Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([NH:11][OH:12])(=[O:10])[CH3:9].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([O:12][NH:11][C:8](=[O:10])[CH3:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)NO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
60% sodium hydride (11.68 g, 0.292 mol) was added to a dimethylformamide solution (200 ml) of acetohydroxamic acid (21.9 g, 0.292 mol) with cooling in an ice bath. After stirring for 1 hour at room temperature, benzylbromide (50 g, 0.292 mol) was added thereto and allowed to react for 24 hours at room temperature. The reaction solution was poured into 500 ml of water, and extracted with ethyl acetate. The organic layer was rinsed with water and dried. After removing the solvent by evaporation, the residue was purified with silica gel chromatography to obtain 31.3 g of N-benzyloxyacetamide (yield: 65%). The proton NMR spectrum of the compound is 1.85 s (3H); 4.89 bs (2H); 7.37 s (5 H); 8.30 bs, 8.81 bs (1H) (solvent: CDCl3).
Reaction SMILES: C(O[C@H](C)[C@H](NC(OC[CH:19]1[C:31]2C=CC=C[C:26]=2C2C1=CC=CC=2)=O)C(O)=O)C1C=CC=CC=1.[NH2:33][C@H:34]([C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C@H](O)CO)=[CH:60][CH:59]=1)[C:35]([NH:37][C@@H:38]([C@H:50]([C:52]1C=CC=CC=1)[CH3:51])[C:39]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=1[Cl:49])=[O:40])=[O:36].[C:70]([O:74]C(N[C@H](C1C=CC(OC[C@H]2COC(C)(C)O2)=CC=1)C(O)=O)=O)(C)(C)C>>[Cl:49][C:43]1[CH:44]=[C:45]([I:48])[CH:46]=[CH:47][C:42]=1[NH:41][C:39](=[O:40])[C@@H:38]([N:37]1[C:35](=[O:36])[C@@H:34]([C:58]2[CH:59]=[CH:60][C:61]([O:64][CH2:65][CH:19]3[CH2:26][CH2:31]3)=[CH:62][CH:63]=2)[NH:33][C:70]1=[O:74])[CH:50]([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)C(=O)Nc1ccc(I)cc1Cl
Product: CC(C)[C@@H](C(=O)Nc1ccc(I)cc1Cl)N1C(=O)N[C@H](c2ccc(OCC3CC3)cc2)C1=O

Procedure:
Prepared by the same method as described in example 3 except that (i) 2-chloro-4-iodo-aniline was used in place of 4-bromo-2-chloro-aniline in step 1, (ii) (S)-2-tert-butoxycarbonylamino-3-methyl-butyric acid was used in place of (S,S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1, and (iii) (R)-tert-butoxycarbonylamino-(4-cyclopropylmethoxy-phenyl)-acetic acid (prepared as described in example 109) was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 2.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[N:17]=[N:16][C:15]([N:18]([CH2:26][C:27]2([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:30][CH2:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1)#[N:11].[SH2:38]>CN1C(=O)CCC1>[C:10]([C:12]1[N:17]=[N:16][C:15]([N:18]([CH2:26][C:27]2([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:30][CH2:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1)(=[S:38])[NH2:11]
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C#N)nn1
Reactant: S
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C(N)=S)nn1

