Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])=[O:24])=[C:18]([Cl:34])[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].[CH3:43][NH:44][CH2:45][CH2:46][OH:47].O>CN(C)C=O>[Cl:34][C:18]1[CH:17]=[C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:44]([CH2:45][CH2:46][OH:47])[CH3:43])=[C:6]([O:35][CH3:36])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)[CH:21]=[CH:20][C:19]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCBr
Reactant: CNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCN(C)CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A starting compound (N-(4-{[7-(2-bromoethoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-(2,4-difluorophenyl)urea, 50 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 48 mg (yield 97%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]([C:7]1[S:11][C:10]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=2[CH:8]=1)(O)[CH2:4][CH3:5])[CH3:2].[C:19]1([CH3:26])[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][CH:20]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([C:3]([C:7]1[S:11][C:10]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=2[CH:8]=1)([C:21]1[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([CH3:26])[CH:20]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1cc2ccc(C(=O)O)cc2s1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2ccc(C(=O)O)cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A solution of 2-(1-ethyl-1-hydroxy-propyl)-benzo[b]thiophene-6-carboxylic acid (3.80 g, 14.4 mmol) and o-cresol (1.94 g, 18.0 mmol) in CH2Cl2 (100 mL) at −40° C. is added BF3-Et2O (1.02 g, 7.20 mol). After stirring for 10 min, the reaction mixture is allowed to warm up to 0° C. over 30 min. The reaction is quenched with water (15 mL) and the aqueous layer is extracted with EtOAc (50 mL). The organic layer is dried over Na2SO4, concentrated, and purified by silica gel column chromatography (2% HOAc in 50% EtOAc/Hex) to give the product (3.98 g, 78%).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][OH:9].[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:14]([CH2:24][CH3:25])[CH:13]=1)#[N:11]>CO>[CH2:24]([C:14]1[CH:13]=[C:12]([C:10](=[NH:11])[NH:8][OH:9])[CH:17]=[C:16]([CH3:18])[C:15]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH3:25]
Reactant: CCc1cc(C#N)cc(C)c1CCC(=O)O
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCc1cc(C(=N)NO)cc(C)c1CCC(=O)O
Yield: 81.1 %

Procedure:
Potassium tert.butoxide (2.71 g, 24.1 mmol) is carefully dissolved in methanol (25 mL). To this solution hydroxylamine hydrochloride (1.44 g, 20.7 mmol) followed by 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid (1.50 g, 6.90 mmol) dissolved in methanol (7.5 mL) is added. The mixture is refluxed for 8 h and the solvent is evaporated. The residue is dissolved in 2 N aq. HCl and extracted with EA. The pH of the aq. phase is adjusted to pH 5 by adding sat. aq. NaHCO3 and the mixture is extracted three times with EA. The combined organic extracts are dried over Na2SO4, filtered, evaporated and dried to give 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid (1.4 g) as a white solid; LC-MS: tR=0.60 min, [M+1]+=251.17.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the method of Example 56. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, d, 1H, J=3.6 Hz), 7.39 (d, 1H, J=5.2 Hz), 7.17 (d, 2H, J=8.4 Hz), 7.08 (dd, 1H, J=5.2, 3.6 Hz), 7.00 (q, 1H, J=9.5 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.78 (ddd, 1H, J=11.6, 6.4, 2.8 Hz), 6.65-6.60 (m, 1H), 4.18 (t, 2H, J=6.4 Hz), 3.22 and 3.12 (d of ABq, 2H, J=13.6 Hz), 2.98 (t, 2H, J=6.4 Hz), 2.37 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[S:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:24][N:23]=2)=[CH:17][CH:16]=1)([O-])=O.[Sn](Cl)Cl.O>CN(C=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[S:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:24][N:23]=2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2c1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-(4-(6-nitroquinolin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine (228 mg, 455 μmol) in 1 mL of DMF, was added tin (II) chloride (431 mg, 2273 μmol) and 115 uL of water. After 15 minutes of sonication, the reaction was stirred at rt. After 2 days, water was removed under vacuum azeotropically with benzene. DCM was added to the suspension. Yellow solids precipitated out of the solution and were filtered off with DCM. The filtrate was concentrated and purified by RPLC on an acidic Gilson column system. Fractions containing the product were washed with sat. NaHCO3. The product was extracted with DCM. The organic was washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified further by performing a column chromatography using 60:40 DCM:(90:10:1 DCM:MeOH:NH4OH). Yellow solid, N-(4-(6-aminoquinolin-4-ylthio)phenyl)-4-phenylphthalazin-1-amine was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(Nc3cccc(F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-fluoroaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=24%). MS ISP (m/e): 390.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.10 (s very broad, 2H), 7.70-7.50 (m, 2H), 7.45 (t, 2H), 7.39 (s, 1H), 7.30-7.10 (m, 4H), 7.02 (s, 1H), 6.63 (t broad, 1H), 6.30 (t, 2H), 3.62 (s, 3H), 2.14 (s broad, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:10][CH:8]2[CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]3[S:13][CH:12]=[CH:11][C:7]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: CCN1CCc2sccc2C(O)C1
Product: CCN1CCc2sccc2C(Oc2cccc(Br)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 6-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 45) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)nc1
Product: O=Cc1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43c (1.20 g, 6.44 mmol) and phenylboronic acid (1.18 g, 9.65 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (10:1) as eluent. Light yellow solid. Yield: 1.10 g, 94%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=7.44-7.52 ppm (m, 3H), 7.87 (d, J=8.2 Hz, 1H), 8.04-8.08 (m, 2H), 8.20 (dd, J=8.2, 2.2 Hz, 1H), 9.10 (dd, J=2.2, 0.6 Hz, 1H), 10.11 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=120.5, 127.5, 129.0, 129.8, 130.4, 136.5, 138.0, 152.4, 162.2, 190.4; MS (ESI): m/z=184.31 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:17]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.N>O1CCCC1>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(N)c(C(N)=O)cc1OC
Temperature: 7.5 °C
Yield: 60.3 %

