Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: Cc1ccccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 150 °C
Yield: 54.1 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(2-methylphenyl)-3-piperidinecarboxamide (90 mg, 0.209 mmol), 3 mL of EtOH, Hunig's base (0.11 mL, 0.627 mmol), and hydrazine anhydrous (0.026 mL, 0.836 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (50 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 1.73 (m, 1H), 1.91-2.15 (m, 2H), 2.26 (m, 4H), 2.70-2.92 (m, 1H), 3.44 (m, 1H), 3.50-3.84 (m, 1H), 4.30 (d, J=12.6 Hz, 1H), 4.67-5.11 (m, 1H), 6.79-6.95 (m, 1H), 7.09-7.33 (m, 4H), 7.47 (d, J=7.8 Hz, 1H), 7.83 (s, 1H) 7.99 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[C:14]([OH:21])[CH:13]=1.O>C(OCC)(=O)C>[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:10][C:4]3[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=3[N:9]=2)=[C:14]([OH:21])[CH:13]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2nc(-c3ccc(N)cc3O)[nH]c2cc1C
Temperature: 130 °C
Yield: 28 %

Procedure:
To polyphosphoric acid at 130° C. were added 4,5-dimethylbenzene-1,2-diamine (500 mg, 3.67 mmol) and 4-amino-2-hydroxybenzoic acid (562 mg, 3.67 mmol), and the resulting mixture was then heated to 130° C. for 16 h. The solution was then poured into water and the resulting precipitate was dissolved in ethyl acetate and washed with Na2CO3. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 260 mg (28%) of the title compound (LCMS RT=6.14 min, MH+254.1)
Reaction SMILES: C(OC([N:7]([CH2:15][CH:16]([C:18]1([CH3:23])[O:22][CH2:21][CH2:20][O:19]1)[OH:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1>O1CCCC1.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>[CH2:8]([NH:7][CH2:15][CH:16]([C:18]1([CH3:23])[O:19][CH2:20][CH2:21][O:22]1)[OH:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CCOC(=O)N(Cc1ccccc1)CC(O)C1(C)OCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1(C(O)CNCc2ccccc2)OCCO1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2 g) was added to a mixture of 2-[2-(N-allyloxycarbonyl-N-benzylamino)-1-hydroxyethyl]-2-methyl-1,3-dioxolane (10.5 g), triphenylphosphine (0.86 g), and morpholine (3 ml) in tetrahydrofuran (100 ml) at ambient temperature in a stream of nitrogen. The mixture was stirred at the same condition for 2 hours and concentrated under reduced pressure to give a residue. The residue was subjected to a column chromatography on silica gel (150 g) and eluted with a mixture of methanol and chloroform (2:98, and then 5:95, V/V) to give 2-(2-benzylamino-1-hydroxyethyl)-2-methyl-1,3-dioxolane (5.60 g) as a syrup.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 69.8 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (490 mg, 1.53 mmol), 5-fluoro-1,3-dihydro-indol-2-one (219 mg, 1.45 mmol) and piperidine (100 μL, 1.0 mmol) were dissolved in 5 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction mixture was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 5 (460 mg, 69.9%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C1(C)C=CC=CC=1>[CH2:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:28]([NH:27][CH2:25][CH3:26])=[O:29])[S:3][C:4]=2[CH:10]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCN=C=O
Reactant: Nc1nc2ccc(Cc3ccccc3)cc2s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc(Cc3ccccc3)cc2s1
Temperature: 95 °C
Yield: 54.8 %

