Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:14])[C:11]=1[O:12][CH3:13])[CH2:5][N:6]=[C:7]=[S:8].[CH:15]([NH:17][NH2:18])=[O:16]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:14])[C:11]=1[O:12][CH3:13])[CH2:5][NH:6][C:7](=[S:8])[NH:18][NH:17][CH:15]=[O:16]
Reactant: COc1c(F)cc(CN=C=S)cc1F
Reactant: NNC=O
Solvent: CCO
Product: COc1c(F)cc(CNC(=S)NNC=O)cc1F
Yield: 104 %

Procedure:
3,5-Difluoro-4-methoxybenzyl isothiocyanate (11.7 g, 25.5 mmole) and formyl hydrazine (1.7 g, 28.7 mole) were refluxed in ethanol (30 ml) for one hour. The reaction was evaporated to dryness, triturated with hexane:ethyl acetate (1:1), filtered, and recrystallized from ethanol-hexane to yield 7.3 g (62%) of crude 4-(3',5'-difluoro-4'-methoxybenzyl)-1-formyl-3-thiosemicarbazide.
Reaction SMILES: CNCCNC.Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[I-:25].[Na+].N>O1CCOCC1.[Cu]I>[C:20]([O:19][C:18](=[O:24])[NH:17][C:14]1([C:11]2[CH:12]=[CH:13][C:8]([I:25])=[CH:9][CH:10]=2)[CH2:16][CH2:15]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Br)cc2)CC1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(I)cc2)CC1

Procedure:
0.43 mL (4 mmol) of N,N′-dimethylethylenediamine is added to a reaction mixture of 0.4 g (2 mmol) of copper (I) iodide, 6.2 g (19.86 mmol) of tert-butyl [1-(4-bromophenyl)-cyclopropyl]carbamate, and 6 g (40 mmol) of sodium iodide in 15 mL of 1,4-dioxane and refluxed for 24 hours under nitrogen. Then the cooled suspension is combined with 30% ammonia solution, poured onto distilled water, and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered, and the solvent is distilled off. Yield: 6.60 g (93% of theory); C14H18INO2 (M=359.20); calc.: molecular ion peak (M+H)+: 360; found: molecular ion peak (M+H)+: 360; Rf value: 0.8 (silica gel, dichloromethane/ethanol (50:1)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:18])=[C:5]([S:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][CH:8]=1>S(O)(C)(=O)=O>[CH3:16][O:15][C:13](=[O:14])[CH2:12][C:11]1[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:18])[C:5]=2[S:9][CH:10]=1
Reactant: COC(=O)CC(=O)CSc1cccc(OC)c1C
Agent: CS(=O)(=O)O
Product: COC(=O)Cc1csc2c(C)c(OC)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Methyl 4-((3-methoxy-2-methylphenyl)sulfanyl)-3-oxobutanoate (3.51 g) was added to MsOH (20 mL) at room temperature. The mixture was stirred at room temperature for 15 min. The mixture was poured into ice-water at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with 1N NaOH and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (3.10 g).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C@H:16]([O:20][CH2:21][CH:22]=[N:23][OH:24])[CH2:17][CH:18]=[CH2:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClN1C(=O)CCC1=O>ClCCl.S([O-])([O-])=O.[Na+].[Na+]>[CH2:7]([O:14][CH2:15][C@@H:16]1[O:20][CH2:21][C:22]2=[N:23][O:24][CH2:19][C@@H:18]2[CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Agent: O=C1CCC(=O)N1Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Reaction time: 3 h

Procedure:
Pyridine (23.1 mL, 286 mmol) was added to a solution of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) (35.6 g, 143 mmol) in dichloromethane (350 mL). N-Chlorosuccinimide (19.4 g, 145 mmol) was added in portions over roughly 2 hours. The reaction was stirred for 3 hours, then diluted with an aqueous solution of sodium sulfite (5 g in 100 mL water). The mixture was stirred for 20 minutes, and the aqueous layer was extracted with dichloromethane; the combined organic layers were washed with water, dried, and concentrated. Purification via silica gel chromatography (Eluent: 1:2 ethyl acetate/hexanes) afforded the product. Yield: 21.2 g, 85.7 mmol, 60%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 4.77 (d, J=13.4 Hz, 1H), 4.55-4.65 (m, 3H), 4.22 (dd, J=13.5, 