. The reaction temperature was gradually increased to room temperature, and the reaction mixture was allowed to react for 8 hours. The temperature of the reaction solution was decreased to −78° C., after which the reaction solution was added with dichlorosilacyclohexane (5.07 g, 30 mmol) and then allowed to react for 12 hours. After the reaction, volatile material was removed, the resultant reaction product was extracted with 100 ml of hexane, and more volatile material was removed, thus obtaining 7.01 g of chloro-2,3,4,5-tetramethylcyclopentadienyl silacyclohexane as light yellow oil. Subsequently, the chloro-2,3,4,5-tetramethylcyclopentadienyl silacyclohexane thus obtained was dissolved in 100 ml of tetrahydrofuran, without additional purification, and 2.18 g of lithium tert-butylamide was added in droplets thereto at 0° C., after which the reaction mixture was allowed to react at room temperature for 2 hours. After the reaction, the volatile material was removed, the resultant reaction product was extracted with 100 ml of hexane, and more volatile material was removed, thus obtaining 7.42 g of (tert-butylamido)(2,3,4,5-tetramethylcyclopenta-2,4-dienyl)silacyclohexane as light yellow oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:15](=[O:26])[N:14]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:13]2=[O:38].CCN(CC)CC>C(Cl)Cl>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[CH2:27][N:14]1[C:13](=[O:38])[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([CH2:9][NH:8][C:1](=[O:3])[CH3:2])[CH:11]=2)[N:16]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:15]1=[O:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Cn2c(=O)c3cc(CN)ccc3n(C3CCOCC3)c2=O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
0.066 g of acetic anhydride is added at 0° C. to a solution of 0.23 g of the compound obtained in Step 12.2 and 0.11 g of Et3N in 5 ml of DCM. The mixture is stirred at room temperature for 2 hours. The organic phase is washed with saturated NH4Cl solution, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (99/1, v/v) to (95/5, v/v) to give 0.195 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].I[CH3:17]>>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13]([OH:15])=[O:14]
Reactant: CI
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1Cl
Product: CC(C(=O)O)c1cccc(C(F)(F)F)c1Cl