Procedure:
A suspension of 2-amino-6-benzyl-benzothiazole (0.040 g, 0.17 mmol), triethylamine (0.104 mL, 0.77 mmol, 4.5 eq), and ethyl isocyanate (0.049 mL, 0.64 mmol, 3.8 eq) in 1 mL toluene was heated at about 95° C. for about 16 hours. The precipitate was filtered off, washed with Et2O and MeOH, and dried under vacuum to give the desired compound 0.029 g (56%). LC/MS 312.3 (M+1); LC retention time 2.62 min.
Reaction SMILES: N([O-])=O.[Na+].CC1(C)N([O])C(C)(C)CCC1.CC(O[Na])=[O:18].[F:21][C:22]([F:34])([C:25]([F:33])([F:32])[C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH2:23][OH:24].O=O>C(O)(=O)C>[F:21][C:22]([F:34])([C:25]([F:32])([F:33])[C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[C:23]([OH:18])=[O:24]
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: CC(=O)O[Na]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=N[O-]
Agent: O=O
Solvent: CC(=O)O
Product: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
60 mL of acetic acid, 0.46 g sodium nitrite, TEMPO (0.35 g), CH3CO2Na (6.88 g) and 6.5 g of 2,2,3,3,4,4,5,5-octafluoro-pentan-1-ol were placed in a 100 mL1 glass flask equipped with a balloon containing oxygen, a reflux condenser and a stirrer. The mixture was stirred for 16 hr at 60° C. upon which the mixture was acidified as described in example 17 and extracted with diethyl ether (three times). The combined organic phases were washed with water and dried over magnesium sulfate. The solvent was removed at a rotary evaporator and the residue was distilled to give 3.82 g of acid (20 mmHg, 65° C.). Yield: 55%.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH:12]([C:15]([CH3:17])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>CO.O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:17][C:15](=[O:16])[CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 ml of 15% strength potassium hydroxide solution are added dropwise to 198.4 g (1.6 mol) of freshly distilled 4-fluorobenzaldehyde and 137.6 g (1.6 mol) of methyl isopropyl ketone in 300 ml of methanol and stirred overnight at room temperature. The mixture is then neutralized using 10 ml of acetic acid, 1 l of water is added and the mixture is extracted with two 500 ml portions of ether. The combined organic phases are washed with 500 ml of saturated sodium chloride solution and dried over sodium sulphate. After removing the solvent, the residue is distilled under high vacuum.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.Cl.[NH2:13][C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]1>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH:13][C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:16][CH2:15]1
Reactant: COCc1cccc(C=O)c1
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Product: COCc1cccc(CNC2(C(=O)OC)CC2)c1
Yield: 82 %

Procedure:
Prepared as in Example 12-1b from 3-(methoxymethyl)benzaldehyde (Example 12-14b) and methyl 1-aminocyclopropanecarboxylate hydrochloride. Yield 82%. MS 250 (MH+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=2)[N:32]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[N:31]=1)#[CH:29].CCN(C(C)C)C(C)C.[BH4-].[Na+]>C1COCC1.CCOC(C)=O.CC(N(C)C)=O>[C:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([CH2:39][OH:40])[CH:37]=2)[N:32]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[N:31]=1)#[CH:29]
Reactant: C#Cc1nn(C2CCCCO2)c2ccc(C(=O)O)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#Cc1nn(C2CCCCO2)c2ccc(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
BOP (3.18 g; 7.19 mmol; 1.20 eq.) was added to a solution of 3-ethynyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylic acid (1.97 g; 5.97 mmol; 1.0 eq.) in DIEA (7 mL; 41.2 mmol; 6.9 eq.) and THF (350 mL). After 1 h, DMA (100 mL) was added in one portion followed by sodium borohydride (0.70 g; 18.5 mmol; 3.1 eq.). The reaction mixture was stirred at RT for 20 min, diluted with EtOAc and washed sequentially with 1 N HCl, NaHCO3 (sat) and NaCl (sat) solutions, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (EtOAc: n-heptane, gradient from 10:90 to 50:50) gave the title compound as a clear oil (1.26 g; 78.2%). 1H NMR (300 MHz, DMSO-d6) δ 7.75 (d, J=8.7 Hz, 1H), 7.65 (d, J=0.6 Hz, 1H), 7.43 (dd, J=8.7, 1.5 Hz, 1H), 5.87 (dd, J=9.5, 2.3 Hz, 1H), 5.29 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 4.58 (s, 1H), 3.93-3.82 (m, 1H), 3.80-3.68 (m, 1H), 2.44-2.27 (m, 1H), 2.08-1.91 (m, 2H), 1.83-1.64 (m, 1H), 1.63-1.51 (m, 2H). HPLC (max plot) 95.2%; Rt %2.78 min. UPLC/MS: (MS+) 257.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]([F:48])=[CH:35][C:34]=1[N:49]1[C:61](=[O:62])[C:60]2[S:59][C:58]3[CH2:57][CH2:56][CH2:55][CH2:54][C:53]=3[C:52]=2[CH:51]=[N:50]1)(=[O:30])[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:48][C:36]1[CH:35]=[C:34]([N:49]2[C:61](=[O:62])[C:60]3[S:59][C:58]4[CH2:57][CH2:56][CH2:55][CH2:54][C:53]=4[C:52]=3[CH:51]=[N:50]2)[C:33]([CH2:32][O:31][C:28](=[O:30])[CH3:29])=[C:38]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:37]=1
Reactant: C=CC(=O)N[C@H]1CCCN(c2cccc(Nc3cc(Br)cn(C)c3=O)n2)C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1-n1ncc2c3c(sc2c1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(Nc3cc(-c4cc(F)cc(-n5ncc6c7c(sc6c5=O)CCCC7)c4COC(C)=O)cn(C)c3=O)n2)C1
Temperature: 90 °C
Reaction time: 7 h
Yield: 33.6 %

