Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:13]2[N:14]=[CH:15][CH:16]=[N:12]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2nccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A 18-mL vial was charged with 1-(chloromethyl)-4-nitro-benzene (500 mg, 3 mmol, 1 eq.), triazole (310 mg, 4.5 mmol, 1.5 eq.), potassium carbonate (1.24 g, 9 mmol, 3 eq.) and DMF (5 ml). After the resulting mixture was stirred at rt overnight, water (20 ml) was added. The precipitate was collected by filtration and washed with small amount of water. After drying, 340 mg of the title compound was obtained as a mixture of two regioisomers (340 mg, 55% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]([CH3:24])([CH3:23])[CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[F:22])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33](=[O:38])=[N:34][C:35](Cl)=[O:36]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]([CH3:24])([CH3:23])[CH2:9][N:10]1[C:35](=[O:36])[NH:34][C:33](=[O:38])[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[F:22])[C:11]1=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NC(=O)Cl
Reactant: COc1cccc(NC(=O)NCC(C)(C)NC(=O)OC(C)(C)C)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(-n2c(=O)[nH]c(=O)n(CC(C)(C)NC(=O)OC(C)(C)C)c2=O)c1F
Reaction time: 1 h

Procedure:
To 20 mL of anhydrous CH2Cl2 was added 0.93 g of {2-[3-(2-Fluoro-3-methoxy-phenyl)-ureido]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester and triethylamine (1.0 eq, 0.36 mL). N-(chlorocarbonyl) isocyanate (1.0 eq, 0.11 mL) was added to the solution in one portion. The reaction stalled after one hour, so additional triethylamine (1.0 eq, 0.36 mL) and N-(chlorocarbonyl) isocyanate was added. The reaction was determined to be complete by LC/MS after two hours. Excess isocyanate was quenched with the dropwise addition of H2O (1 mL). The reaction was then diluted with 20 mL H2O, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography and eluted with 60% EtOAc/hexanes to yield 0.65 g (59%). Rf=0.66 in 60% EtOAc/hexanes. 1H NMR (CDCl3) δ: 7.19 (dt,1H), 7.09 (dt,1H), 6.90 (dt,1H), 5.15 (ds,1H), 4.1 (q,2H), 3.92 (s,3H), 1.42 (s,9H), 1.38 (d,6H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=5)=[C:18]([C@H:27]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]([CH3:38])=[CH:16][C:14]=4[N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH3:39])[N:3]=1.[CH3:40][N:41]1[CH2:46][CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:34]([O:33][C@@H:27]([C:18]1[C:17]([CH3:38])=[CH:16][C:14]2[N:15]=[C:11]([C:7]3[CH:6]=[C:5]4[C:10]([C:2]([C:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH:43]=5)=[N:3][N:4]4[CH3:39])=[CH:9][CH:8]=3)[S:12][C:13]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:37])([CH3:36])[CH3:35]
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(Br)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C5=CCN(C)CC5)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A vial was charged with (S)-ethyl 2-(2-(3-bromo-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (36 mg, 57 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (13 mg, 57 mmol), KHCO3 (6.3 mg, 63 μmol), Pd(PPh3)4 (6.7 mg, 5.7 mmol), 2 M aq K2CO3 (250 mL), and dioxane (1 mL). The vessel was sealed and heated to 100° C. for 1 h. The reaction was cooled to 23° C., and filtered (0.45 micron teflon syringe filter). The filtrate was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C36H39ClN4O3S: 643.2, 645.2 (M+H+); Found: 643.0, 645.0 (M+H+). 1H NMR (400 MHz, CD3OD): δ 8.27 (s, 1H), 8.10 (d, J=8.7 Hz, 1H), 7.97-7.82 (m, 2H), 7.72-7.48 (m, 4H), 6.61 (s, 1H), 5.27 (s, 1H), 4.38-4.18 (m, 2H), 4.14 (s, 3H), 4.06-3.93 (m, 2H), 3.65-3.46 (m, 1H), 3.21-3.07 (m, 3H), 3.03 (s, 3H), 2.61 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.00 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]OS(C)(=O)=O)[CH:5]=[C:4]([CH3:14])[N:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:8][C:6]1[CH:5]=[C:4]([CH3:14])[N:3]=[C:2]([Br:1])[CH:7]=1)=[N+:16]=[N-:17]
Reactant: Cc1cc(COS(C)(=O)=O)cc(Br)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN=[N+]=[N-])cc(Br)n1
Reaction time: 15 h