Procedure:
NMP (40 mL) and DIPEA (10 mL) were added to t-butyl 6-cyanopyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (3.9 g, 10 mmol), and hydrogen sulfide was bubbled through the reaction mixture for 2 h. The reaction was diluted with water, and the resultant yellow solid was filtered and dried under vacuum to give 2.1 g of t-butyl 6-carbamothioylpyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH:10]([CH3:13])[CH2:11][OH:12])[CH3:9])[NH:5][C:4](=[O:14])[N:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([O:12][CH2:11][CH:10]([N:8]([C:6]1[NH:5][C:4](=[O:14])[N:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:9])[CH3:13])(=[O:25])=[O:24]
Reactant: CC(CO)N(C)c1cc(Cl)nc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COS(C)(=O)=O)N(C)c1cc(Cl)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one (1.0 g, 4.6 mmol) and triethylamine (1.9 mL, 14 mmol) in tetrahydrofuran (THF) (15 mL) was added MsCl (0.72 mL, 9.2 mmol) at 0˜5° C. The reaction mixture was stirred at room temperature overnight, and then quenched with 1 M NaHCO3 solution, diluted with water and extracted with ethyl acetate. Combined organic parts were dried over anhydrous Na2SO4, filtered and concentrated to give the residue as yellow oil. The crude was used into next step without further purification.
Reaction SMILES: [CH2:1]([C@:4]1([C:15]([O:17]C)=[O:16])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([OH:14])=[CH:9][CH:10]=2)[O:5]1)[CH2:2][CH3:3].[CH2:19]([C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]=1[OH:39])[CH2:20][CH3:21].Cl[C:41]1[CH:46]=C(OC2C=CC=CC=2)C=C[C:42]=1O>>[CH2:19]([C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]=1[O:39][CH2:42][CH2:41][CH2:46][O:14][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][CH2:13][C@:4]([CH2:1][CH2:2][CH3:3])([C:15]([OH:17])=[O:16])[O:5]2)=[CH:10][CH:9]=1)[CH2:20][CH3:21]
Reactant: Oc1ccc(Oc2ccccc2)cc1Cl
Reactant: CCCc1cc(Oc2ccc(CC(C)C)cc2)ccc1O
Reactant: CCC[C@]1(C(=O)OC)CCc2ccc(O)cc2O1
Product: CCCc1cc(Oc2ccc(CC(C)C)cc2)ccc1OCCCOc1ccc2c(c1)O[C@@](CCC)(C(=O)O)CC2

Procedure:
The title compound was prepared following the procedures described in Example 17, Step B-C employing (2R)-methyl 2-propyl-7-hydroxychromane-2-carboxylate instead of ethyl 7-hydroxychromane-2-carboxylate, and 2-propyl-4-(4-isobutylphenoxy)phenol (U.S. Pat. No. 6,008,237) instead of 2-chloro-4-phenoxyphenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7]O.C(N(CC)CC)C.CS([Cl:25])(=O)=O.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][Cl:25]
Reactant: COCOc1ccc(Br)cc1CO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(Br)cc1CCl
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
To a solution of 5-bromo-2-methoxymethoxybenzyl alcohol (27.2 g) and triethylamine (23 ml) in dichloromethane (550 ml) was added, at 0° C., methanesulfonyl chloride (13.9 g). The mixture was stirred for 15 hours, while warming up to room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with an aqueous saline solution, which was then dried (anhydrous magnesium sulfate), followed by concentration to give an oily product. The oily product was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-bromo-2-methoxymethoxybenzyl chloride (21.6 g) as an oily product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>C(#N)C>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([NH:13][C:11]1[CH:10]=[N:9][N:8]([CH2:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:14])[CH:12]=1)=[O:20]
Reactant: O=C=NCCCl
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCCCl)cn1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine (419 mg, 2.18 mmol) and 2-chloroethyl isocyanate (230 mg, 2.18 mmol) in acetonitrile (5 mL) were heated at 65° C. for 16 hours. The reaction was cooled to room temperature and concentrated on the rotovap. The residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient), dried and triturated with ethyl acetate/hexanes (1/9) to afford (1-(2-chloroethyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)1H-pyrazol-4-yl)urea (258 mg, 40%) as a yellow solid. MS M+H calculated 298.10; found 298.1.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10]O)[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=O)=O)=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].C(N(CC)CC)C.C1(C)C=CC(S)=CC=1>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)[O:8][C@@H:7]([N:12]2[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Agent: Cc1ccc(S)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CSc1ccc(C)cc1
Reaction time: 16 h

