Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9](Cl)(Cl)=[O:10].Cl.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][NH:33][CH2:34]4)=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:37])[N:22]=2)[CH2:17][CH2:16]1>>[NH2:37][C:23]1[N:24]=[C:25]([C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][N:33]([C:9]([N:2]([CH:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH3:1])=[O:10])[CH2:34]3)=[CH:29][CH:28]=2)[CH:26]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]2)[N:22]=1
Reactant: O=C(Cl)Cl
Reactant: CNC1CCCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N(C)C3CCCCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from N-methylcyclohexanamine (Aldrich, Cat. #103322), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=464.5.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:25]2[CH2:26][C@H:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][C@H:24]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])=[O:14])[CH2:9][CH2:10]1)(=[O:4])[CH3:3]
Reactant: CC(=O)N1CCN(CC(=O)O)CC1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: CC(=O)N1CCN(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 24.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-acetylpiperazin-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 115, (2S,4R)-1-(2-(4-acetylpiperazin-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (9.5 mg, 24.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.96 (s, 1H), 7.53-7.60 (m, 2H), 7.25-7.30 (m, 2H), 7.14-7.22 (m, 5H), 6.92-6.99 (m, 4H), 4.67-4.71 (m, 1H), 3.70-3.75 (m, 1H), 3.45-3.50 (m, 1H), 3.23-3.30 (m, 2H), 3.10-3.27 (m, 4H), 2.53-2.62 (m, 3H), 2.37-2.45 (m, 2H), 2.14-2.30 (m, 2H), 1.85-1.99 (m, 2H). MS (EI) for C31H33FN4O4. found 545.6 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].Cl[C:23]1[N:31]=[C:30]([F:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C.[F:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([NH:64][CH:65]([C:67]3[N:68]([C:79]4[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=4)[C:69](=[O:78])[C:70]4[C:75]([CH:76]=3)=[CH:74][CH:73]=[CH:72][C:71]=4[CH3:77])[CH3:66])[N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[CH:51][N:50]=1>CCCCO>[F:32][C:30]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[C:23]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:31]=1.[F:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([NH:64][CH:65]([C:67]3[N:68]([C:79]4[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=4)[C:69](=[O:78])[C:70]4[C:75]([CH:76]=3)=[CH:74][CH:73]=[CH:72][C:71]=4[CH3:77])[CH3:66])[N:55]2[CH:58]2[CH2:63][CH2:62][CH2:61][CH2:60][O:59]2)=[CH:51][N:50]=1
Reactant: Cc1cccc2cc(C(C)N)n(-c3ccccc3)c(=O)c12
Reactant: Fc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: Cc1cccc2cc(C(C)Nc3nc4cnc(F)nc4n3C3CCCCO3)n(-c3ccccc3)c(=O)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2cc([C@H](C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (200 mg, 0.72 mol), 6-chloro-2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (compound 5202) (369 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture was stirred at 120° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the desired product, 3-(1-(2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5203) (167 mg, 47% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].O=S(Cl)[Cl:15]>>[Cl:1][C:2]1[C:3]([I:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1I
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)cc(Cl)c1I
Yield: 98 %

Procedure:
A mixture of 3,5-dichloro-2-iodo-benzoic acid (9.0 g, 28 mmol) and SOCl2 (100 mL) was heated to reflux overnight. The solvent was removed to give crude 3,5-dichloro-2-iodobenzoyl chloride (9.4 g, 98%). 1H NMR (CDCl3): 7.64 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][N:11]([CH2:14][CH:15](Cl)[CH3:16])[CH:12]=[O:13]>>[CH3:10][N:11]([CH2:14][CH:15]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:16])[CH:12]=[O:13]
Reactant: Cc1cccc(C)c1N
Reactant: CC(Cl)CN(C)C=O
Product: Cc1cccc(C)c1NC(C)CN(C)C=O
Yield: 22 %

