Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=O)(C)(C)C.[NH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21](O)=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1>>[NH:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[C:15]([NH2:14])=[N:16][CH:17]=[CH:18]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Nc1nccc2cc(O)ccc12
Product: Nc1nccc2cc(O[C@H]3CCNC3)ccc12

Procedure:
This compound was prepared from (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (195 mg, 1.04 mmol) and 1-amino-6-hydroxyisoquinoline (200 mg, 1.25 mmol) by the Mitsunobu procedure described in 3C, subsequent Boc deprotection according to procedure described in 3D gave (S)-6-(pyrrolidin-3-yloxy)-isoquinolin-1-ylamine, El-MS: m/z=230.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:12]([O-])=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>O.Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[C:9]([OH:11])=[N:12][NH:5]2
Reactant: O=N[O-]
Reactant: Nc1cccc(Br)c1C(=O)O
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1n[nH]c2cccc(Br)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a mixture of 3-bromo-2-carboxyaniline (6.6 g, 30.6 mmol, see Aust. J. Chem., 1999, 52, 1061) in H2O (28 ml) and HCl (conc., 6 ml) was added a solution of NaNO2 (2.11 g, 30 mmol) in H2O (5 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes then a solution of Na2SO3 (10.4 g, 82.5 mmol) in H2O (28 ml) was added slowly. The mixture was stirred at room temperature for 2 hours and HCl (conc., 9 ml) was slowly added. The resulting mixture was stirred at room temperature for additional 18 hours, then at 80° C. for 4 hours, and finally cooled to room temperature. The reaction mixture was basified to dissolve the precipitate and then reacidified. The precipitated 4-Bromo-1H-indazol-3-ol CLXXXIII was filtered and dried in vacuo (yellow powder, 3.19 g, 49% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[NH2:24].[H+].[B-:26]([F:30])([F:29])([F:28])[F:27].[N:31]([O-])=O.[Na+]>C1COCC1.O>[F:27][B-:26]([F:30])([F:29])[F:28].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:24]#[N:31]
Reactant: O=N[O-]
Reactant: COc1cc2c(Cl)c(N)cnc2cc1OCCCN1CCCCC1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Cl)c([N+]#N)cnc2cc1OCCCN1CCCCC1
Temperature: 0 °C
Yield: 80 %

Procedure:
4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-ylamine (0.300 g) was dissolved in THF (5 ml) with stirring and then cooled in ice-water bath to below 0° C., to this added 48% aqueous fluoboric acid (0.7 ml) and mixture stirred for 10 mins. A solution of sodium nitrite (0.10 sg) in water (1 ml) was added keeping the temperature below 10° C. The reaction mixture was the stirred for 1 hr, during that time yellow solid precipitated. This solid was filtered, dried to give 4-chloro-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-diazonium tetrafluoroborate (0.250 g, 80%)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[C:21]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([Cl:26])=[N:18][CH:17]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[C:11]1[O:12][C:15]([C:16]2[CH:17]=[N:18][C:19]([Cl:26])=[CH:20][C:21]=2[NH:22][CH:23]([CH3:24])[CH3:25])=[N:14][N:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)o1
Temperature: 50 °C

Procedure:
tert-Butyl (3-((tert-butyldimethylsilyl)oxy)-1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (54) (100 mg, 0.18 mmol) in DCM (5 mL) was stirred at room temperature. Added triphenyl phosphine (0.56 mmol, 3 equiv.), Et3N (1.5 mol, 8 equiv.) and CCl4 (0.56 mmol, 3 equiv.). The reaction mixture was heated at 50° C. for 3 h. Reaction mixture was diluted using DCM. The DCM layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and EtOAc:Pet. Ether as eluent to provide the desired compound, tert-butyl (2-((tert-butyldimethylsilyl)oxy)-1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate (55). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.567 min; LCMS (ES-API), m/z 512.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14]CC)=[O:13])[C:6](=[O:17])[C:5]12[CH2:21][O:20][C:19]2[CH:22]=[C:23]3[C:27](=[CH:28][C:18]1=2)[CH2:26][CH2:25][O:24]3.O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC(OCC)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6](=[O:17])[C:5]12[CH2:21][O:20][C:19]2[CH:22]=[C:23]3[C:27](=[CH:28][C:18]1=2)[CH2:26][CH2:25][O:24]3
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2cc(Cl)ccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2cc(Cl)ccc21
Yield: 98 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl (5′-chloro-2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 98% yield as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.27-7.25 (m, 1H), 7.16 (d, 1H), 6.72 (d, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 4.93 (dd, 2H), 4.69-4.63 (m, 1H), 4.54-4.51 (m, 3H), 2.95 (t, 2H); 13C NMR (75 MHz, CDCl3) δ 177.8, 170.9, 162.1, 162.1, 143.1, 131.7, 130.0, 128.6, 124.7, 119.6, 118.7, 117.0, 106.7, 92.8, 77.2, 72.3, 58.1, 41.2, 28.9; MS (ES−) m/z 370.4 (M−1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([C:7]([SH:10])([CH3:9])[CH3:8])[NH2:6].[CH2:12]1CCN2C(=NCCC2)CC1.CI>CN(C=O)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([C:7]([S:10][CH3:12])([CH3:9])[CH3:8])[NH2:6]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: Cl
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](N)C(C)(C)SC
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 0° C. solution of D-penicillamine methyl ester hydrochloride (0.250 g., 1.25 mmoles) in DMF (4 mL) was added DBU (0.382 ml., 2.56 mmoles), followed by methyl iodide (0.081 ml., 1.31 mmoles). After 1 hour, the solution was partitioned between brine and ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified on silica, eluting with 6% methanol in dichloromethane to give S-methyl-D-penicillamine methyl ester as a colorless oil in 81% yield: 1H--NMR (CDCl3) δ 1.25 (s, 3H) 1.35 (s, 3H), 2.02 (s, 3H), 3.44 (s,1H), 3.72 (s, 3H); FAB HRMS:expected (M+H)=178.0902, found (M+H)=178.0905.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])=[CH:2]1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][Br:13])=[CH:2]1
Reactant: Cc1ccccc1-c1ccsc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccccc1-c1ccsc1