Procedure:
A solution of 3'-O-acetylthymidine 26 (0.511 g, 1.8 mmol) and toluene-4-sulfonyl chloride (0.514 g, 2.7 mmol) in dry pyridine (3 cm3) was stirred at room temperature. After 16 h, saturated aqueous sodium hydrogen carbonate (2 cm3) was added and, after a further 10 min, the products were partitioned between chloroform (50 cm3) and saturated aqueous sodium hydrogen carbonate (50 cm3). The dried (MgSO4) organic layer was concentrated under reduced pressure. The residue was fractionated by short column chromatography on silica gel: the appropriate fractions, eluted with chloroform-methanol (99:1 v/v), were combined and evaporated under reduced pressure. The residue was dissolved in acetonitrile (2.5 cm3) at room temperature and triethylamine (0.90 cm3, 6.5 mmol) and toluene-4-thiol (0.805 g, 6.5 mmol) were added to the stirred solution which was kept under an atmosphere of argon. After 60 h, the products were concentrated under reduced pressure and the residue was fractionated by short column chromatography on silica gel: the appropriate fractions, eluted with chloroform-methanol (99:1 v/v) were combined and evaporated under reduced pressure to give 3'-O-acetyl-5'-S-(4-methylphenyl)-5'-thiothymidine 31 as a colourless glass (0.60 g, 85% based on 3'-O-acetylthymidine) (Found: M+ =390.1249. 12C191H2214N216 O532S requires: 390.1249); Rt 12.05 min (programme 1); δH [(CD3)2SO] 1.76 (3 H, d, JO.9), 2.05 (3 H, s), 2.25 (1 H, m), 2.26 (3 H, s), 2.49 (1 H, m), 3.32 (2 H, m), 4.02 (1 H, m), 5.18 (1 H, m), 6.13 (1 H, dd, J 6.0, 8.6), 7.14 (2 H, d, J7.9), 7.29 (2 H, d, J 8.2), 7.51 (I H, m), 11.38 (1 H, br s); δC [(CD3)2 SO] 12.1, 20.5, 20.8, 35.2, 35.4, 75.7, 81.9, 83.9, 110.0, 129.1, 129.7, 131.6, 135.7, 136.0, 150.5, 163.6, 169.9.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].Br[CH:19]([CH2:21][CH2:22][CH3:23])[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH3:20][CH:19]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH2:21][CH2:22][CH3:23]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CCCC(C)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(C)n1ccc2c(C=O)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-indole-4-carbaldehyde (1) (1.0 g, 6.88 mmol) in dimethylformamide (DMF, 35 mL) was added potassium t-butoxide (KOtBu, 1.16 g, 10.32 mmol) at 0° C. After the resulting solution was stirred for 30 min at 0° C., 2-bromopentane (2) (1.05 ml, 8.27 mmol) was added dropwise, and the reaction solution was warmed up to room temperature gradually and stirred for 12 h at room temperature. Water (5 ml) was added to quench the reaction. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with H2O (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (6:1 hexane/ethyl acetate) recovered 1H-indole-4-carbaldehyde (1) (500 mg) and gave 1-(pentan-2-yl)-1H-indole-4-carbaldehyde (3) mixed with residual 2-bromopentane (2), which was used in the following step directly.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6](=O)[CH2:7][CH2:8][C:9](=O)[CH3:10]>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]1[CH3:5]
Reactant: CC(=O)CCC(C)=O
Reactant: NCCO
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1CCO
Yield: 87.1 %

Procedure:
A mixture of 20 g (0.33 mol) of 2-aminoethanol and 38 g (0.33 mol) of 2,5-hexanedione was stirred until the vigorous reaction subsided. 100 ml of toluene was added and the solution was refluxed to 15 hours in a Dean-Stark apparatus. The solvent was removed in vacuo and the resulting oil was kugelrohr distilled at 110° C./1.5 mm to yield 40 g (87%) of a white solid. NMR: (CDCl3) δ 2.1 (1H, s), 2.2 (6H, s), 3.7 (4H, m), 5.6 (2H, s).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[NH2:7][C:8]1[N:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]>C1(C)C=CC=CC=1>[Br:17][C:14]1[CH:15]=[N:16][C:8]2[NH:7][C:2](=[O:3])[NH:12][C:10](=[O:11])[C:9]=2[CH:13]=1
Reactant: NC(=O)c1cc(Br)cnc1N
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]c(=O)c2cc(Br)cnc2[nH]1
Yield: 154.9 %