Procedure:
One proceeds as described in Method C) of Example 14 with the difference that 2,6-dimethyl-aniline and 1-(N-methylformamido)-2-chloro-propane are applied as starting substances. The title compound is obtained with a yield of 22%; b.p.: 155°-165° C./80 Pa, m.p.: 69.5°-72° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][CH:16]=2)O1.Br[C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:29]([N+:40]([O-:42])=[O:41])[CH:28]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C.COCCOC>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])=[C:29]([N+:40]([O-:42])=[O:41])[CH:28]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cncc3ccccc23)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
Water (15 mL), sodium carbonate (4.6 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline (5.1 g), and bis(triphenylphosphine)palladium(II) dichloride (0.24 g) were added to an ethylene glycol dimethyl ether (50 mL) solution of tert-butyl 4-bromo-2-nitrobenzoate (5.0 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-75% hexane/ethyl acetate] to obtain 5.8 g of tert-butyl 4-(isoquinolin-4-yl)-2-nitrobenzoate as a brown oily substance.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:20]#[N:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:8](OCC)=[O:9].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:20]#[N:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:8]([NH:1][NH2:2])=[O:9]
Reactant: CCOC(=O)C(C#N)(CCCCl)c1ccc(F)cc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(CCCCl)(C(=O)NN)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Hydrazine (340 mg) was added to a solution of ethyl 5-chloro-2-cyano-2-(4-fluorophenyl)pentanoate (300 mg) in ethanol (3 mL), and the reaction solution was stirred at room temperature for 40 minutes. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was filtered through a silica gel, and the filtrate was concentrated under reduced pressure to obtain a crude product of 5-chloro-2-cyano-2-(4-fluorophenyl)pentanoic acid hydrazide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]Cl)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:12]Cl.[N+](C1C=C(SSC2C=CC=C([N+]([O-])=O)C=2)C=CC=1)([O-])=O.S(Cl)Cl.[CH:37]([S:39]([C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[CH2:38]>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10][CH:37]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:38][Cl:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=CS(=O)(=O)c1ccc(C)cc1
Reactant: ClCl
Reactant: O=[N+]([O-])c1cccc(SCl)c1
Agent: ClSCl
Agent: O=[N+]([O-])c1cccc(SSc2cccc([N+](=O)[O-])c2)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)C(CCl)Sc2cccc([N+](=O)[O-])c2)cc1

Procedure:
A solution of 0.642 mole of m-nitrobenzenesulfenyl chloride in enough carbon tetrachloride to make 1060 ml was prepared by passing chlorine for 6.5 hours into a solution of 99 g (0.321 mole) of bis(m-nitrophenyl)disulfide in 1 liter of carbon tetrachloride at 45° C. One-quarter of this solution (265 ml, equivalent to 0.161 mole of the sulfenyl chloride) was treated with 29.2 g (0.160 mole) of p-tolyl vinyl sulfone. Upon standing for several weeks crystals separated. Filtration gave 18 g (30%) of crude product m.p. 92°-101°. Recrystallization from 30 ml of ethyl acetate gave pure material m.p. 103.5°-104.5°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:16]2[N:15]=1)[CH3:6].ClCCl.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[N:16]2[N:15]=1)[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Using an ice-acetone bath, 48.6 ml of trifluoroacetic acid (TFA) and 12.1 ml of 70% strength nitric acid are cooled to −10° C, 3.0 g (8.86 mmol) of the compound from example 25A, dissolved in 7 ml of TFA are added dropwise, and the mixture is stirred at 0° C. for 20 hours. The reaction solution is stirred into 400 ml of ice-water and 200 ml of dichloromethane and neutralized using about 200 ml of saturated sodium bicarbonate solution. The aqueous phase is separated off and extracted 3 times with dichloromethane, and the combined organic phases are dried and concentrated. The residue is chromatographed on silica gel using toluene with added ethyl acetate in a gradient from 11 to 60%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[CH:13]=[O:14])[CH3:8]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH:13]=[O:14])[CH3:8]
Reactant: CCOc1cc(C=O)ccc1F
Reactant: Cc1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1-n1cnc(C)c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
4-methylimidazole (244 mg) was added to a DMF (3 mL) solution of 3-ethoxy-4-fluorobenzaldehyde (250 mg) obtained above, and the reaction solution was agitated at 150° C. for 4 hours. The reaction solution was concentrated as it was after the reaction ended, water and ethyl acetate were added to the obtained reaction residue, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 1:4), and 60 mg (18%) of 3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Cl.[CH2:2]([O:4][C@@H:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)[CH2:6][OH:7])[CH3:3].C(N(CC)CC)C.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[N:40]=[C:41]=[O:42].O>C(Cl)Cl>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[NH:40][C:41](=[O:42])[N:17]([CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C@H:5]([O:4][CH2:2][CH3:3])[CH2:6][OH:7])=[CH:14][CH:13]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCc1ccc(C[C@@H](CO)OCC)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(CCc1ccc(C[C@@H](CO)OCC)cc1)C(=O)Nc1ccc(F)cc1F
Reaction time: 8 h
Yield: 60.5 %