Procedure:
prepared from 2-chloro-3-(trifluoromethyl)phenylacetic acid and iodomethane;
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:28][CH2:27][CH2:26][C@H:14]1[C:15]([O:17]C(C1C=CC=CC=1)=O)=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4].[OH-].[K+]>O.C1COCC1>[NH:1]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:28][CH2:27][CH2:26][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Boc-Gly-Nleu-Pro-OBz (7.9 g, 0.0166 mol.) was dissolved in a mixture of 50 ml H2O and 80 ml THF. The solution was chilled to 0° C. KOH (1.9 g, 0.033 mol.) dissolved in 30 ml H2O was added while stirring the solution. The stirring was continued at room temperature for one hour. The THF was removed under reduced pressure. The aqueous solution was chilled to 0° C. and acidified to about pH=3 by addition of concentrated HCl (swirling the solution vigorously at the same time). The product was extracted from the aqueous solution by ethyl acetate. The combined organic layer was dried using Na2SO4 and the ethyl acetate was removed under reduced pressure to obtain the product (5.7 g, 89%). TLC Rf=0.38 (developing solvents: CMA, 85:15:3). FAB-MS, observed (M+H)+ =386. 1H-NMR (500 MHz, DMSO-d6, 27° C., assignment by TOCSY) δ 6.69 (m, Gly-NH), 6.57 (m, Gly-NH), 4.56 (m, Pro-α), 4.28-4.14 (m, Pro-α), 4.14-3.97 (m, Nleu-α), 3.83-3.62 (m, Gly-α), 3.62-3.44 (m, Gly-α, Pro-δ), 3.44-3.28 (m, Pro-δ), 3.12-2.92 (m, Nleu-β), 2.23-1.58 (m, Pro-β, Pro-γ, Nleu-γ), 1.34 (m, Boc-CH3), 0.85 (m, Nleu-δ), 0.78 (m, Nleu-δ).
Reaction SMILES: [CH:1]1([CH2:7][S:8]([NH:11][C:12]2[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[C:34]2[C:29](=[CH:30][C:31]([CH2:35][NH2:36])=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[ClH:66]>ClCCl.CN(C)C=O.C(O)(C)(C)C.O>[ClH:66].[NH2:24][C:25]1[C:34]2[C:29](=[CH:30][C:31]([CH2:35][NH:36][C:20](=[O:21])[CH2:19][N:14]3[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][S:8]([CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)(=[O:9])=[O:10])[C:13]3=[O:23])=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Cc1ccc(NS(=O)(=O)CC2CCCCC2)c(=O)n1CC(=O)O
Reactant: NCc1ccc2c(N)nccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc(NS(=O)(=O)CC2CCCCC2)c(=O)n1CC(=O)NCc1ccc2c(N)nccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 0.14 g of [3-(cyclohexylmethylsulfonylamino)-6-methyl-2-oxo-1,2-dihydropyridinyl]-acetic acid and 0.07 g of 1-amino-6-(aminomethyl)isoquinoline in 5 mL dichloromethane and 2 mL N,N-dimethylformamide was added 0.19 g 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU). After 16 h at room temperature additional 50 mg TBTU and 0.10 mL N-methylmorpholine were added and the mixture was stirred at room temperature for an additional 16 h. Dichloromethane was added and the reaction mixture was washed with aqueous saturated sodium hydrogencarbonate and water. Both aqueous washes were extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate and concentrated. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol=9/1 v/v) to yield the free base. This free base was dissolved in a mixture of t-butanol/water=1/1 (v/v) and one equivalent hydrochloric acid was added. Lyophilisation yielded 135 mg of the title compound. MS ESI+: 498 (M+H).
Reaction SMILES: C([C@@:3]12[N:10]([C:11](=[O:37])[CH:12]([NH:25][C:26](=[O:36])[C:27]3[CH:32]=[CH:31][C:30]([CH:33]=[N:34][NH2:35])=[CH:29][CH:28]=3)[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C(C)(C)C)=[CH:16][CH:15]=3)[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)C>C(Cl)Cl>[NH2:35][N:34]=[CH:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[C:11]([N:10]2[CH:7]3[CH2:8][CH2:9][C@@H:3]2[CH2:4][CH2:5][CH2:6]3)=[O:37])=[O:36])=[CH:32][CH:31]=1
Reactant: CC[C@]12CCCC(CC1)N2C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)c1ccc(C=NN)cc1
Solvent: ClCCl
Product: NN=Cc1ccc(C(=O)NC(Cc2ccc(O)cc2)C(=O)N2C3CCC[C@H]2CC3)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 150 mg of ethyl (S)-8-[2-(4-aminoiminomethyl-benzoylamino)-3-(4-t-butoxyphenyl )propionyl]-8-azabicyclo[3.2.1]octan-endo-3-yloxyacetate hydrochloride is stirred at room temperature in 5 ml of CH2Cl2 and 2.5 ml of trifluoroacetic acid and evaporated. With ether the residue gives crystals which are filtered off under suction and dissolved in 5 ml of EtOH. 40 mg of NaOH dissolved in 1 ml of water are added to the solution and the mixture is stirred at room temperature. The reaction solution is neutralized with 1N hydrochloric acid and evaporated. Chromatography of the residue on silica gel RP-18 with water/THF gives 75 mg of (S)-8-[2-(4-aminoiminomethyl-benzoylamino)-3-(4-hydroxyphenyl)propionyl]-8-azabicyclo [3.2.1]octan-endo-3-yloxyacetic acid, MS: 495 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: Cn1ccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.416 mmol), K2CO3 (115 mg, 0.831 mmol) in DMF (2 mL) at 0° C., was added 3-(chloromethyl)-1-methyl-1H-pyrazole (54.3 mg, 0.416 mmol). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for overnight. Water was added and the mixture was extracted with EtOAc (2×). The aqueous layer was basified and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to give 2-chloro-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (104 mg) which was used in the next step without further purification. MS [M+H] Found 335.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][CH2:18]3)[C:13]2=[O:33])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]2=[O:33])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)cn1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)cn1
Temperature: 0 °C
Yield: 104.1 %

Procedure:
(S)-Benzyl 4-(3-(6-(methylsulfonyl)pyridin-3-ylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (0.23 g, 0.49 mmol) was dissolved in MeOH (5 mL) and cooled to 0° C. The material was purged with N2 by three vacuum pump/N2 balloon cycles. Palladium on carbon (10 wt. % dry basis, wet, Degussa type, 0.053 g, 0.49 mmol) was added and the system was purged with 1 atm H2 by three vacuum pump/H2 balloon cycles. The reaction continued to stir under H2 until the starting material was consumed. The mixture was filtered through GF/F paper and concentrated to give (S)-3-(6-(methylsulfonyl)pyridin-3-ylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (0.17 g, 0.51 mmol, 100% yield).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[C:12]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:41]=[CH:40][C:34]4[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=4[C:32]=3[CH2:42][CH2:43][CH3:44])[CH:11]=[CH:10][C:9]=2[N:8]=1)C.O1CCCC1.O.O.[OH-].[Li+]>S(=O)(=O)(O)O.CO.C(OCC)(=O)C>[O:39]=[C:35]1[C:34]2[CH:40]=[CH:41][C:31]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:12]3[CH:11]=[CH:10][C:9]4[N:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:45])=[O:3])[CH:16]=[CH:15][C:14]=4[C:13]=3[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:32]([CH2:42][CH2:43][CH3:44])[C:33]=2[O:38][CH2:37][CH2:36]1
Reactant: CCCc1c(OCCCCCOc2ccc3nc(CCC(=O)OCC)ccc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(OCCCCCOc2ccc3nc(CCC(=O)O)ccc3c2CCC(=O)O)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 28.5 h
Yield: 29.6 %