Procedure:
Oxalyl chloride (100 mL, 1.16 mmol) was added dropwise to a suspension of 2-amino-5-bromo-nicotinamide (500 mg, 2.31 mmol) in toluene (5 mL) and the resulting mixture was heated to reflux for 4 h. The reaction mixture was cooled and the mustard-colored solid which had formed was collected by filtration. The solid was washed with a small amount of water, MeOH, and then dried under high vacuum (40° C.) overnight to give the title compound (435 mg, 77%): 1H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 11.60 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 161.4, 154.8, 151.2, 150.17, 137.8, 112.6, 111.6.
Reaction SMILES: [C:1]([C:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)C1(C#N)CCOCC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CN)CCOCC1
Yield: 82.9 %

Procedure:
A mixture of tert-butyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (18.95 g, 0.0897 mol, step 1 of Example 1) and Raney Ni (1.00 g) in methanol (200 mL) was hydrogenated (3 atm) at room temperature for 12 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 16.01 g (83%) of the title compound as yellow syrup.
Reaction SMILES: [CH2:1]([O:12][P:13]([OH:16])([OH:15])=[O:14])[C@H:2]1[O:7][C@H:6]([OH:8])[C@H:5]([NH2:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[C:17](N1C(=O)CCC1=O)(=[O:19])[CH3:18]>C1COCC1.O>[CH3:18][C:17]([NH:9][CH:5]1[CH:6]([OH:8])[O:7][CH:2]([CH2:1][O:12][P:13]([OH:16])([OH:15])=[O:14])[CH:3]([OH:11])[CH:4]1[OH:10])=[O:19]
Reactant: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O[C@@H]1O
Reactant: CC(=O)N1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC1C(O)OC(COP(=O)(O)O)C(O)C1O

Procedure:
In one process, GlcN-6-P was acetylated in THF/water using N-acetylsuccinimide (NAS) to form GlcNAc-6-P. Acetic anhydride can also be used. That N-acetyl compound was treated with an enzyme preparation from Candida utilis containing N-acetylglucosamine phosphomutase (EC 2.7.5.2) and UDP-GlcNAc pyrophosphorylase (EC 2.7.7.23) to first form GlcNAc-1-P and then UDP-GlcNAc in the presence of UTP and inorganic pyrophosphatase (EC 3.6.1.1) to destroy the inorganic pyrophosphate formed.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:32])[C:20]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH:19]1[C:29](Cl)=[O:30].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][O:12][C:29]([CH:19]1[C:20]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[C:18]1([CH3:32])[CH3:17])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C12C=Cc1ccccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C(C(=O)OCc2ccc(F)c(Oc3ccccc3)c2)C12C=Cc1ccccc12
Yield: 86.3 %

