Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:16]C(=O)C)=[C:5]([O:12]C(=O)C)[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1)#[N:2].[OH-].[Na+].Cl>CO.[Cl-].[Na+]>[C:1]([C:3]1[C:4]([OH:16])=[C:5]([OH:12])[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1)#[N:2]
Reactant: CC(=O)Oc1cc(C(C)=O)cc(C#N)c1OC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc(O)c(O)c(C#N)c1
Reaction time: 0.75 h

Procedure:
0.33 g of 5'-cyano-3',4'-diacetoxyacetophenone dissolved in 3.3 ml of methanol is treated with 2.7 ml of 1.0N sodium hydroxide solution and the reaction mixture is stirred at 23° for 45 minutes. The mixture is subsequently acidified with 2N hydrochloric acid, diluted with 5 ml of saturated sodium chloride solution and extracted twice with 30 ml of ethyl acetate each time. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The residue is recrystallized from toluene/acetonitrile. There is obtained 5'-cyano-3',4'-dihydroxyacetophenone as brownish crystals which decompose above 215°.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.CON(C)[C:18](=[O:21])[CH2:19][CH3:20].[Cl-].[NH4+]>CCOCC.O.C(OCC)(=O)C>[S:6]1[C:10]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: c1ccc2sccc2c1
Reactant: CCC(=O)N(C)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: CCC(=O)c1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes; 28.9 ml) was added dropwise under nitrogen at 0° C. to a stirred solution of benzo[b]thiophene (6.21 g) in ether (90 ml), then the mixture was stirred 0° C. for 15 minutes and cooled to −70° C. A solution of N-methoxy-N-methylpropionamide (5.42 g) in ether (40 ml) was added over 10 minutes, then the mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 3.5 hours. The mixture was poured into saturated aqueous ammonium chloride solution (200 ml) and ethyl acetate (100 ml) and water (50 ml) were added. The organic phase was separated, washed with saturated aqueous sodium chloride solution (150 ml), dried (Na2SO4) and the solvents were removed in vacua. The residue was triturated with petroleum ether (b.p. 40-60° C.) (25 ml) and the resulting solid was collected by filtration and dried in vacuo to give 1-(benzo[b]thiophen-2-yl)propan-1-one (7.05 g) as a colourless solid, m.p. 79-81° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][OH:30])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16].O[C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][C:39]=1[CH3:46].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][O:30][C:38]3[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[CH:40][C:39]=3[CH3:46])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16]
Reactant: Cc1cc(C=O)ccc1O
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(C=O)cc3C)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
A solution of DIAD (395 μL, 2.15 mmol) in THF (0.8 mL) was added dropwise to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (430 mg, 1.44 mmol), 4-hydroxy-3-methylbenzaldehyde (200 mg, 1.47 mmol) and PPh3 (564 mg, 2.15 mmol) in THF (15 mL) at 25° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (EtOAc:toluene, 1:3) to yield the title compound (385 mg, 64% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:5]=[C:6]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C>[CH3:23][O:22][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([N:14]([CH3:26])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: COC(OC)c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(OC)c1cc(N(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To tert-butyl 3-(dimethoxymethyl)-5-(trifluoromethyl)phenylcarbamate (125 mg, 0.37 mmol) in DMF (5 ml) at 0° C., sodium hydride (22 mg, 0.56 mmol) was added. After stirring at rt for 0.5 h, methyl iodide (263 mg, 1.85 mmol) was added and stirred overnight at rt. Reaction mixture was then cooled, quenched with methanol, extracted with ether. Organic layer was dried and evaporated and the crude residue was column purified (10% ethylacetate/90% hexanes) to yield 110 mg of tert-butyl 3-(dimethoxymethyl)-5-(trifluoromethyl)phenyl(methyl)carbamate.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][CH2:3]1>CCO.[OH-].[OH-].[Pd+2]>[OH:1][C:2]1([CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NCCC1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC1(O)CCNCC1
Reaction time: 12 h
Yield: 100.4 %