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 2-amino-4,5-dimethoxybenzoic acid (20 g, 101.43 mmol, 1.00 equiv), tetrahydrofuran (400 mL), EDC.HCl (39 g, 203.44 mmol, 2.01 equiv) and HOBt (27.5 g, 203.52 mmol, 2.01 equiv). This was followed by the addition of 4-methylmorpholine (20.6 g, 203.96 mmol, 2.01 equiv) dropwise with stirring at 5-10° C. To this was added ammonia (30 mL) dropwise with stirring at 5-10° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 300 mL of ethyl acetate. The resulting mixture was washed with 1×300 mL of brine. The aqueous layer was extracted with 5×100 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 12 g (crude, 61.2% yield) of 2-amino-4,5-dimethoxybenzamide as a yellow solid. MS (ESI) m/z 197 [M+H]+
Reaction SMILES: [O-][CH2:2]C.[Na+].[N:5]1[CH:10]=[C:9]([CH2:11][C:12]2[C:13](=[O:19])[NH:14][C:15](=[S:18])[NH:16][CH:17]=2)[CH:8]=[N:7][CH:6]=1.CI>CCO>[CH3:2][S:18][C:15]1[NH:16][CH:17]=[C:12]([CH2:11][C:9]2[CH:10]=[N:5][CH:6]=[N:7][CH:8]=2)[C:13](=[O:19])[N:14]=1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
Into a stirred solution of sodium ethoxide (157.7 mg, 2.32 mmol, 2 eq) in EtOH (5.2 ml) was added 5-pyrimidin-5-ylmethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (270 mg, 1.22 mmol, 1 eq) at rt. After 30 min, the reaction mixture was treated with methyl iodide (190.7 μl, 3.05 mmol, 2.5 eq) and was stirred at rt overnight. Solvent was evaporated and water (1 ml) was added. pH was adjusted ˜4 with 1N HCl and precipitate was formed to give 2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (196 mg, yield=62.4%, purity=91%). [M+H]+=235.28. 1H NMR (300 MHz; CDCl3) δ/ppm 2.45 (s, 3H), 3.62 (s, 2H), 3.50 (s, 2H), 7.89 (s, 1H), 8.69 (s, 2H), 9.00 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([N:22](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(Cl)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2ccc(Cl)nc2)n1
Reaction time: 24 h
Yield: 98.7 %