Procedure:
A mixture of (S)—N-(1-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yl)piperidin-3-yl)acrylamide 114f (127 mg, 0.3 mmol), (4-fluoro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-triene-5-yl}-6-(tetra-methyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 108c (179 mg, 0.36 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol) and K3PO4 (159 mg, 0.75 mmol) in acetonitrile (5 mL) and water (1.0 mL) was stirred at 90° C. under N2 for 7 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-TLC (EA/MeOH=25/1) to give N-[(3S)-1-[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]-3-piperidyl]prop-2-enamide 115a (73 mg, 33%) as yellow solid. MS-ESI: [M+H]+ 724.3
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1.[C:18](OCC)(=[O:21])[NH:19][NH2:20]>C(O)CCC>[CH3:8][C:6]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[N:4][N:3]2[C:18](=[O:21])[NH:19][N:20]=[C:2]2[CH:7]=1
Reactant: CCOC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1cccc([N+](=O)[O-])c1
Solvent: CCCCO
Product: Cc1cc2n[nH]c(=O)n2nc1-c1cccc([N+](=O)[O-])c1

Procedure:
A mixture comprising 7.0 g. of 3-chloro-5-methyl-6-(m-nitrophenyl)-pyridazine (U.S. Pat. No. 4,092,311), 5.8 g. of ethyl carbazate and 60 ml. of butanol is refluxed for 18 hours, then cooled in an ice bath and filtered. The solid is air dried giving 2.96 g. of the desired product as a yellow solid, m.p.>300° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[C:22]2[O:21][CH2:20][C@H:19]([N:23]=CC3C=CC(OC)=CC=3)[CH2:18][C:17]=2[C:16]([O:33][CH3:34])=[CH:15][CH:14]=1.Cl.NO.C([O-])([O-])=O.[Na+].[Na+]>O.CO.C(Cl)Cl>[F:12][C:13]1[C:22]2[O:21][CH2:20][C@H:19]([NH:23][OH:6])[CH2:18][C:17]=2[C:16]([O:33][CH3:34])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C=N[C@H]2COc3c(F)ccc(OC)c3C2)cc1
Agent: Cl
Agent: NO
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(F)c2c1C[C@@H](NO)CO2
Yield: 89 %

Procedure:
3 -Chloroperoxybenzoic acid (85%; 7.6 g, 37.6 mmol) was added in portions to a stirred and cooled solution (+4° C.) of (R)-8-fluoro-5-methoxy-3-[N-(4-methoxybenzylidene)-amino]-3,4-dihydro-2H-1-benzopyran (10.8 g, 34 mmol) and methylene chloride (65 mL). The mixture was stirred over night at room temperature. Precipitated 3-chlorobenzoic acid was filtered off and the clear yellow filtrate was concentrated in vacuo. The oily residue was taken up in a solution of hydroxylamine hydrochloride (2.83 g, 40.8 mmol) and anhydrous methanol (60 mL) and the resulting solution was stirred at room temperature for 2 h. The solvent was evaporated to give a thick orange oil. Water was added to the oil, pH was adjusted to 8-9 with saturated aqueous Na2CO3 and the mixture was washed with ether (3×150 mL). The organic phases were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was flash chromatographed on silica with EtOAc (15 to 50%) in hexane as eluent. The resulting impure product was flash chromatographed a second time on silica with EtOH- CHCl3 (1:99) as eluent to give 6.45 g (89% yield) of the title compound as a colourless crystalline solid. Mp: 111°-113° C. [α]21D =+66.4° (C=1.3; CHCl3). GC-MS (70 eV) M=213 (56%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C@H:15]([NH:17][CH2:18][CH:19]([OH:28])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.CO.CCOCC>[CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C@H:15]([N:17]2[CH2:18][CH:19]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:28][CH:30]2[C:29]([O:33][CH3:34])=[O:32])[CH3:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C=O
Reactant: CCCCNCc1ccc(CC[C@@H](C)NCC(O)COc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCNCc1ccc(CC[C@@H](C)N2CC(COc3ccccc3)OC2C(=O)OC)cc1