Procedure:
To a mixture of 0.126 g (0.2 mmol) of 6-[[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyl]oxy]-2,5-quinolinedipropanoic acid diethyl ester from the preceding example, 2.5 mL of tetrahydrofuran and 2.5 mL of water was added 25.7 mg (0.61 mmol) of lithium hydroxide monohydrate. The mixture was stirred at room temperature for 28.5 hr, acidified with 7 drops of 3N aqueous sulfuric acid, and worked-up with ethyl acetate in the usual manner. The residue was taken up in small amount of ethyl acetate and methanol and filtered. Most of the solvent in the filtrate was evaporated and hexane was then added to induce crystallization. The title compound (33.4 mg, 29.1%) was thus obtained as a white solid, mp 123°-128° C.
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.C(O)C.[OH-].[K+]>O>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:15][C:11]1[S:10][CH:14]=[CH:13][CH:12]=1
Reactant: CC1N(C)C=C[NH+]1C
Reactant: O=Cc1cccs1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1C=C[NH+](C)C1C=Cc1cccs1

Procedure:
A mixture of 5.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2ml of 2-thiophenecarboxaldehyde, 20 ml of absolute ethanol and 1 g of potassium hydroxide is refluxed for 25 minutes. Water is added to the cooled mixture and the resulting solid is filtered off. Recrystallization from ethanol yields 3.8 g of the title compound, melting point 309°-311° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:16])[C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([OH:14])[CH2:13][C:7]=3[C:6]=2[CH:15]=1.[C:17]1([S:23]([O-:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1>[Cl:16][C:4]1[C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([OH:14])[CH2:13][C:7]=3[C:6]=2[CH:15]=[C:2]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH:3]=1
Reactant: OC1CCc2oc3c(Cl)cc(Br)cc3c2C1
Reactant: O=S([O-])c1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1cc(Cl)c2oc3c(c2c1)CC(O)CC3
Temperature: 110 °C
Yield: 28.3 %

Procedure:
A mixture of the product of step B (120 mg, 0.39 mmol), sodium benzenesulfinate (77 mg, 0.47 mmol), di-palladium-tris(dibenzylideneacetone) (36 mg, 0.04 mmol), cesium carbonate (190 mg, 0.58 mmol) and xantphos (45 mg, 0.08 mmol) was suspended in anhydrous toluene (5.0 mL). The reaction flask was purged with argon and heated to 110° C. for 1 h. After cooling to ambient temperature, the reaction mixture was diluted with dichloromethane and filtered through a celite bed. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) and triturated with MTBE to give 6-chloro-8-(phenylsulfonyl)-1,2,3,4-tetrahydrodibenzo[b,d]furan-2-ol (40 mg, 27%, AUC HPLC 97.1%) as a white solid: mp 236-240° C.; 1H NMR (DMSO-d6, 400 MHz) δ 8.15 (d, J=1.6 Hz, 1H), 8.05-8.01 (m, 2H), 7.89 (d, J=1.6 Hz, 1H), 7.71-7.66 (m, 1H), 7.64-7.59 (m, 2H), 4.92 (d, J=4.0 Hz, 1H), 4.11-4.04 (m, 1H), 2.94-2.76 (m, 3H), 2.60-2.52 (m, 1H), 2.00-1.87 (m, 2H); ESI MS m/z 363 [M+H]+.
Reaction SMILES: [NH3:1].[NH2-].[Na+].Br[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12]>>[Cl:12][C:6]1[CH:5]=[C:10]([CH:9]=[C:8]([Cl:11])[CH:7]=1)[NH2:1]
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: N
Agent: [NH2-]
Agent: [Na+]
Product: Nc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 75.5 %

Procedure:
In the second step of Example 1, 500 ml of liquid ammonia, 10 g (0.25 mole) of sodium amide and 11.3 g (0.05 mole) of 1-bromo-2,4-dichlorobenzene were charged and the reaction was carried out for 1 hour to obtain 6.1 g of 3,5-dichloroaniline. (yield: 75.5%).