Procedure:
A solution of 4-(2-(6-chloropyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (70 mg, 0.126 mmol) in TFA (10 mL) was heated to 80° C. After 24 h, the mixture was concentrated to a slurry. Water (5 mL) was added, followed by the addition of Na2CO3 in batches until the pH was basic. The mixture was filtered and the solid was washed with water, then MeOH, to give the product as a brown solid (39 mg). LCMS (ES, pos.): calcd for C14H12ClN7: 313.1; found: 314.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.16 (s, 1H); 8.87 (d, J=2.74 Hz, 1H); 8.82 (dd, J=7.83, 1.76 Hz, 1H); 8.48 (dd, J=8.80, 2.74 Hz, 1H); 8.39 (dd, J=4.50, 1.76 Hz, 1H); 7.92 (br. s., 1H); 7.78 (br. s., 1H); 7.46 (d, J=8.61 Hz, 1H); 7.01 (dd, J=7.83, 4.70 Hz, 1H); 2.44 (s, 3H).
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[CH:12][C:11]=1N.[I:21]I>C(Cl)(Cl)Cl>[I:21][C:11]1[C:10]([CH3:9])=[CH:15][C:14]([C:16]([F:19])([F:18])[F:17])=[N:13][CH:12]=1
Reactant: Cc1cc(C(F)(F)F)ncc1N
Reactant: II
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(F)F)ncc1I
Reaction time: 0.08 h

Procedure:
Isoamyl nitrite (96%, 59 μL, 49.9 mg, 0.426 mmol) was added to a solution of 4-methyl-6-(trifluoromethyl)pyridin-3-amine (50.0 mg, 0.284 mmol) and iodine (79.2 mg, 0.312 mmol) in CHCl3 (1 mL) at room temperature under N2. The solution was stirred for 5 min then heated at reflux for 2 h. The reaction mixture was diluted with CHCl3, washed with saturated Na2SO3, dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 1-5% EtOAc in hexanes gradient) to afford 5-iodo-4-methyl-2-(trifluoromethyl)pyridine. Rf=0.77 (10% EtOAc/hexanes). LCMS calc.=288.0; found=288.0 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 8.96 (s, 1H); 7.54 (s, 1H); 2.50 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[OH:23])[CH3:8].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[CH2:7]([O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH2:21][CH3:22])[CH:15]=[CH:14][C:13]=1[O:23][CH:25]([CH3:27])[CH3:26])[CH3:8]
Reactant: CC(C)I
Reactant: CCOCOc1ccc(O)c(OCOCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCOc1ccc(OC(C)C)c(OCOCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.4 %

Procedure:
Potassium carbonate (2.85 g, 20.7 mmol) was added to 3a (500 mg, 2.07 mmol) in N,N-dimethylformamide (4.10 mL) at room temperature. After 10 minutes, 2-iodopropane (2.06 mL, 20.7 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×20 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 5:1→1:1 Hexane:EtOAc) to afford 4c as a yellow oil (0.32 g, 55%): 1H NMR (CD2Cl2, 400 MHz) δ 6.87 (s, 1H), 6.86 (d, J=4.9 Hz, 1H), 6.66 (dd, J=11.6, 3.4 Hz, 1H), 5.23 (s, 2H), 5.17 (s, 2H), 4.44-4.38 (m, 1H), 3.83-3.72 (m, 4H), 1.33 (s, 3H), 1.31 (s, 3H), 1.27-1.23 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 152.4, 149.1, 143.2, 118.6, 109.5, 107.5, 94.4, 93.9, 72.8, 64.3, 64.1, 22.2 (2C), 15.1, 15.1; IR (film) νmax 2976, 1591, 1504, 1528, 1391, 1258, 1217, 1107, 1011, 847 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C15H24O5, 285.1702. found, 285.1746; [M+Na]+ calcd for C15H24O5, 307.1522. found, 307.1310.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[N:7][C:6]2[O:9][CH2:10][CH2:11][S:12][C:5]=2[CH:4]=1)=C.I([O-])(=O)(=O)=[O:14].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[N:7]1[C:6]2[O:9][CH2:10][CH2:11][S:12][C:5]=2[CH:4]=[C:3]([CH:1]=[O:14])[N:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c(nn1)OCCS2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cc2c(nn1)OCCS2
Temperature: 25 °C
Yield: 35.9 %