1.3 Hz, 1H), 3.79 (dd, J=11.7, 8.0 Hz, 1H), 3.69-3.76 (m, 1H), 3.57 (dd, half of ABX pattern, J=10.2, 5.9 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.3 Hz, 1H), 3.40-3.5 (m, 1H), 2.21 (ddd, J=12.9, 6.5, 1.8 Hz, 1H), 1.57 (ddd, J=13, 12, 11 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([N:23]([CH3:38])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:26]=2)[CH:17]=[N:16]3)[CH:10]=[N:9]1)=O)(C)(C)C.Cl.N>O1CCOCC1.C1COCC1>[CH3:38][N:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)[CH:26]=1)[C:18]1[CH:17]=[N:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)[CH:14]=2)[N:19]=1
Reactant: CN1CCN(c2cccc(CN(C)c3cnc4cc(-c5cnn(C(=O)OC(C)(C)C)c5)ccc4n3)c2)CC1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(CN(C)c3cnc4cc(-c5cn[nH]c5)ccc4n3)c2)CC1
Reaction time: 1 h
Yield: 56501.7 %

Procedure:
To a solution of 4-(2-{Methyl-[3-(4-methyl-piperazin-1-yl)-benzyl]-amino}-quinoxalin-6-yl)-pyrazole-1-carboxylic acid tert-butyl ester (0.110 g, 0.000214 mmol) in 1,4-dioxane (1.5 mL), was added HCl in dioxane (1.0 ml) at room temperature. The mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and washed with diethyl ether (5.0 mL) to afford the crude compound (0.075 g). The compound was basified by ammonia in THF and then further purified by preparative TLC to afford the title compound (0.050 g, 54%). The mobile phase used for the Preparative TLC was DCM:Methanol (9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12]3[CH:11]=[CH:10][S:9][C:8]=3[C:7](=O)[C:6]=2[CH:16]=1.Cl[CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.[Mg].BrC(Br)C.[Cl-].[NH4+].FC(F)(F)C(O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][C:12]3[CH:11]=[CH:10][S:9][C:8]=3[C:7](=[C:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:6]=2[CH:16]=1
Reactant: O=C1c2cc(Br)ccc2OCc2ccsc21
Reactant: CN1CCC(Cl)CC1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(=C2c3cc(Br)ccc3OCc3ccsc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
6-Bromo-10H-9-oxa-3-thiabenzo[f]azulen-4-one (21.6 g, 100 mmol) was added to a Grignard reagent prepared from 4-chloro-N-methylpiperidine (20 mL, 150 mmol), a metal magnesium (3.6 g, 150 mmol), dibromoethane (0.1 mL), and THF (200 mL). The reaction mixture was stirred at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the solution to stop the reaction, and a product was then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, the resulting residue was dissolved in dichloromethane (300 mL), trifluoroacetic acid (77 mL, 1.0 mol) was added thereto, and the mixture was stirred overnight. The solvents were distilled off under a reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue. The product was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the resulting residue was then purified by column chromatography (hexane-ethyl acetate=3:2), to give 16.2 g (81%) of the captioned compound.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33]C)=[O:32])=[CH:23]2.O[CH2:43][CH2:44][CH2:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]([CH:30]([CH2:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:43][CH2:44][CH2:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)=[CH:28][CH:27]=2)[C:31]([OH:33])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OCCCNc1ccccn1