Procedure:
To a solution of Compound 2a (7.23 mmol) in carbon tetrachloride (150 mL) was added N-bromosuccinimide (7.5 mmol) and benzoyl peroxide (0.1 g). The solution was heated at reflux and irradiated with 250 watt sunlamp for 2 hours. The cooled reaction mixture was filtered through a pad of silica gel and the silica gel washed with diethyl ether (3×75 mL). The solvent was removed in vacuo and the residue fractionated to afford Compound 2b as a clear oil (b.p. 100°-103° C./0.1 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](N2C=CN=C2)=[O:10])=[C:4]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9](=[O:10])[N:28]([CH2:27][C:26]([F:30])([F:29])[F:25])[C:16]2([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[OH:24]
Reactant: NCC(F)(F)F
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1NC(=O)n1ccnc1
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(F)cc2)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 19 h

Procedure:
To a suspension of N-[4-chloro-2-(4-fluorobenzoyl)phenyl]-1H-imidazole-1-carboxamide (63.0 g, 183.3 mmol) in THF (315 mL) was added 2,2,2-trifluoroethylamine (24.5 g, 247.4 mmol). The reaction was heated to 50° C. After 19 h at 50° C., the reaction was cooled to ambient temperature and concentrated in vacuo. The light yellow oil was partitioned between n-butyl chloride (110 mL) and aqueous 10% citric acid (60 mL) with vigorous stirring. The resulting precipitate was collected by vacuum filtration and placed under vacuum alongside P2O5 for 16 h to give 6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[C:13]([OH:15])=[O:14].C(O)(=O)C.[B-]C#N.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH:12]([C:11]([CH3:18])([CH3:17])[CH3:10])[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)C(=O)C(=O)O
Reactant: COc1cccc(N)c1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1cccc(NC(C(=O)O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a mixture of 3-methoxyaniline (100 mg, 0.812 mmol) and trimethylpyruvic acid (211 mg, 1.624 mmol) in methanol (3 mL) at rt was added acetic acid (0.930 mL, 16.24 mmol). The mixture was stirred for 30 min at rt then heated at 70° C. for 2 hrs. The mixture was cooled down to rt before adding sodium cyanotrihydroborate (1.624 mL, 1.624 mmol). The mixture was stirred overnight at rt. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×10 mL). The organic layer was washed with sat. NaHCO3 and brine solution, and then dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by preparative HPLC to get a white solid (30.5 mg, 16%) as product.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:16](=[O:33])[NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si](C(C)(C)C)(C)C)[CH:20]=2)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[OH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][C:16]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1)=[O:33]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc(O)c1)c1cc(-c2ccccc2)c(C(=O)O)s1