Procedure:
A solution of 1,1-dimethylethyl {2-[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]ethyl}carbamate (3.2 g, 9.5 mmol) and Pd(OH)2 (1.92 g, 60 wt %) in EtOH (50 mL) was hydrogenated using a Parr Shaker under 50 psi. After 12 h, the solution was filtered through Celite® and concentrated yielding the title compound (2.33 g, quant.) as a yellow oil: LCMS (ES) m/e 245 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH:7]=1)=[O:5].CO.[BH4-].[Na+].[NH3:33]>>[CH2:21]([N:18]1[CH2:17][CH2:16][CH:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH:4]([OH:5])[C:3]([NH2:33])=[O:2])=[CH:7]2)[CH2:20][CH2:19]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(=O)c1cn(C2CCN(Cc3ccccc3)CC2)c2ccccc12
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)C(O)c1cn(C2CCN(Cc3ccccc3)CC2)c2ccccc12
Yield: 103 %

Procedure:
Dissolve [1-(1-benzylpiperidin-4-yl)-1H-indol-3-yl]oxoacetic acid methyl ester (1.29 g, 3.43 mmol) in 2 M ammonia: methanol (35 mL) and stir at room temperature under nitrogen for 1.5 hours. Concentrate to a white solid and slurry into absolute ethanol (40 mL). Add sodium borohydride (0.65 g, 5 equiv) and stir 3 hours at room temperature under nitrogen. Concentrate then dilute with ethyl acetate and quench with water. Wash organic layer with brine. Dry over magnesium sulfate, filter and concentrate to give crude product (1.28 g, 103%). MS (ES, m/z): 364.2 (M+1).
Reaction SMILES: OC1C=C(C=C(O[C@@H](C)CO)C=1)C(OC)=O.[N:17]1([C:21]([C:23]2[CH:57]=[CH:56][C:26]([O:27][C:28]3[CH:29]=[C:30]([CH:41]=[C:42]([O:44][C@@H:45]([CH3:55])[CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:43]=3)[C:31]([NH:33][C:34]3[CH:39]=[N:38][C:37]([CH3:40])=[CH:36][N:35]=3)=[O:32])=[C:25](F)[CH:24]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1.[Cl:59]C1C=C(C=CC=1F)C(N1CCC1)=O>>[N:17]1([C:21]([C:23]2[CH:57]=[CH:56][C:26]([O:27][C:28]3[CH:29]=[C:30]([CH:41]=[C:42]([O:44][C@@H:45]([CH3:55])[CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH:43]=3)[C:31]([NH:33][C:34]3[CH:39]=[N:38][C:37]([CH3:40])=[CH:36][N:35]=3)=[O:32])=[C:25]([Cl:59])[CH:24]=2)=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Agent: COC(=O)c1cc(O)cc(O[C@@H](C)CO)c1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1

Procedure:
3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide was prepared from methyl 3-hydroxy-5-[(1S)-2-hydroxy-1-methylethoxy]benzoate in an analogous fashion to 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide but replacing 1-(3,4-difluorobenzoyl)azetidine with 1-(3-chloro-4-fluorobenzoyl)azetidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:31]=[CH:32][CH:33]=2)O1>C(OCC)(=O)C.CCCCCC>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:29]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1cccc(OC2CCNc3ncc(-c4cccc(N5CCOCC5)c4)cc32)c1
Yield: 49 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]morpholine (23.9 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow foam (49% yield). LCMS: m/z=422.18 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00-2.11 (m, 1H), 2.22-2.26 (m, 1H), 3.19 (t, J=4.8 Hz, 4H), 3.40-3.45 (m, 1H), 3.58-3.64 (m, 1H), 3.88 (t, J=4.8 Hz, 4H), 5.14 (bs, 1H), 5.37 (t, J=1.0 Hz, 1H), 6.82-6.92 (m, 2H), 6.92 (s, 1H), 6.95-7.02 (m, 2H), 7.03-7.08 (m, 1H), 7.20-7.33 (m, 2H), 7.55 (d, J=1.9 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[O:21][CH3:22])=[CH:11][C:10]([C:23](O)=[O:24])=[C:9]2[CH3:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][CH2:28][NH:27][C:23]([C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[N:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]=1[CH3:26])=[O:24]
Reactant: NCCCO
Reactant: COc1ccc(OC)c(-c2cc(C(=O)O)c(C)n2CC2CCCCC2)c1
Product: COc1ccc(OC)c(-c2cc(C(=O)NCCCO)c(C)n2CC2CCCCC2)c1