Procedure:
To a solution of methanesulfonic acid 2-bromo-6-methyl-pyridin-4-ylmethyl ester (410 mg, 1.46 mmol) in DMF (2.0 mL) was added sodium azide (238 mg, 3.66 mmol). After 15 hours, the reaction was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was passed through a pad of silica gel eluting with 30% ethyl acetate in heptane to afford 4-azidomethyl-2-bromo-6-methyl-pyridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[CH2:20]([C:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:20]([C:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:1][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:9][CH:8]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)NOCCO)cc1
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CC(OCCONC(=O)c2ccc(C(=O)C(C)(C)C)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2.8 grams (10.6 mmol) of N-(2-hydroxy-ethoxy)-4-pivaloylbenzamide in 5 ml of methylene chloride and 3 ml of pyridine at 0° C. are added 3.92 grams (12.7 mmol) of ρ-anisylchlorodiphenylmethane. The mixture is warmed to room temperature over two hours and then diluted with 40 ml of methylene chloride. This solution is washed with 50 ml of 10% sodium bicarbonate and 30 ml of brine, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatography using 5:1 hexane/ethyl acetate as the eluent to obtain the protected product, N-(2-[ρ-anisyldiphenylmethyloxy]ethoxy)-4-pivaloylbenzamide.
Reaction SMILES: Br[C:2]1[C:3]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.[O:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:24]1=[O:30].O>CCOCC>[CH2:12]([C:3]1[C:2]([C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:24]([OH:30])=[O:23])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCc1nc2ccccc2cc1Br
Reactant: O=C1CCCC(=O)O1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CCCCCCc1nc2ccccc2cc1C(=O)CCCC(=O)O
Temperature: -100 °C
Reaction time: 2 h

Procedure:
To the solution of 3-bromo-2-hexyl-quinoline in ether was added tert-butyl lithium at −100° C. The reaction mixture was stirred for 2 hours at −100° C. To the reaction mixture a solution of dihydro-pyran-2,6-dione in ether was added at −100° C. and stirred for 30 minutes and was allowed to warm up to RT. The stirring was continued for 3 hours. The water was added to the reaction mixture and was stirred for 20 minutes. Solvent was evaporated under vacuum and water was added to the crude mixture. It was then acidified by using dilute HCl and was extracted with ether. The product was purified by column chromatography.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=O.[BH4-].[Na+]>>[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: CC(C)(C)CC=O
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)CCNCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 68.2 %