Procedure:
A mixture of 5-[3-(tert-Butyl-dimethyl-silanyloxy)-benzylcarbamoyl]-3-phenyl-thiophene-2-carboxylic acid methyl ester (180 mg, 0.37 mmol), lithium hydroxide monohydrate (310, mg, 7.47 mmol), THF (4 mL) and water (2 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 140 mg (100%). MS m/e 354.0 (M+H+).
Reaction SMILES: [N+](C1C=CC(C([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=O)=CC=1)([O-])=O.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:24](Cl)=[O:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:24]([N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17])=[O:25]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Product: O=C1CCCCCN1C(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using 3,5-dichlorobenzoylchloride (Aldrich) in place of 4-nitrobenzoyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH:17]=[N+:18]([CH3:20])[CH3:19].BrC1C=CC=CC=1C=O.CNC>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH:17]([N:18]([CH3:20])[CH3:19])[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[NH:8][CH:7]=1
Reactant: C[N+](C)=Cc1ccccc1Br
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: CNC
Agent: O=Cc1ccccc1Br
Agent: [Cl-]
Product: CN(C)C(c1ccccc1Br)c1c[nH]c2cccc([N+](=O)[O-])c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-nitroindole and (2-bromo-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-bromo-benzaldehyde and dimethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[BH4-].[Na+].[OH-].[Na+].Cl.[F:25][CH:26]([F:30])[C:27](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:27][CH:26]([F:30])[F:25])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: O=C(O)C(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc(N(CC(F)F)C2CCOCC2)c1C
Temperature: 50 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (500 mg, 1.5 mmol) in difluoroacetic acid (15 ml), was treated with sodium tetrahydroborate (1000 mg, 26 mmol) portionwise over 12 minutes. The reaction mixture was warmed to 50° C. and stirred for 4 hours. The reaction mixture was allowed to reach room temperature and then poured over ice (130 ml) and left for 5 minutes. The mixture was basified by the addition of 6M NaOH (aq) (35 ml) and the pH adjusted to 7 using 1M HCl (aq) (20 ml). The resulting suspension was allowed to stand until the solution was clear and the resulting solid collected by filtration and dried in-vacuo at 40° C. to give the title compound (572 mg, 96%) as a white solid. LC-MS 100%, m/z=391.9, 392.9, 393.9, 394.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.79 (d, J=1.89 Hz, 1H) 7.44 (d, J=1.89 Hz, 1H) 5.44-5.71 (m, 1H) 4.00 (dd, J=11.51, 4.10 Hz, 2H) 3.91 (s, 3H) 3.41 (td, J=13.99, 4.18 Hz, 2H) 3.32 (t, J=11.27 Hz, 2H) 2.97 (tt, J=11.37, 3.84 Hz, 1H) 2.47 (s, 3H) 1.72-1.81 (m, 2H) 1.59-1.67 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:5]([NH:11][CH:12]=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[P:24]([O:33]C(C)C)([O:29][CH:30]([CH3:32])[CH3:31])[O:25][CH:26]([CH3:28])[CH3:27]>>[CH2:22]([O:21][C:19]([CH2:18][O:17][CH2:16][CH2:15][CH2:14][C:3]([CH2:2][P:24]([O:29][CH:30]([CH3:32])[CH3:31])([O:25][CH:26]([CH3:28])[CH3:27])=[O:33])=[CH:4][CH:5]([NH:11][CH:12]=[O:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:20])[CH3:23]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CBr
Product: CCOC(=O)COCCCC(=CC(NC=O)C(=O)OCC)CP(=O)(OC(C)C)OC(C)C
Reaction time: 18 h

Procedure:
6.4 g (15 mmol) of ethyl 4-bromomethyl-7-ethoxycarbonylmethoxy-2-formylamino-hept-3-enoate and 14.8 ml (60 mmol) of triisopropyl phosphite (90%) are heated to 80° C. and stirred for 18 hours under a pressure of 100 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is chromatographed over silica gel with hexane/ethyl acetate (1:2:5%) to give ethyl 7-ethoxycarbonylmethoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate as a brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]CC3C=CC=CC=3)=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)n1ccc2cc(C(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)n1ccc2cc(C(=O)O)ccc21
Yield: 87 %

Procedure:
The benzyl 1-(2,2-dimethylpropionyl)-1H-indole-5-carboxylate (220 mg) obtained above was dissolved in ethanol, and 5% palladium on carbon (44 mg) was added thereto and stirred overnight at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (140 mg, Y.:86%).
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[C:10]1([CH:17]=[CH:16][CH:15]=[C:13]([OH:14])[CH:12]=1)[OH:11].O[C:19]([CH3:26])([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:20]>O>[OH:11][C:10]1[CH:12]=[C:13]([OH:14])[CH:15]=[CH:16][C:17]=1[C:19]([CH3:26])([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:20]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCC(C)(C)c1ccc(O)cc1O
Reaction time: 8 h

