Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25]3[N:30]=[CH:31][CH:32]=[CH:33][C:24]4=3)=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:34][C:35]1[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[I:34][C:35]1[CH:40]=[CH:39][C:38]([N:26]2[C:27]3[C:23](=[CH:22][C:21]([C:14]4[C:13]5[C:8]([C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)=[C:20]6[C:15]=4[CH:16]=[CH:17][CH:18]=[CH:19]6)=[CH:9][CH:10]=[CH:11][CH:12]=5)=[CH:29][CH:28]=3)[C:24]3[CH:33]=[CH:32][CH:31]=[N:30][C:25]2=3)=[CH:37][CH:36]=1
Reactant: Ic1ccc(I)cc1
Reactant: c1ccc(-c2c3ccccc3c(-c3ccc4[nH]c5ncccc5c4c3)c3ccccc23)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Ic1ccc(-n2c3ccc(-c4c5ccccc5c(-c5ccccc5)c5ccccc45)cc3c3cccnc32)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
6-(10-phenylanthracen-9-yl)-9H-pyrido[2,3-b]indole (1.76 g, 4.19 mmol), 1,4-diiodobenzene (2.76 g, 8.37 mmol), CuI (319 mg, 1.67 mmol), K3PO4 (1.78 g, 8.37 mmol), trans-1,2-dicyclohexanediamine (0.2 mL, 1.67 mmol) were put in a 250 mL two-neck flask and dissolved in 1,4-dioxane. The solution was refluxed and stirred at 120° C. for 12 hours. After completion of the reaction, the solution was extracted with methylenechloride/H2O and distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of n-hexane and methylenechloride (1:5) and was re-crystallized in a solution of methylene chloride and petroleum ether such that the solid compound was obtained, (1.67 g, yield: 64%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][N:40](C(OC(C)(C)C)=O)[CH:41]=2)O1>C(O)C.C1(C)C=CC=CC=1.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>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:37]3[CH:38]=[N:39][NH:40][CH:41]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C
Reaction time: 60 h

Procedure:
1-Methylethyl((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol) was dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (96 mg, 0.325 mmol, available from Aldrich) and tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90° C. for 22 hours reaction time. The reaction was left to stand at room temperature for 2.5 days. It was refluxed again at 90° C. for 24 hours. A second sample of 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (96 mg, 0.325 mmol) was added to the reaction mixture after this time and heating continued. A third sample of 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (96 mg, 0.325 mmol) was added to the reaction mixture after 102.5 hours reaction time and the mixture was allowed to stir overnight under nitrogen at the same temperature. Another sample of 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (96 mg, 0.325 mmol) was added after 199 hours total reaction time. After 248 hours reaction time the mixture was cooled to room temperature and partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter was extracted 3 more times using EtOAc (3×40 mL). Organic fractions were combined, washed (brine (50 mL), dried (sodium sulfate), filtered and evaporated to dryness to give an orange/brown oil (248 mg). The residue was purified by SP4 on a 25+S silica cartridge using a gradient of 0 to 2.5% 2M methanloic ammonia in ethyl acetate. Product-containing fractions were evaporated to dryness and purified again using MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (18 mg). LCMS (Method C): Rt=0.73, MH+=357
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][CH:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][CH:14]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[CH3:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(C)NC(c2ccc(F)cc2)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)cc(C(C)NC(c2ccc(F)cc2)c2cccc(N)c2)c1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 2.70 g of N-[1-(3,5-dimethoxyphenyl)ethyl]-N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.13 g of nickel chloride hexahydrate and 1.00 g of sodium borohydride were reacted, to obtain 892 mg of isomer A and 546 mg of isomer B of the title compound as pale yellow oils, respectively.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([C:17]1[C:18]([OH:39])=[CH:19][CH:20]=[C:21]2[C:26]=1[O:25][C:24](=[O:27])[C:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:22]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ClC(Cl)(Cl)C(=N)O[C@H:44]1[C@@H:49]2[O:50][C:51](=[O:53])[O:52][C@@H:48]2[C@@H:47]([O:54][CH3:55])[C:46]([CH3:57])([CH3:56])[O:45]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:10]([C:17]1[C:18]([O:39][C@H:44]2[C@@H:49]3[O:50][C:51](=[O:53])[O:52][C@@H:48]3[C@@H:47]([O:54][CH3:55])[C:46]([CH3:57])([CH3:56])[O:45]2)=[CH:19][CH:20]=[C:21]2[C:26]=1[O:25][C:24](=[O:27])[C:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:22]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Reactant: O=C(Nc1cc2ccc(O)c(Cc3ccccc3)c2oc1=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2ccc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2Cc2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.2 %