Procedure:
5.05 g (0.0232 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 5.4 g (0.0232 mol) of 3,3-dimethyl-spiro(cyclopropane-1,1'-indene)-2-carboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 50 ml of toluene, were added dropwise at 20°-25° C., while stirring. The mixture was stirred at 25°-35° C. for a further 3 hours. The reaction mixture was poured into 150 ml of water, to which 5 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.3 g (86.4% of theory) of 3,3-dimethylspiro-(cyclopropane-1,1'-indene)-2-carboxylic acid 3-phenoxy-4-fluoro-benzyl ester were obtained as a viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.[OH-].[Na+]>CN(C=O)C.CO>[O:24]1[CH2:25][CH2:26][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH:35]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:32]=2)[CH2:28][CH2:29]1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccc(CN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-morpholinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24](C(F)(F)F)=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=[C:40]2C(C(N3CCNCC3)=C[CH:38]=[N:39]2)=CC=1.C(N(C(C)C)CC)(C)C.CN(C)C1C=CC(N=C=O)=CC=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([N:39]([CH3:40])[CH3:38])=[CH:25][CH:26]=4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Agent: CN(C)c1ccc(N=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(C)c1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
As described for 7-chloro-4-[4-(4-trifluoromethylphenylaminocarbonyl)piperazin-1-yl]quinoline, 7-chloro-4-(piperazin-1-yl)quinoline (200 mg, 0.81 mmol), diisopropyl(ethyl)amine (209 mg, 1.62 mmol), and 4-(dimethylamino)phenyl isocyanate (157 mg, 0.97 mmol) are reacted to give the title product after flash chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:32])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@H:7]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:8][C@@H:9]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:11][S:12][CH3:13].O.CC(O)=O>CO.[OH-].[Na+]>[CH3:1][NH:2][C:3](=[O:32])[C@H:4]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[NH:5][C:6](=[O:22])[C@H:7]([CH2:18][CH:19]([CH3:20])[CH3:21])[NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](CC(C)C)N[C@H](CCSC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](CC(C)C)N[C@H](CCSC)C(=O)O
Yield: 20.6 %

Procedure:
N[1-(R)-Carbomethoxy-3-methylthiopropyl]-L-leucyl-O-methyl-L-tyrosine N-methylamide (100 mg, 0.2 mM) was dissolved in MeOH (10 ml) and treated with IN NaOH (0.25 ml, 0.25 mM). After 18 h another portion of IN NaOH (0.5 ml, 0.5 mM) and H2O (2 ml) were added. After a further 18 h the reaction mixture was acidified with AcOH and evaporated in vacuo. The resulting white solid was chromatographed on C18 -Silica eluting with a gradient of 10% to 40% MeOH in H2O. The relevant fractions were pooled and evaporated in vacuo; the residue was recrystallised from hot H2O to yield the title compound (20 mg); m.p. 170-180; (Found: C,56.88; H,7.49; N,9.05; calculated for C22H35N3O5S,.0.6H2O: C,56.90; H,7.86; N,9.0 5%); νmax (Nujol) 3340, 1650 and 1625 cm-1 ; δ (d6DMSO) 0.82 (6H,t,J=7 Hz, (CH3)2CH), 1.17 and 1.5-1.9 (5H, m, CHCH(CH3)2 and SCH2CH2), 2.04 (3H, s,CH3S), 2.3 (2H, m, --SCH2), 2.6 (3H, d, J=5 Hz, NHCH3), 2.6-2.95 (3H, m, CH2C6H4 and α-CH),), 3.14 (1H, t, J=7 Hz, α-CH), 3.7 (3H, s, OCH3), 4.25 (1H, m, --CH), 6.8 and 7.12 (2×2H, each d, each J=9 Hz, C6H4), 7.88 (1H, q, J=5 Hz, NHCH3) and 8.18 (1H, d, J=9 Hz, NHCH); m/e 454 (100%, [m+1]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:31])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:31][S:40]([C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)(=[O:42])=[O:41])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted according to general operating instructions 13 with 4-chlorobenzenesulfonic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH2:14].[BH4-].[Na+]>CO.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Br)cc(N)c1N
Temperature: 0 °C

Procedure:
To a solution of 2-amino-5-bromo-3-nitro-benzoic acid methyl ester (5 g, 18.18 mmol) in methanol (15 mL) was added nickel chloride (10.8 g, 45.4 mmol) and was cooled to 0° C. To this cold solution, sodium borohydride (3.45 g, 90 mmol) was added in small portions. After the addition, the reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were dried, concentrated and the resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as grey coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][CH2:27][CH2:26]1>>[O:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]([CH3:19])[CH2:10]2)[CH2:27][CH2:26]1
Reactant: c1ccc2c(c1)NCCO2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCOc4ccccc43)CC2C)cc1OC
Yield: 59 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 3,4-dihydro-2H-1,4-benzoxazine (495 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (320 mg, yield: 59%) as a colorless oil. (cis:trans=1:2.3)