Reactant: COC(=O)C(Cc1ccccc1)Cc1cc2cc(O)ccc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccccc1)Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.18 g, 0.7 mmol) was added to a solution of methyl 3-(5-hydoxylindolyl)-2-benzylpropanoate (0.12 g, 0.39 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.07 g, 0.47 mmol), as prepared instep b of Example 1, and tri-n-butylphosphine (0.14 g, 0.7 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated in vacuo and the residue purified by flash chromatography on silica gel (10%-50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.064 g, 38%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (br s, 1H), 7.40 (m, 1H), 7.37 (m, 1H), 7.22 (m, 2H), 7.00 (m, 3H), 6.84 (dd, J=8.9, 2.4 Hz, 1H), 6.54 (m, 1H), 6.40 (d, J=8.4 Hz, 2H), 6.36 (d, J=3.1 Hz, 1H), 4.77 (br s, 1H), 4.40 (m, 1), 4.17 (m, 3H), 3.52 (m, 5H), 3.24 (m, 1), 3.08 (m, 1H), 2.76 (m, 1H), 2.11 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[O:25][CH2:33]3)[C:9]2=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)c1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: COc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1H)-one was obtained (74%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.42-7.27 (m, 10H), 7.16-6.92 (m, 4H), 6.59-6.49 (m, 3H), 6.37 (dd, J=8.4, 2.4 Hz, 1H), 5.02 (d, J=9.0 Hz, 1H), 4.75 (d, J=9.0 Hz, 1H), 3.77 (s, 3H); MS (ES+) m/z 434.3 (M+1), 456.3 (M+23).
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:9]1([CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][N:17]=[C:18]=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:9]1([CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][NH:17][C:18]([N:1]2[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]2=[O:3])=[O:19])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C=NCC(c1ccccc1)c1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Solvent: ClCCl
Product: O=C(NCC(c1ccccc1)c1ccccc1)n1ccc(=O)[nH]c1=O
Yield: 76 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 1, starting from uracil (0.37 g, 3.34 mmol); 1.3 equivalents of 2,2-diphenylethyl isocyanate were used herein. The crude was taken up in dichloromethane; the title compound precipitated and was filtered off. The title compound (0.85 g, 76%) was isolated as white powder. 1H NMR (400 MHz, DMSO-d6): δ 3.97 (dd, J=8, 0, 5.5 Hz, 2H), 4.32 (t, J=7.9 Hz, 1H), 5.78 (d, J=8.4 Hz, 1H), 7.17-7.25 (m, 2H), 7.27-7.39 (m, 8H), 8.19 (d, J=8.4 Hz, 1H), 9.20 (t, J=5.5 Hz, 1H), 11.66 (s, 1H). 13C NMR (101 MHz, DMSO-d6): δ 44.93, 50.61, 103.98, 127.09, 127.18, 128.60, 138.79, 142.58, 142.91 150.27, 151.93, 161.03. MS (ESI) m/z: 334 [M-H]−.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[NH2:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[CH2:17]1>C(Cl)Cl>[C:1]([NH:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(S(C)=O)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
Acetic anhydride (0.173 ml, 1.83 mmol) and pyridine (0.296 ml, 3.67 mmol) were added to a solution of 5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.100 g, 0.367 mmol) in DCM (3 ml). The reaction mixture was stirred for 4 h at r.t. and then evaporated to dryness under vacuum. The residue was purified by PTLC (10% methanol in DCM) to give product as a white solid (0.115 g, 99%). M.p. 143-5° C. MS (m/z): [M+H]+=315.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([N:12]3[CH2:18][C:17]4([CH3:20])[CH2:19][CH:13]3[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16]4)=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][CH2:32][N:1]1[C:9]2[C:4](=[C:5]([C:10]([N:12]3[CH2:18][C:17]4([CH3:20])[CH2:19][CH:13]3[CH2:14][C:15]([CH3:22])([CH3:21])[CH2:16]4)=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH3:31]
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2cccc3[nH]ccc23)C1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2c(C(=O)N3CC4(C)CC3CC(C)(C)C4)cccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