Procedure:
(2S)-2-Ethoxy-3-{4-[2-(heptylamino)ethyl]phenyl}propan-1-ol hydrochloride (21 mg, 0.059 mmol) and triethyl amine (0.009 ml, 0.065 mmol) were mixed in DCM. 2,4-Di fluorophenyl isocyanate (9.2 mg, 0.059 mmol) was added. The mixture was stirred overnight. Water was added. The organic phase was washed with brine and dried with magnesium sulfate. The solvent was evaporated in vacuum and an oil mixture was left. Chromatography of the oil mixture on a column (ISOLUTE, SI, 200 mg/1 ml) using DCM and MeOH/DCM (1:99) as eluant gave 17 mg desired product, yield 60%.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH:7]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Br[CH2:37][N:38]1[C:42](=[O:43])[N:41]([CH3:44])[N:40]([CH3:45])[C:39]1=[O:46]>CN(C)C=O>[CH3:3][CH:4]([CH3:35])[CH2:5][C@@H:6]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:7]([CH2:37][N:38]1[C:42](=[O:43])[N:41]([CH3:44])[N:40]([CH3:45])[C:39]1=[O:46])([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: Cn1c(=O)n(CBr)c(=O)n1C
Reactant: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(Cn1c(=O)n(C)n(C)c1=O)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
0.284 g of 60% sodium hydride was added to a stirred ice-cold solution of 3.01 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1,1,2(R)-pentanetricarboxylate in 50 ml of dry dimethylformamide under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 0° and for an additional 1.5 hours at ambient temperature, and again cooled to 0° before the addition of 1.6 g of 4-bromomethyl-1,2-dimethylurazole. The mixture was allowed to return to ambient temperature and was stirred for 3 hours. The volatiles were evaporated under high vacuum and the residue was dissolved in ethyl acetate and washed with 5% aqueous citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography on silica gel using hexane/ether (1:1) followed by ether for the elution. There were obtained 2.464 g of 1,2-dibenzyl 1 -tert.butyl 4-methyl-l-[(1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl) methyl]-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Li+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2cc[nH]c12
Yield: 99.4 %

Procedure:
Methyl 5-bromo-1H-indole-7-carboxylate (5 g, 19.7 mmol) was dissolved in methanol (200 mL) and a solution of lithium hydroxide (0.99 g, 41 mmol) in water (10 mL) was added. The mixture was heated at reflux for 50 hours. The methanol was removed in vacuo and the residue diluted with aqueous hydrochloric acid (2 M). The resulting precipitate was filtered off and dried in a heated vacuum pistol to give the title compound as a beige solid (4.7 g).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH2:11].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)C>C(Cl)Cl>[CH3:23][CH2:22][CH2:21][CH:20]([CH3:25])[CH3:19].[F:8][C:9]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:10]=1[NH:11][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCC(C)C
Product: O=C(Nc1cc([N+](=O)[O-])ccc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
Triethylamine (5.85 ml) was added to a an ice-cooled solution of 2-fluoro-5-nitroaniline (3.9 g) in dry methylene chloride under an argon atmosphere. Benzoyl chloride (4.18 ml) was added gradually. The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between water and methylene chloride, the organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate, filtered and evaporated to dryness to give a sticky solid. Trituration with hot isohexane and diethyl ether gave N-(2-fluoro-5-nitrophenyl)benzamide as a solid (3.2 g, 49%); NMR (CDCl3) 7.26 (dd, 1H), 7.6 (m, 3H), 7.91 (d, 2H), 8.03 (m, 1H), 8.15 (broad s, 1H), 9.48 (dd, 1H); m/s: M+H+ 261.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:35]([O:37]C)=[O:36])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:20][C:19]4[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:35]([OH:37])=[O:36])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])[CH2:20][C:19]4[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCOCC1)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCOCC1)Cc1ccccc1-3
Temperature: 90 °C
Yield: 83 %