Procedure:
A solution of 3-ethenyl-6,7-dihydro[1,4]oxathiino[2,3-c]pyridazine (320 mg) in 1,4-dioxane/water (20 ml/5 ml) was treated with an aqueous solution of osmium tetroxide (4% w/v, 2 ml) and sodium periodate (1.08 g), initially stirred in an ice-bath, then allowed to warm to room temperature. After 2.5 hours the mixture was evaporated to dryness and dissolved in 1,4-dioxane and chloroform. Silica gel was added and the mixture was evaporated to dryness, added to a silica column (50 g) and chromatographed, eluting with 0-100% ethyl acetate in hexane, to afford a white solid (116 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][Si](C)(C)N[Si](C)(C)C.[K].IC.[Cl-].[NH4+]>CN(C=O)C>[CH2:18]([C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:25][CH3:26])=[N:12][N:11]=1)[CH3:27]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: [Cl-]
Agent: [K]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Reaction time: 1 h
Yield: 1.3 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.00 g, 2.85 mmol) in DMF (10 mL) was added potassium hexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) at ambient temperature and the resulting mixture was stirred for 1 h. After addition of iodomethane (0.20 mL, 3.13 mmol) the reaction mixture was stirred for 20 h at this temperature. Further potassium hexamethyldisilazane (0.91 M in tetrahydrofuran, 3.44 mL, 3.13 mmol) and iodomethane (0.20 mL, 3.13 mmol) were added and stirring was continued for another 1.5 h. The reaction mixture was poured onto aqueous ammonium chloride (saturated, 50 mL) and was extracted with ethyl acetate. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 0:80:20) afforded the title compound (14 mg, 1%) as a white solid. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=5)[NH:24][CH:23]=4)[O:12][C:8]3=2)[N:3]=1.C=O.[C:35]([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:35][N:17]([CH2:16][CH:13]1[O:12][C:8]2=[C:9]3[C:4](=[CH:5][CH:6]=[C:7]2[O:15][CH2:14]1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=2)[NH:24][CH:23]=1
Reactant: [BH3-]C#N
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCCCCc1c[nH]c2ccc(C#N)cc12)O3
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN(C)CCCCc1c[nH]c2ccc(C#N)cc12)O3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2S)-3-{4-[(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amino]-butyl}-1H-indole-5-carbonitrile (0.13 g, 0.30 mmol) and formaldehyde (37 wt. % in water, 0.24 g, 3.0 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.35 g, 0.54 mmol) and acetic acid (0.035 mL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen for 4 hours, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.11 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 155° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([O:11][CH3:12])[CH:10]=1)[NH:7][C:6](=[O:13])[C:5]2=[O:14].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:26](O)[CH2:27][OH:28]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([O:11][CH3:12])[CH:10]=1)[NH:7][C:6](=[O:13])[C:5]12[O:28][CH2:27][CH2:26][O:14]1
Reactant: COc1cc(Br)cc2c1NC(=O)C2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(Br)cc2c1NC(=O)C21OCCO1
Yield: 5 %

Procedure:
A stirred mixture of 5-bromo-7-methoxyindoline-2,3-dione (3.6 g, 14 mmol), p-TSA (1.14 g, 6 mmol) and toluene (100 mL) was refluxed using a Dean-Stark apparatus for 0.2 h. Ethylene glycol (9.3 g, 150 mmol, 10.7 eq.) was added and refluxed using a Dean-Stark apparatus for another 2 hours. The mixture was cooled and concentrated to 20 mL. EtOAc (100 mL) was added, washed with water (20 mL), brine (50 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure. Purified by column (CH2CL2/EtOAc=8:1) to give the desired product as a light brown solid (0.21 g, crude, 5%). 1H NMR (400 MHz, DMSO-d6): δH 10.66 (s, 1H), 7.48 (s, 1H), 7.26-7.27 (m, 1H), 7.13-7.14 (m, 1H), 4.25-4.31 (m, 4H), 3.86 (s, 3H). MS (ESI) m/e [M+1]+ 300/302.