Procedure:
To 100 parts of glacial acetic acid containing 9.8 parts of 98% sulphuric acid was added 22 parts of resorcinol followed by 13 parts of 2-hydroxy-2-methyl-heptane at room temperature. After storing overnight at the same temperature the reaction mixture was poured into 1000 parts of water. The organic phase which separated out, was after decanting off the water, taken up in ether, washed with sodium bicarbonate solution, and finally with water. The ether solution was then evaporated and the residue distilled to give 2-(2,4-dihydroxyphenyl)-2-methyl-heptane (compound of the formula (4)) with a boiling point (b.p.12) of from 202°-204° C. and with the following percentage composition by weight:
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[C:3]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=1.[NH2:16][C@@H:17]([CH3:34])[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1.CN(C=O)C>C(Cl)Cl>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([CH2:18][C@@H:17]([NH:16][C:7]([C:6]3[N:1]=[CH:2][C:3]([C:10]4[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=4)=[CH:4][CH:5]=3)=[O:9])[CH3:34])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccc(-c2cccnc2)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccc(-c2cccnc2)cn1
Yield: 22.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 3,3′-bipyridine-6-carboxylic acid (0.861 mmol, 172 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.718 mmol, 200 mg) using DMF (2 ml) as the solvent. After the reaction had stopped, DCM was added and the reaction mixture was evaporated. The residue was purified by flash chromatography and trituration from methanol, respectively. 75 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.18 (d, 3H), 4.35-4.59 (m, 3H), 7.02 (d, 1H), 7.55-7.62 (m, 1H), 7.87-7.93 (m, 2H), 7.98 (s, 1H), 8.06-8.10 (m, 1H), 8.19-8.25 (m, 1H), 8.35 (dd, 1H), 8.68 (dd, 1H), 8.99-9.05 (m, 2H), 9.13 (d, 1H).
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[S:11][C:12]3[CH:18]=[C:17]([S:19][C:20]#[N:21])[CH:16]=[CH:15][C:13]=3[N:14]=2)C=CC=CC=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH2:32])[CH2:26][CH2:25]1>>[S:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([NH:9][C:8]([NH:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)=[O:22])[S:11][C:12]=2[CH:18]=1)[C:20]#[N:21]
Reactant: CN1CCN(CCN)CC1
Reactant: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Product: CN1CCN(CCNC(=O)Nc2nc3ccc(SC#N)cc3s2)CC1

Procedure:
The 1-(6-thiocyanato-1,3-benzothiazol-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea was prepared according to the method described in Example 9c, but using 982 mg of phenyl(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate and 473 mg of 2-(4-methylpiperazin-1-yl)ethylamine. The residue obtained is chromatographed on a Merck cartridge (25 g of silica 15-40 μm), elution being carried out with a 90/10 mixture of dichloromethane/methanol. 1.13 g of 1-(6-thiocyanato-1,3-benzothiazol-2-yl)-3-[2-(4-methylpiperazin-1-yl)ethyl]urea are thus recovered in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]=[O:11])[CH3:2].[OH-:12].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])[CH3:2]
Reactant: CCc1ccccc1CC=O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1ccccc1CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the crude (2-ethylphenyl)acetaldehyde in 20 ml of EtOH was added a solution of 2.29 g (13.52 mmol) of AgNO3 in 7.5 ml of water and a solution of 2.08 g (37.2 mmol) of KOH in 13 ml of water at 0° C. The reaction mixture was stirred at 0° C. for 2 h and was filtered to remove the precipitated silverhydroxide. The filtrate was extracted with CH2Cl2 (20 ml×3) and the organic fractions were discarded. The aqueous layer was acidified with 6N HCl to PH=1 and was extracted with CH2Cl2 (50 ml×3). The combined organic layers were dried over MgSO4 and concentrated to give 2-ethylphenylacetic acid.
Reaction SMILES: C(NC(C1C=CC([O:12][C:13]2[C:18]([F:19])=[CH:17][C:16]([CH2:20][C:21]([O:23]C)=[O:22])=[C:15]([F:25])[CH:14]=2)=C([N+]([O-])=O)C=1)=O)(C)(C)C.C(NC(=O)C1C=CC(Cl)=C([N+]([O-])=O)C=1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.C(OCC)(=O)C>[F:25][C:15]1[CH:14]=[C:13]([OH:12])[C:18]([F:19])=[CH:17][C:16]=1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: COC(=O)Cc1cc(F)c(Oc2ccc(C(=O)NC(C)(C)C)cc2[N+](=O)[O-])cc1F
Agent: CC(C)(C)NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)Cc1cc(F)c(O)cc1F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Methyl 2-(4-(4-(tert-butylcarbamoyl)-2-nitrophenoxy)-2,5-difluorophenyl)acetate (A.6) To a solution of compound A.4 (500 mg, 2.66 mmol) and N-tert-butyl-4-chloro-3-nitrobenzamide (A.5) (682 mg, 2.66 mmol) in DMSO (25 ml), Cs2CO3 (1.73 g, 5.32 mmol) was added in one portion. The reaction mixture was stirred at 80° C. for 1 hour, diluted with ethyl acetate and then 10% citric acid was added to adjust pH=2. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in methanol (10 ml) then chlorotrimethylsilane was added to the solution. The reaction was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate in hexane.eluent) to give compound A.6 (340 mg, 30%, 2 steps). LC-MS ESI (pos.) m/z: 423.1 (M+H).