Procedure:
Boron trifluoride etherate (7.80 μL, 0.062 mmol) was added to 23e (80.0 mg, 0.21 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (299 mg, 0.83 mmol) in anhydrous CH2Cl2 (5.20 mL). After stirring at room temperature for 48 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25e as a colorless foam (47.0 mg, 39%): 1H NMR (CDCl3, 500 MHz) 8.22 (s, 1H), 7.46 (s, 1H), 7.35-7.27 (m, 5H), 7.17-7.06 (m, 5H), 6.86 (d, J=10 Hz, 1H), 6.01 (d, J=10 Hz, 1H), 5.65 (d, J=1.6 Hz, 1H), 5.23 (s, 2H), 5.16 (s, 2H), 4.77-4.70 (m, 1H), 4.10 (s, 1H), 3.50 (s, 3H), 3.28 (s, 1H), 3.16 (d, J=7.4 Hz, 1H), 1.25 (s, 3H), 1.18 (s, 3H); 13C NMR (CDCl3, 125 MHz) 155.1, 153.2 (2C), 153.1, 148.6 (2C), 139.6 (2C), 128.7, 128.6 (2C), 128.4 (2C), 128.3 (2C), 128.3 (2C), 126.5, 126.2, 123.1, 122.4, 121.7, 117.6, 114.9, 111.5, 94.7, 82.8, 67.6, 60.6 (2C), 29.7, 27.6, 21.9; IR (film) νmax 2926, 2854, 2359, 2341, 1811, 1709, 1607, 1522, 1456, 1381, 1366, 1259, 1209, 1171, 1078, 1049, 968, 766, 700 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C33H31NO10, 602.2026; found, 602.2053.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14][C:15](=[O:30])[CH2:16][N:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[C:19]([C:26]([F:29])([F:28])[F:27])=[N:18]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[C:8]1([CH2:7][C@H:6]([NH:14][C:15](=[O:30])[CH2:16][N:17]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[C:19]([C:26]([F:27])([F:28])[F:29])=[N:18]2)[C:2]2[N:1]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[CH:4][N:3]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Reactant: Ic1ccccc1
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N[C@@H](Cc1ccccc1)c1nccn1-c1ccccc1
Temperature: 115 °C

Procedure:
To (S)-N-(1-(1H-imidazol-2-yl)-2-phenylethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide (111 mg, 0.27 mmol) in NMP (0.6 mL) was added iodobenzene (27 μL, 0.24 mmol), Cu2O (1 mg), PEG 3500 (50 mg), 4,7-dimethoxy-1,10-phenanthroline (6 mg) and Cs2CO3 (110 mg, 0.34 mmol). The reaction was heated to 115° C. for 4 hr. After cooling to ambient temperature, the reaction mixture was filtered over a heavy metal scavenging column and eluted with DCM. The solvents were removed in vacuo and the residue purified by RP HPLC to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s), 7.55 (s, 1H), 7.42 (t, 1H), 7.14 (q, 2H), 7.01 (d, 1H), 6.84 (dd, 1H), 4.77-4.71 (m, 1H), 3.08 (d, 1H), 2.36 (s, 1H), 1.62 (d, 2H). MS (m/z) 494.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[OH-].[NH4+:14]>C(OCC)(=O)C>[NH2:14][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([C:11]#[N:12])[C:2]=1[Cl:1]
Reactant: [NH4+]
Reactant: N#Cc1nc(F)c(F)c(F)c1Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)c(F)c(N)c1Cl
Yield: 88.3 %

Procedure:
A solution of 3-chloro-4,5,6-trifluoropicolinonitrile (200 g) in ethyl acetate (EtOAc; 3 L) was cooled to 10° C. To this was slowly added 14% aqueous ammonium hydroxide (NH4OH; 1296 g) keeping the temperature between 18-23° C. The aqueous solution was separated from the organic solution. The organic phase was washed sequentially with a 50/50 solution of aqueous saturated NaCl and water (500 mL) and saturated NaCl solution (250 mL). The organic phase was concentrated under vacuum at 50° C. to about 500 mL volume as the product crystallized out. To this slurry was added heptane (1 L), and the remaining EtOAc was removed under vacuum to give the final slurry. The solids were collected by filtration. This solid was washed with pentane and dried under vacuum to give 4-amino-3-chloro-5,6-difluoropicolinonitrile (173.8 g, 90%, 99.6% purity) as a white crystalline solid: mp 190-191.5° C.; 13C{1H} NMR (101 MHz, DMSO-d6) δ 150.03 (dd, J=232.4, 12.5 Hz, C6), 144.29 (dd, J=11.4, 6.9 Hz, C4), 133.72 (dd, J=257.9, 30.8 Hz, C5), 122.14 (dd, J=19.6, 4.9 Hz, C2), 119.31 (s, C3), 114.25 (s, CN); 19F NMR (376 MHz, DMSO-d6) δ −91.24 (d, J=24.2 Hz), −154.97 (d, J=24.2 Hz); EIMS m/z 189 ([M]+). Anal. Calcd for C6H2ClF2N3: C, 38.02; H, 1.06; N, 22.17. Found: C, 37.91; H, 1.00; 22.02.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([CH:19]=O)[CH:16]=[C:15]2[C:21]#[N:22])=[CH:10][CH:9]=1)=[O:7])[CH3:4].[CH3:23]S(C)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:3]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([CH:19]=[CH2:23])[CH:16]=[C:15]2[C:21]#[N:22])=[CH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: CS(C)=O
Reactant: CCOC(=O)c1ccc(-n2cc(C=O)cc2C#N)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1cc(C#N)n(-c2ccc(C(=O)OCC)cc2)c1
Temperature: 60 °C
Reaction time: 0.83 h