To a solution of (1H-indol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (82 mg, 0.27 mmol) in dry DMF (2 mL) at room temperature under an inert atmosphere of nitrogen was added sodium hydride (17 mg, 0.69 mmol, 60% dispersion in oil), and after stirring for 30 min ethyl bromopropionate (100 mg, 0.55 mmol) was added, and the reaction mixture was stirred for 72 h at 60° C. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3×50 mL). The combined organic phases were dried (MgSO4), filtered, and evaporated in vacuo. The resulting solid was purified by preparative HPLC, dried in vacuo at 50° C. affording 29 mg (27%) of the title compound as a solid. MS-ESI m/z 397; 1H NMR (400 MHz, DMSO) δ 0.88-1.08 (m, 6H), 1.14-1.22 (m, 7H), 1.28-1.29 (m) and 1.58-1.67 (m, 1H), 1.37-1.43 (m, 3H), 1.77-1.81 (m, 1H), 2.32-2.36 (m) and 3.10-3.20 (m, 1H), 2.81 (t, 2H), 3.35 (dd) and 3.75 (dd, 1H), 4.02-4.04 (m) and 4.68-4.70 (m, 1H), 4.11 (q, 2H), 4.46 (t, 2H), 6.44-6.50 (m, 1H), 7.10-7.13 (m, 1H), 7.17-7.26 (m, 2H), 7.38 (d, 1H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1.[OH-].[Na+]>O>[CH3:6][N:7]([CH3:15])[C:8]1[CH:9]=[C:10]([NH:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
Methanesulphonyl chloride (838 mg, 7.35 mmol) was added slowly to a cooled solution (5° C.) of N,N-dimethyl-1,3-phenylenediamine (1.00 g, 7.35 mmol) and sodium hydroxide (5M, 1.5 cm3) in water (10 cm3). The reaction was allowed to warm to room temperature overnight. The mixture was extracted with chloroform (3×15 cm3). The combined extracts were dried over sodium sulphate, filtered and the solvent removed under reduced pressure. Column chromatography (1:20 methanol/dichloromethane) gave the target material as a brown oil (1.24 g, 79%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:26])[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(#N)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:26])[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCC2(CC1)OCCO2
Agent: [Pt]
Solvent: CC#N
Product: Nc1cnc2ccccc2c1NCC1(O)CCC2(CC1)OCCO2
Reaction time: 4 h
Yield: 99.1 %

Procedure:
A mixture of 8-{[(3-nitroquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol (12.0 g, 33.4 mmol) and 5% platinum on carbon (1.2 g) in acetonitrile (120 mL) was hydrogenated at 50 psi (3.5×105 Pa) for 4 hours (h) on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent with dichloromethane and ethanol. The filtrate was concentrated to give 8-{[(3-aminoquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol as a orange solid (10.9 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: NCCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(NCCCCO)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1.09 g (4.65 mmol) of 4-oxoazepane-1-carboxylic acid tert-butyl ester and 864 μl (9.30 mmol) of 4-aminobutan-1-ol were suspended in 40 ml of ethanol, stirred at room temperature for 40 minutes, 532 μl (9.30 mmol) of glacial acetic acid were added, and the mixture was stirred for a further 10 min. Sodium triacetoxyborohydride (1.97 g, 9.30 mmol) was added, and the mixture was stirred at room temperature overnight and evaporated to dryness in vacuo. The residue was taken up in water and extracted 4 times with EA. The organic phase was dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH3:5].Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(N(CC)CC)C>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.[Cu]I.O.CCOC(C)=O>[Br:15][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([C:3]#[C:4][CH3:5])[CH:14]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC#Cc1cncc(Br)c1
Yield: 42.7 %

Procedure:
A solution of trimethyl(prop-1-yn-1-yl)silane (1.7 g, 11.48 mmol), 3,5-dibromopyridine (2.72 g, 11.48 mmol), Pd(PPh3)4 (0.66 g, 0.57 mmol), TBAF (1.0 M solution in THF, 11.48 mL, 11.48 mmol), copper(I) iodide (0.66 g, 3.44 mmol), and triethylamine (5.28 mL, 37.9 mmol) was stirred at rt for 12 h. The reaction mixture was worked up with EtOAc and water, and the crude product was purified by silica gel chromatography eluting with 0-3% EtOAc/Hexanes to give the title compound as a white solid (0.96 g, 42% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.55 (dd, J=12.3, 2.0 Hz, 