Procedure:
The coupling reaction between 1-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid and 3-amino-propan-1-ol was similar to the reaction exemplified in the synthesis of Example 49 to give 1-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid (3-hydroxy-propyl)-amide; MS (ISP) 415.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][N:3]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][N:3]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(O)c1cnc(Cl)nc1
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: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2ncc(C(C)(C)O)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of 2-(2-chloropyrimidin-5-yl)propan-2-ol (30 mg, 0.17 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under nitrogen. The mixture was stirred at room temperature for 1 hour. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.125 mmol) in EtOH (2 mL) was added, followed by addition of satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for 2 h. The reaction was quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (21 mg, yield 25%). LC-MS Method 2 tR=0.98 min, m/z=512, 490, 472, 432; 1H NMR (CD3OD): δ 1.02 (s, 3H), 1.13 (s, 3H), 1.50 (d, 3H), 1.61 (s, 6H), 2.02 (s, 1H), 2.18 (m, 5H), 2.30 (m, 1H), 2.75 (m, 1H), 5.66 (m, 1H), 7.00 (m, 2H), 7.20-7.33 (m, 5H), 8.10 (m, 2H), 8.92 (s, 2H).
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>CO.C(OCC)(=O)C>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH3:1][C@@H:2]([O:6][C:7]1[NH:8][C:9]([NH2:24])=[C:10]2[C:14]([N:15]=1)=[N:13][C:12]([O:22][CH3:23])=[N:11]2)[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.6 %

Procedure:
To a solution of 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (4.8 g, 14.31 mmol) in methanol (100 ml) was added trifluoroacetic acid (8 ml, 104 mmol). The reaction mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo to give a pale yellow solid which was suspended in ethyl acetate (30 ml). The precipitate was filtered off and washed with further ethyl acetate until the filtrate was colourless. The remaining solid was dried by air and then in vacuo to give the title compound as a cream solid (3.85 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C[O:41]CC1>>[CH3:1][C:2]1([CH3:27])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:26])[CH:13]([OH:41])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: C1CCOC1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COc1cc(C(O)C(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C

Procedure:
The 1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (184.1 mg, 0.5 mmol) dissolved in THF (3 mL) is added dropwise to a stirring cold (−78° C.) solution of NaHMDS (0.6 mL, 1.0M in THF) in THF (3 mL). The resulting reaction mixture is stirred for 30 minutes before (+/−)-camphoryl-sulfonyloxaziridine (187 mg, 0.75 mmol) in THF (3 mL) is added dropwise. After 15 minutes the reaction mixture is quenched with sat. NH4I (aqueous) solution (3 mL) and diluted with diethyl ether. The mixture is allowed to warm up to room temperature. The aqueous layer is extracted with diethyl ether. Combined organic layers are washed with water, brine, dried over sodium sulfate, filtered, and concentrated. Crude 1-(2,2-dimethyl-2H-chromen-6-yl)-2-hydroxy-2-(3,4,5-trimethoxy-phenyl)-ethanone is purified using silica gel chromatography.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: COc1cccc(C=O)c1
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cccc(CN2CCC(O)C2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a mixture of pyrrolidin-3-ol (3.8 g, 44 mmol) and 3-methoxybenzaldehyde (5.0 g, 37 mmol) in 1,2-dichloroethane (100 mL), was added sodium triacetoxyborohydride (15.5 g, 73 mmol) portionwise at 0° C. Acetic acid (2.8 mL, 44 mmol) was subsequently added. The reaction mixture was warmed to 45° C. and stirred overnight. A saturated solution of sodium bicarbonate was added and the resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product, 1-(3-methoxybenzyl)pyrrolidin-3-ol, obtained (6.0 g, 79%) as a yellow oil, was used as such in the next reaction: 1H NMR (CDCl3, 400 MHz) δ 7.28-7.18 (m, 1H), 6.92-6.86 (m, 2H), 6.82-6.76 (m, 1H), 4.32 (tdd, J=2.3, 5.0, 7.3 Hz, 1H), 3.83-3.78 (m, 3H), 3.59 (s, 2H), 2.86 (dt, J=4.9, 8.6 Hz, 1H), 2.68 (d, J=9.8 Hz, 1H), 2.53 (dd, J=5.3, 10.3 Hz, 1H), 2.45 (br s, 1H), 2.30 (dt, J=6.5, 8.9 Hz, 1H), 2.24-2.13 (m, 1H), 1.78-1.68 (m, 1H); ESI MS (m/z) 208 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][CH2:10][C:11]1[O:15][C:14]([C:16]2[N:17]=[C:18]([N:21]=[C:22]([NH2:24])[NH2:23])[S:19][CH:20]=2)=[CH:13][CH:12]=1>CN(C)C=O>[NH2:23][C:22](=[N:21][C:18]1[S:19][CH:20]=[C:16]([C:14]2[O:15][C:11]([CH2:10][NH:9][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[CH:12][CH:13]=2)[N:17]=1)[NH2:24]
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: O=C(Cl)c1ccco1
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2ccc(CNC(=O)c3ccco3)o2)cs1
Yield: 17.9 %