Procedure:
387 mg of (RS)-1-[[(R)-3-[α-(butylamino)-p-tolyl]-1-methylpropyl]amino]-3-phenoxy-2-propanol, 102 mg of methyl glyoxylate and 195 mg of p-toluenesulfonic acid monohydrate in 5 ml of benzene were stirred at 20°-25° C. for 6 hours. The mixture was worked up with ether and sodium bicarbonate solution. Chromatography of the crude product on silica gel with ether-methanol gave methyl(2RS,5RS)-3-[(R)-3-[α-(butylamino)-p-tolyl]-1-methylpropyl]-5-phenoxymethyl-2-oxazolidinecarboxylate, [α]D =-9° (c=0,1 in methanol); ε219 =18140, ε270 =1830, ε277 =1430.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:10][C:9]2[N:8](COCC[Si](C)(C)C)[N:7]=[C:6]([C:19]3[N:20](COCC[Si](C)(C)C)[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O>[CH3:1][C:2]1([CH3:41])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CC(=O)N(C)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Temperature: 90 °C
Yield: 42 %

Procedure:
Under an argon atmosphere, to a solution of N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine (100 mg, 0.18 mmol) and triethylamine (75 μl, 0.54 mmol) in chloroform (1.5 ml) was added acetyl chloride (19 μl, 0.27 mmol) at room temperature, and the mixture was stirred for 2 hr. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylacetamide. A solution of the obtained N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylacetamide in N,N-dimethylformamide (1.4 ml) was added to tetrabutylammonium fluoride (1.8 ml, 1.8 mmol) concentrated in advance under reduced pressure. Ethylenediamine (0.7 ml) was added, and the mixture was stirred with heating at 90° C. for 24 hr. After cooling, water and ethyl acetate were added, and the organic layer was separated. Then, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give the title compound (26 mg, yield 42%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 82.9 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, 4-bromonitrobenzene (726 mg, 3.6 mmol) were added. The mixture was heated to reflux for 3 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution and dried with Na2SO4. After evaporation of the solvent the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 5/1); 605 mg (yield 82%) of pure title product were obtained.
Reaction SMILES: CCCCCC.[H-].[K+].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1.[CH:19]([N:22]=[C:23]=[S:24])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][C:23]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([Cl:9])[CH:18]=2)[CH:14]=[CH:15]1)=[S:24])([CH3:21])[CH3:20]
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: CC(C)N=C=S
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)NC(=S)n1ccc2ccc(Cl)cc21
Reaction time: 1 h
Yield: 62.6 %

Procedure:
A stirred slurry of hexane washed potassium hydride (0.56 g, 13.9 mmol) in 25 mL of dry THF was treated portionwise with 6-chloroindole (2.0 g, 13.9 mmol). The mixture was heated at reflux until a clear solution was obtained. A solution of isopropyl isothiocyanate (1.4 g, 13.9 mmol) in 5 mL THF was slowly added and stirring was continued for 1 hour. The solvent was evaporated and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual amber solids were recrystallized from EtOH to provide 2.2 g of the title compound as a cream colored solid, m.p. 92-93° C. (63% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]([N+:26]([O-:28])=[O:27])=[C:22]([CH:25]=1)[NH:23][CH3:24].CNCCNC.C(=O)([O-])[O-].[K+].[K+].N>[Cu](I)I.CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]([N+:26]([O-:28])=[O:27])=[C:22]([NH:23][CH3:24])[CH:25]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 73.3 %

Procedure:
A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (10 g), 5-bromo-N-methyl-2-nitroaniline (9.80 g), N,N′-dimethylethylenediamine (4.76 ml), copper iodide (8.08 g), potassium carbonate (17.59 g) and DMSO (200 ml) was heated at 150° C. for 2 h. The mixture was poured into 28% NH3 solution. The resulting precipitate was collected and washed with IPA. The solid was dissolved in DMSO (100 ml) at 80° C., and allowed to cool to room temperature to give a precipitate. After filtration, the precipitate was washed with IPA and dried to give the title compound (12 g) as a yellow solid.