2H), 7.83 (t, J=1.9 Hz, 1H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:29][C:30]([NH2:34])([CH3:33])[CH2:31][OH:32]>C(Cl)Cl>[OH:32][CH2:31][C:30]([NH:34][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13])([CH3:33])[CH3:29]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(CO)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To an oven dried 250 mL round bottomed flask was weighed quinaldic acid (866 mg, 5.0 mmol). A magnetic stir bar was added and the flask was put under N2 atmosphere. The flask was charged with DCM (50 mL) and cooled to 0° C. in an ice bath. The flask was charged with N-methyl morpholine (720 μL, 7.5 mmol) and isobutlychloroformate (752 μL, 5.75 mmol) via syringe addition. The reaction was allowed to stir at 0° C. for 10 min until the solution became cloudy. At which point 2-methyl-2-aminopropanol (550 uL, 5.75 mmol) was added slowly to the flask via syringe. The reaction mixture was allowed to slowly warm to room temperature. The reaction was quenched after 2 h with 1M HCl solution (30 mL) and transferred to a separatory funnel with DCM (50 mL). The layers were partitioned and the organic phase was washed with H2O (2×30 mL) and brine (1×40 mL). After drying over Na2SO4 and filtration, the mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography eluting with a 1:1 mixture of EtOAc and hexanes to afford N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide as a colorless oil in 91% yield (1.112 g, 4.55 mmol) according to the following reaction
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[I:16]I>CN(C=O)C>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([I:16])=[N:10][NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)c1ccc2cn[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
To a solution of 6-tert-butyl-1H-indazole (1.02 g, 5.84 mmol) in DMF (20 ml) at room temperature was added potassium hydroxide (983 mg, 17.5 mmol) and iodine (2.22 g, 8.76 mmol). The maroon reaction mixture was stirred at room temperature for 1 h then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water, sat LiCl, and sat NaCl, then dried over MgSO4 and concentrated to afford 1.92 g 6-tert-butyl-3-iodo-1H-indazole as a light brown solid.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:26]2[C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:23](=[O:36])[C:22]=2[C:21]([OH:37])=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45]N(C=O)C.C([O-])([O-])=O.[K+].[K+].CI>O>[CH:1]([O:14][C:15]1[C:26]2[C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:23](=[O:36])[C:22]=2[C:21]([O:37][CH3:45])=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(c(O)c3c(ncn3Cc3ccccc3)c2OC(c2ccccc2)c2ccccc2)C(=O)N1Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Reaction time: 16 h
Yield: 73 %

Procedure:
Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione 258 (103 mg, 0.177 mmol, 1 equiv.) was added to a flask containing DMF (4 mL) followed by K2CO3 (122 mg, 0.88 mmol, 5 equiv.). To this was added methyl iodide (MeI, 109 μL, 1.76 mmol, 10 equiv.) under a nitrogen atmosphere and stirred for 16 hours. To the reaction was added water (50 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed several times with water (3×30 mL), saturated NaHCO3 (40 mL), brine solution (30 mL). It was dried over Na2SO4, filtered and concentrated in vacuo and purified by silica gel chromatography using 7/3 Hexanes/Ethyl acetate to obtain 4-benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-methoxy-1H-1,3,6-triaza-s-indacene-5,7-dione 259 (73%, 75 mg, 0.125 mmol). 1H NMR (300 MHz) CDCl3 δ 8.09 (s, 1 H), 7.94 (s, 1 H), 7.88 (s, 1 H), 7.64-7.43 (m, 4 H), 7.41-7.46 (m, 2 H), 7.17-7.43 (m, 10 H), 6.98-7.04 (m, 3 H), 5.56 (s, 2 H), 4.80 (s, 2 H), 3.84 (s, 3 H). MS: 620.1 (M+23). TLC Rf: 0.6 Hexanes/Ethyl acetate (1/1).