Procedure:
Using a method similar to Example 201, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol), 3,3-dimethylbutyraldehyde (75 mg, 0.750 mmol), and NaBH4 (38 mg, 1.00 mmol) gives the title compound (130 mg) as a white foam. Mass spectrum (ion spray): m/z=382 (M+1); 1HNMR (CDCl3): 8.55 (s, 1H), 8.14 (d, 1H), 7.22-7.14 (m, 2H), 6.90 (m, 2H), 5.76 (br. s, 2H), 3.03 (m, 1H), 2.92-2.80 (m, 2H), 2.71-2.55 (m, 3H), 2.49-2.41 (m, 1H), 1.85-1.65 (m, 4H), 1.42 (t, 2H), 0.90 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].C(=O)(O)[O-].[K+]>C(#N)C.O>[Cl:24][CH2:25][C:26]([NH:12][C:11]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(CCl)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
To 7.7 g (25 mmol) of 3,4-dibenzyloxyaniline in 50 ml of 1:1 acetonitrile/water at 0° C. was added chloroacetyl chloride (3.0 ml) while keeping the pH at 6.5 with saturated aqueous potassium bicarbonate. When the pH remained constant for 15 minutes, an additional 3 ml of chloroacetyl chloride was added in small portions while maintaining the pH at 6.5. When the pH remained constant for 15 minutes, the acetonitrile was evaporated, and the resulting aqueous solution was filtered. The precipitate was washed thoroughly with water to yield, upon drying in vacuo, 8.98 g of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:24][C:25](=[CH2:27])[CH3:26].C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:25]([O:17][C:16]([C:7]1[N:8]2[CH:11]([S:12][CH2:13][C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:10]([NH2:14])[C:9]2=[O:15])=[O:18])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)C2SC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.04 mole) is added to 100 ml of dioxane, 10 ml of concentrated sulfuric acid and 50 ml of liquid isobutylene in a pressure bottle. The mixture is shaken overnight. The bottle is chilled, opened and the contents poured into an ice cold solution of sodium bicarbonate. Extraction of the aqueous phase with ethyl acetate followed by drying and evaporation of the ethyl acetate phase gives the title compound, M.P. 111°-112° C. See J. Med. Chem., 9, 444 (1966).
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[F:42][C:43]([F:54])([F:53])[O:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=1>C1COCC1>[F:42][C:43]([F:53])([F:54])[O:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][NH:50][C:30]([C:28]2[CH:27]=[CH:26][C:12]3[N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=4)[C:9]([CH2:8][O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:10][C:11]=3[CH:29]=2)=[O:31])=[CH:47][CH:46]=1
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 4-trifluormethoxy-benzylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 616.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH:5]1[CH2:8][NH:7][CH2:6]1.C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>C(O)(C)C>[Cl:23][C:24]1[N:29]=[C:28]([N:7]2[CH2:8][CH:5]([O:4][C:3]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=3[Cl:1])[CH2:6]2)[CH:27]=[CH:26][N:25]=1
Reactant: Clc1ccc(OC2CNC2)c(Cl)c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1ccc(OC2CN(c3ccnc(Cl)n3)C2)c(Cl)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of 3-(2,4-dichlorophenoxy)azetidine (1.0 g, 4.6 mmol) in isopropanol (14 mL) was added N,N-diisopropylethylamine (DIPEA) (1.0 mL, 6.9 mmol) and 2,4-dichloropyrimidine (0.686 g, 4.6 mmol and the reaction mixture was heated at 80° C. for 7 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL) and water (2×20 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(3-(2,4-dichlorophenoxy)azetidin-1-yl)pyrimidine (0.600 g, 40%) as a solid. Observed mass (M+1): 330.0
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C@@H:13]1([C:21]([OH:23])=O)[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:14]1.[OH-].[NH4+]>C(OCC)(=O)C>[C@@H:13]1([C:21]([NH2:3])=[O:23])[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:14]1
Reactant: O=C(O)[C@H]1CC12CCOCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)[C@H]1CC12CCOCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
18.85 g of carbonyldiimidazole are added to a solution of 17.66 g of (S)-6-oxaspiro[2.5]-octane-1-carboxylic acid (prepared in analogy to building block FFFFa from (R)-4-benzyl-3-((S)-6-oxaspiro[2.5]-octane-1-carbonyl)oxazolidin-2-one (building block FFFFb)) in 330 ml of ethyl acetate. The reaction solution is left to stand at room temperature for 6 hours and then 330 ml of 25% ammonium hydroxide solution are added. The reaction mixture is stirred at room temperature for 16 hours, the phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water until neutral, dried with sodium sulphate and evaporated. The title compound is obtained from the residue by flash chromatography (SiO2 60 F) as a yellowish oil which may crystallize if sufficiently pure. Rf=0.28 (dichloromethane-methanol-conc. ammonia 25% 200:20:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]2[N:22]=[N:23][NH:24][CH:25]=2)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:18][C:19]([C:21]3[N:22]=[N:23][NH:24][CH:25]=3)=[O:20])[CH2:10][C@:11]([CH2:16][OH:17])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(Br)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Temperature: 90 °C
Yield: 19.9 %

Procedure:
(2S,4R)-5-(4-bromophenyl)-2-hydroxymethyl-2-methyl-4-[(1H-[1,2,3]triazole-4-carbonyl)amino]pentanoic acid (38 mg, 92 μmol) was combined with 3-chlorophenylboronic acid (28.9 mg, 185 μmol), sodium carbonate (29.4 mg, 277 μmol), water (0.2 mL) and dioxane (1.5 mL). The reaction vessel was sealed, air was removed by vacuum, and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18 μmol) was quickly added and air was removed by vacuum. The mixture was heated at 90° C. for 45 minutes. The mixture was acidified to pH ˜3 and filtered, and the solvate was concentrated. The residue was dissolved in AcOH (0.7 mL) and purified by preparative HPLC to yield the title compound (8.1 mg). MS m/z [M+H]+ calc'd for C22H23ClN4O4, 443.14. found 443.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.CON(C)[C:12](=[O:24])[CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([C:12](=[O:24])[CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:7]=[CH:6][CH:5]=1
Reactant: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Reactant: Clc1cccc(Br)c1
Solvent: C1CCOC1
Product: CN(CCC(=O)c1cccc(Cl)c1)C(=O)OC(C)(C)C