Procedure:
Sodium hydroxide (200 μL, 0.2 mmol) was added to a solution of the preceding methyl ester (60 mg, 0.127 mmol) in methanol (1.2 mL) and tetrahydrofuran (1.2 mL) in a microwave vial. The vial was sealed and the contents heated at 90° C. for 10 min in a microwave apparatus, at which time the vial was cooled and additional NaOH was added (200 μL, 0.2 mmol). The solution was heated for another 5 min at 90° C. when LC/MS showed complete hydrolysis of the ester. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a colorless solid (50 mg, 83%). ESI-MS m/z 473 (MH+), 1H NMR (500 MHz, CD3OD) δ 1.24–1.35 (m, 1 H), 1.40–1.55 (m, 2 H), 1.60–1.68 (m, 1 H), 1.77–2.22 (m, 6 H), 2.76 (m, 1 H), 2.88–3.04 (m, 1 H), 3.44–3.51 (m, 1 H), 3.58–3.93 (m, 9 H), 4.47–4.59 (m, 1 H), 4.89 (m, 1 H), 7.31–7.43 (m, 1 H), 7.47 (m, 3 H), 7.72 (m, 1 H), 7.88 (m, 1 H), 8.16 (m, 1 H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[N:20]=[C:21]([CH3:24])[O:22][C:23]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1.C(O)C.C(O)(=O)/C=C/C(O)=O>CS(C)=O>[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:12][CH:13]3[O:14][C:15]4[C:16](=[CH:17][CH:18]=[C:19]5[N:20]=[C:21]([CH3:24])[O:22][C:23]5=4)[O:25][CH2:26]3)[CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)oc4c3O2)cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1nc2ccc3c(c2o1)OC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)CO3
Temperature: 80 °C
Yield: 60.9 %

Procedure:
(8R)-2-Methyl-7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethyl 4-methylbenzenesulfonate (0.45 g, 1.2 mmole) and 4-(4-fluorobenzoyl)piperidine (0.73 g, 3.54 mmole) were combined in 10 mL of DMSO under nitrogen. This solution was heated to 80° C. under nitrogen for 4 hours. After completion, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel using first methylene chloride to remove impurities and then 1% methanol/methylene chloride to elute 0.28 g of the (S)-enantiomer of the title compound. This was recrystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.30 g of pale yellow solid, m.p. 229-230° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.OCCN1C2C(=CC=CC=2)CC(O)C1.Br.[NH:21]([CH2:28][CH2:29]O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:31]([CH:33]1O[CH2:34]1)[Cl:32]>C(O)(C)C.C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:29][CH2:28][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:34][CH:33]1[CH2:31][Cl:32]
Reactant: OCCNc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ClCC1CO1
Agent: Br
Agent: OCCN1CC(O)Cc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cl
Product: ClCCN1c2ccccc2CC1CCl
Reaction time: 4 h

Procedure:
A solution of 184 ml. of phosphorus oxychloride in 180 ml. of chloroform is added dropwise, with stirring, to a solution of 235 g. of 1-(2-hydroxyethyl)-3-hydroxy-1,2,3,4-tetrahydroquinoline (an oil, hydrobromide, m.p. 167°), obtainable by dropwise addition of 2-anilinoethanol to a solution of epichlorohydrin in isopropanol, boiling for 4 hours, evaporating and heating the residue at 160° for 3 hours in diethylaniline/cyclohexanol, in 355 ml. of chloroform. The mixture is boiled for 2 hours more and cooled. Excess phosphorus oxychloride is decomposed by adding 600 ml. of water dropwise. The phases are separated and the aqueous phase is extracted several times with chloroform, washed with water until neutral and evaporated to give 1-(2-chloroethyl)-2-chloromethylindoline hydrochloride, an oil, which is converted directly to the free base, b.p. 132°-135°/0.05 mm.