Procedure:
2-Furoyl chloride (0.48 g) was added slowly to a solution of 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (0.80 g) in N,N-dimethylformamide (20 ml) with cooling on an ice bath and the mixture was stirred for an hour with cooling on an ice bath. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (30:1, (V/V). Recrystallization from methanol afforded 2-(diaminomethyleneamino)-4-[5-(2-furoyl)aminomethylfuran-2-yl]thiazole (0.20 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[C:43](=[O:44])[N:42]2[CH2:45][C@@H:39]([CH2:40][C@H:41]2[C:46]([O:48]C)=[O:47])[O:38][C:22]2=[N:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:50][C@H:14]2[O:13][C:12](=[O:51])[NH:11]1.O.[OH-].[Li+].C(O)(=O)C.O>CO.C1COCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[C:43](=[O:44])[N:42]2[CH2:45][C@@H:39]([CH2:40][C@H:41]2[C:46]([OH:48])=[O:47])[O:38][C:22]2=[N:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]([O:31][CH2:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])=[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:50][C@H:14]2[O:13][C:12](=[O:51])[NH:11]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OCCCN(C)C)O2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCCOc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)O)N(C1)C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCCC2
Temperature: 25 °C
Yield: 104.7 %

Procedure:
A solution of the product of step 6 (210 mg, 0.300 mmol) in MeOH (3005 μl), THF (1502 μl) and eater (1502 μl) was treated with lithium hydroxide monohydrate (63.0 mg, 1.502 mmol). The reaction mixture was stirred at room temperature. After 5 hour the reaction was quenched by addition of acetic acid (172 μl, 3.00 mmol) and water (10 mL). The mixture was extracted into dichloromethane (2×10 mL) and ethyl acetate (10 mL). The combined organic extracts were dried over magnesium sulfate filtered and concentrated in rotavap to give the title compound (215 mg, 0.314 mmol, 104% yield) as a white powder. No further purification was carried out for the product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:13]([N:4]1[CH:5]=[C:6]([O:9][CH3:10])[C:7](=[O:8])[C:2]([Cl:1])=[N:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cnnc(Cl)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cn(Cc2ccccc2)nc(Cl)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 126.8 %

Procedure:
3-Chloro-5-methoxypyridazin-4-ol (10.0 g) was dissolved in DMF (300 mL), sodium hydride (3.26 g, 55 wt %) and tetrabutylammonium iodide (4.60 g) were added thereto at 0° C., and the mixture was stirred at the same temperature for 10 min. To the reaction mixture was added benzyl bromide (12.3 g) at 0° C., and the mixture was stirred at room temperature for 20 hr. The reaction mixture was diluted with water, and the mixture was extracted with dichloromethane. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was recrystallized from ethyl acetate/hexane to give the title compound (19.8 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30].O.C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:28][C:29](=[O:30])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(OCC(=O)c2ccccc2)cc1
Yield: 98.6 %

Procedure:
To a solution of [3-(4-hydroxy-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mmol), K2CO3 (33 mg, 0.24 mmol) and tetrabutylammonium iodide (6.7 mg, 0.018 mmol) in DMF (2 mL) was added 2-bromoacetophenone (39.6 mg, 0.2 mmol). After 14 h the reaction mixture was poured into a water/ethyl acetate bilayer. The organic phase was concentrated and {3-[4-(2-oxo-2-phenyl-ethoxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (70 mg, 98%) was isolated from the resulting residue was purified by column chromatography.