Procedure:
To a solution of dimethylsulfoxide (64 ml) was added sodium hydride (480 mg, 60% oil dispersion) at ambient temperature. The suspension was stirred at 60° C. for 50 minutes to give a clear solution. To the cooled solution was added methyltriphenylphosphonium bromide (4.29 g) at ambient temperature in one portion. The mixture was stirred at ambient temperature for half an hour and at 50° C. for half an hour. The yellow mixture was cooled to ambient temperature and therein 1-(4-ethoxycarbonylphenyl)-4-formylpyrrole-2-carbonitrile (2.68 g) was added in one portion. After stirring at ambient temperature for one and half hours, the mixture was quenched with aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was washed with aqueous hydrochloric acid three times, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted by 20% n-hexane in dichloromethane to yield 1-(4-ethoxycarbonylphenyl)-4-vinylpyrrole-2-carbonitrile (1.80 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH:6]([NH:7][CH2:8]1)[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]2.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C(OCC)C>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:7]1[CH2:8][C:2]2([CH3:1])[CH2:9][CH:6]1[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]2)[CH3:18]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Product: CCOC(=O)CCN1CC2(C)CC1CC(C)(C)C2
Reaction time: 8 h

Procedure:
15.3 g of 1,3,3-trimethyl-6-aza-bicyclo[3,2,1]octane (0.15 mol) are introduced into 50 ml of diethyl ether, and 15.1 g of ethyl acrylate are gradually added thereto while stirring. A clear solution forms with a slight increase in temperature. After standing overnight at room temperature, the ether is distilled off. The oil which remains is distilled in vacuo to give 3-(1,3,3-trimethyl-6-aza-bicyclo[3,2,1]oct-6-yl)-propionic acid ethyl ester, b.p. 77°/0.013 mbar.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>CC#N>[C:9]1([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[NH:1][C:16]2=[O:18])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=c1[nH]c2cccnc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 3-amino-N-phenylpyridin-2-amine from Step B (258 mg, 1.39 mmol) in CH3CN (15 mL) was added triphosgene (413 mg, 1.39 mmol) and the reaction mixture was stirred for 10 min at ambient temperature. The mixture was concentrated in vacuo and the crude solid was quenched with H2O (10 mL) and saturated aqueous NaHCO3 (10 mL). The precipitate was filtered, washed with water and air-dried to yield the title compound as a brown solid, which was of sufficient purity for use in the next step. MS: m/z=212 (M+1).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]([OH:10])=[O:9].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28](Cl)(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=1>O1CCOCC1.O.O1CCOCC1>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:7]([NH:6][S:28]([C:24]1[C:25]([CH3:27])=[CH:26][C:21]([O:20][CH3:19])=[CH:22][C:23]=1[CH3:32])(=[O:30])=[O:29])[C:8]([OH:10])=[O:9])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Sodium bicarbonate (1.5 eq) was added to a suspension of (S)-2-amino-4-tert-butoxy-4-oxobutanoic acid (5.1 mmol, 1.2 eq) in dioxane/water (1:1, 20 ml) and the mixture was stirred for 30 min at room temperature. A solution of 4-methoxy-2,6-dimethylbenzenesulfonic acid chloride (4.3 mmol, 1.0 eq) in dioxane (10 ml) was added and the reaction mixture stirred for 16 h at room temperature. On completion of the reaction the organic solvent was removed under vacuum and the aqueous phase acidified with 10% HCl (eq). Extraction was then performed with DCM and the organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume under vacuum. Yield: 45%.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:15]1[N:16]([CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:27]=1)[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[CH2:11]([C:15]1[N:16]([CH2:28][CH2:29][CH2:30][CH:31]=[O:32])[C:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:27]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2cnc3ccccc3c2n1CCCC=O
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of dimethyl sulfoxide (DMSO, 7.88 g, 101 mmol) in dichloromethane (130 mL) was cooled in a dry ice/acetone bath and stirred. Oxalyl chloride (9.40 g, 74 mmol) was added dropwise, followed by a solution of 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (20.0 g, 67.3 mmol) in dichloromethane (320 mL). After five minutes triethylamine (20.42 g, 202 mmol) was added, and the mixture was allowed to warm to room temperature. After the addition of chloroform (500 mL), the mixture was washed successively with a saturated ammonium chloride solution (200 mL) and a saturated aqueous sodium bicarbonate solution (200 mL), dried over sodium sulfate, filtered, and concentrated to a dark solid. This solid was slurried in diethyl ether until a fine solid resulted. The product was filtered and dried to provide 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (17.9 g) as a light brown solid.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][C@H:27](OS(C)(=O)=O)[CH2:26]2)=[CH:21][CH:20]=1.O>CCCCCC.CS(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][C@@H:27]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:26]2)=[CH:35][CH:36]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(Cl)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: Clc1ccc(CCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
60% sodium hydride (34 mg, 0.87 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (4 ml). After stirring at room temperature for 25 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (152 mg, 0.77 mmol) was added to the obtained suspension. They were stirred at room temperature for 25 minutes and then at 50° C. for 25 minutes. A solution of (S)-1-(4-chlorophenethyl)-3-methanesulfonyloxypyrrolidine (252 mg, 0.83 mmol) in dimethyl sulfoxide (2 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 90 minutes. The reaction liquid was poured into water in ice cooling bath. After the extraction with ethyl acetate, the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (2:1) and then with hexane and ethyl acetate (1:2) as the eluents. The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5-[1-(4-chlorophenethyl) pyrrolidine-3-yl]-5,11-dihydrodibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (44 mg, 14%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:8]=[C:9](F)[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH3:16][CH2:17][O-:18].[Na+]>C(O)C>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:8]=[C:9]([O:18][CH2:17][CH3:16])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1[N+](=O)[O-]
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C(=O)O)c([N+](=O)[O-])c(N)c1F