Procedure:
A solution of 1-bromo-3-chloro-benzene (57 g, 0.3 mmol) in dry THF (300 mL) was added drop wise to Mg (10.8 g, 0.45 mmol) at room temperature under N2. The mixture was stirred at refluxed for 1 h. The Grignard reagent was added drop wise to a solution of tert-butyl 3-(methoxy(methyl)amino)-3-oxopropyl(methyl)carbamate (37 g, 0.15 mmol) in dry THF (300 mL) at −78° C. After addition, the mixture was allowed to stir at room temperature overnight. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified through column chromatography. 1H NMR (CDCl3, 400 MHz) δ 1.42 (s, 9H), 2.89 (s, 3H), 3.18 (m, 2H), 3.62 (t, 2H), 7.42 (m, 1H), 7.52 (m, 1H), 7.82 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27](Cl)=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:25][C:24]=2[CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]([S:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:25][C:24]=2[CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: Sc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Sc1ccccc1
Temperature: 60 °C
Yield: 83.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--0.39 ml, 2.5 mmol) was added to a mixture of ethyl 6-(benzyloxy)-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 8, 800 mg, 2.3 mmol) and thiophenol (0.47 ml, 4.6 mmol) in dimethylformamide (4 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 6 hours and then partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using a mixture of 20% dichloromethane and 80% hexane, then 50% dichloromethane and 50% hexane as eluant. The isolated product was crystallised from diisopropyl ether and hexane to give the title compound as a colourless solid (810 mg).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:18](=O)[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>O.CO>[C:1]1([C:7]2[C:8]3[C:18](=[N:21][OH:22])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C1c2ccccc2-c2[nH]nc(-c3ccccc3)c21

Procedure:
A mixture of 3-phenylindeno[1,2-c]pyrazol-4(1H)-one (1.28 g, prepared as described in JP60-130521), hydroxylamine hydrochloride (0.5 g), sodium acetate (0.8 g), water (10 ml) and methanol (100 ml) was boiled under reflux for 66 hours. More hydroxylamine hydrochloride (0.5 g), sodium acetate (0.8 g) and water (10 ml) were added and the mixture was boiled under reflux for a further 16 hours. Further hydroxylamine hydrochloride (0.5 g) and sodium acetate (0.8 g) were added and the mixture was boiled under reflux for a further 20 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure until crystallization began. The mixture was cooled and filtered to give a solid which was washed with water and dried to give 3-phenylindeno[1,2-c]pyrazol-4(1H)-one oxime, m.p. 280° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH:7][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: COc1ccc(F)cc1N
Agent: Br
Product: COc1ccc(F)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 57.5 %

Procedure:
5-fluoro-2-methoxyaniline (115 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-fluoro-2-methoxyphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (54 mg, 56%) as a white solid. Mass Spectrum: M+H+ 470. NMR Spectrum (DMSOd6): 1.58 (d, 3H), 2.71 (bs, 3H), 2.94 (bs, 3H), 3.51-3.64 (m, 4H), 3.70-3.78 (m, 4H), 3.82 (s, 3H), 4.97-5.06 (m, 1H), 5.61 (s, 1H), 6.60 (s, 1H), 6.67 (s, 1H), 6.73 (d, 1H), 6.74 (s, 1H), 7.54 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[S:25])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
A solution of 5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (18 g, 67 mmol) in dry THF was treated with Lawesson's reagent (27 g, 67 mmol) in one portion at room temperature. The mixture was refluxed for 2 h. The title compound was obtained by chromatography on silica gel (PE/EtOAc=30:1 to 10:1). 1H-NMR (400 MHz, DMSO-d6): 11.08 (s, 1H), 7.50 (m, 2H), 7.35 (m, 2H), 4.36 (s, 2H), 4.00 (m, 1H), 3.73 (m, 1H), 1.51 (s, 3H).