Procedure:
1.4 g (6.3 mmol) of 2-nitro-3,4,5-trifluoro-benzoic acid was treated with ammonium hydroxide to produce 3-amino-4,5-difluoro-2-nitro-benzoic acid. LCMS: 219 (M+1)+. 1.2 g (5.5 mmol) of 3-amino-4,5-difluoro-2-nitro-benzoic acid was heated with excess 21% NaOEt in ethanol at 90° C. for 6 h to yield 3-amino-5-ethoxy-4-fluoro-2-nitro-benzoic acid. LCMS: 245 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.[NH2:13][OH:14].C(OCC)(=O)C.O>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[N:13][OH:14])[CH3:10]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=NO)c1cc(O)ccc1O
Yield: 91 %

Procedure:
To a solution of 1-(2,5-dihydroxyphenyl)ethanone (10.0 g, 65.73 mmol) in ethanol (200 mL) was added hydroxylamine hydrochloride (13.7 g, 197.2 mmol). After heating to reflux for 16 hours, the solvent was reduced under reduced pressure. Ethyl acetate (200 mL) and water were added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried and concentrated to provide the product (10 g, 91%) as yellow solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][CH:15]([CH3:17])[CH3:16])=[N:9][CH:10]=[N:11]2)=[CH:6][C:5]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:23][S:24][CH2:25][CH2:26][CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[CH:15]([NH:14][C:8]1[C:7]2[C:12](=[CH:13][C:4]([O:3][CH2:27][CH2:26][CH2:25][S:24][CH3:23])=[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=2)[N:11]=[CH:10][N:9]=1)([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1cc2c(NC(C)C)ncnc2cc1O
Reactant: CSCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(NC(C)C)ncnc2cc1OCCCSC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Sodium hydride (60%, 251 mg, 6.3 mmol) is introduced into N,N-dimethylformamide (13 ml), treated in portions with ethyl 7-hydroxy-4-(isopropylamino)quinazoline-6-carboxylate (1 g, 2.98 mmol) and subsequently stirred at room temperature for 30 minutes. After addition of a solution of 3-(methylthio)-1-(tosyloxy)propane (777 mg, 2.98 mmol) in N,N-dimethylformamide (8 ml), the mixture is stirred at 80° C. for one hour. After cooling, the batch is treated with water and ethyl acetate, and the organic phase is separated off and dried over sodium sulphate. The desired product is obtained after removing the solvents and preparative HPLC in 48% yield (548 mg).