Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1]C(F)(F)C1C=C(C=CC=1)C=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].[CH:34]1([CH:40](C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:1][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:40][N:24]1[CH2:25][C@@H:26]2[C@@H:19]([NH:18][C:16](=[O:17])[CH:15]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:14]([CH3:33])[CH3:13])[CH2:20][CH2:21][C@@H:22]2[CH2:23]1
Reactant: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Product: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3F)C[C@@H]21)c1ccccc1

Procedure:
The title compound was prepared by substituting 2-fluorobenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.66-8.58 (m, 1H), 7.63 (dd, J=3.1, 7.4, 2H), 7.53 (t, J=7.4, 1H), 7.33 (td, J=2.2, 7.6, 2H), 7.28-7.22 (m, J=7.4, 9.9, 2H), 7.17-7.06 (m, J=8.2, 14.8, 26.9, 2H), 4.34 (dd, J=6.0, 11.5, 1H), 3.75 (d, J=13.6, 0.5H), 3.71-3.62 (m, 1H), 3.57 (d, J=13.6, 0.5H), 3.22 (dd, J=2.2, 10.4, 1H), 3.00 (d, J=6.7, 0.5H), 2.69-2.48 (m, J=23.7, 34.8, 3H), 2.47-2.28 (m, 3.5H), 2.17-2.07 (m, 0.5H), 1.93-1.78 (m, J=6.7, 12.4, 20.1, 1H), 1.78-1.62 (m, 1H), 1.49-1.27 (m, J=10.3, 19.5, 26.3, 1.5H), 1.20 (dd, J=2.9, 6.4, 3H), 0.70 (dd, J=1.4, 6.6, 3H); MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].C([O-])(=[O:46])C.C([OH:50])C.[ClH:51].CCCCCCC>C(OCC)(=O)C>[CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:36][CH2:37]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].[OH2:46].[OH2:50].[OH2:20].[ClH:51]
Reactant: CC(=O)[O-]
Reactant: CCO
Agent: CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a suitable vessel were charged amorphous irinotecan acetate (6.35 g) and ethanol (45 mL). The resulting mixture was heated to reflux (about 70° C.) and remained as a suspension. 2N HCl (5.4 mL) was added to the reaction mixture to adjust the pH to less than 4. N-heptane (25 mL) and ethanol (30 mL) were added to the resulting mixture. The solution was then cooled to 0˜10° C. and stirred at this temperature for 1 hour, and then charged with 200 mL of ethyl acetate in order to perform a solvent swap. The solution was then filtrated and washed with ethyl acetate (50 mL). The solid was dried in vacuum. Due to a lower than expected water content, the solid was heated under high humidity for one hour and then cooled to give irinotecan hydrochloride trihydrate Form I (6.6 g).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=[N:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29].[N:31]#CN.C(O)(C(F)(F)F)=O.BrC#N>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:30]([N:28]1[CH2:27][CH:26]([CH2:25][NH:24][C:17]([C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:13]([CH3:14])[CH2:15][CH3:16])=[O:19])[CH2:29]1)#[N:31]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: N#CN
Agent: CN(C)c1ccncc1
Agent: N#CBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC1CN(C#N)C1

Procedure:
Following general procedure 9, to a stirred solution of the amine (48) (186 mg, 1 equiv.), N-carbobenzyloxy-L-isoleucine (265 mg, 1 equiv.) and EDCI (211 mg, 1.1 equiv.) in CH2Cl2 (5 mL) was added DMAP (61 mg, 0.5 equiv.). The resultant mixture was stirred at rt for 16 h. The mixture was then diluted with EtOAc and washed successively with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 30% EtOAc in hexane to 50% EtOAc in hexane) to afford the desired coupled product. The N-Boc group of the coupled product was then converted to the cyanamide (N—CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 50% EtOAc in hexane) to afford the desired solid benzyl (1S,2S)-1-({[(1-cyano-3-azetidinyl)methyl]amino}carbonyl)-2-methylbutylcarbamate (51).
Reaction SMILES: [OH-:1].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9]CCO)[CH:4]=1.ClCl.[OH2:15]>>[C:9]([OH:15])(=[O:1])[C:5]1[CH:6]=[CH:7][CH:8]=[N:3][CH:4]=1
Reactant: [OH-]
Reactant: O
Reactant: OCCCc1cccnc1
Agent: ClCl
Agent: [Na+]
Product: O=C(O)c1cccnc1
Reaction time: 0.08 h

Procedure:
To a reactor is added 25 ml of 50% aqueous NaOH, sufficient water to bring the volume to 50 ml, and 6.9 g (0.05 mol) of 3-(3-pyridinyl)propanol. The solution is brought to 55° C. and 20 g of cupric hydroxide is added. A pH controller is set to maintain the pH above 10 by the incremental addition of 50% aqueous NaOH. After 5 minutes, chlorine is introduced at approximately 1 g/hr. After 48 hours and about 32 g of chlorine have been added, the reaction mixture is assayed for the appearance of product by high performance liquid chromatography. A yield of 5.96 g of nicotinic acid is obtained. This represents a product yield of 97%. The reaction is illustrated as follows: ##STR9##
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:40])=[C:4]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C:5]([I:34])=[C:6]([C:32]=1[I:33])[C:7]([N:9]([CH2:21][CH:22]([O:28]C(=O)C)[CH2:23][O:24]C(=O)C)[CH2:10][CH:11]([O:17]C(=O)C)[CH2:12][O:13]C(=O)C)=[O:8].[C:41]([O:44][CH:45]([CH2:49][CH2:50][CH2:51][Cl:52])[C:46](Cl)=[O:47])(=[O:43])[CH3:42].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:41]([O:44][CH:45]([CH2:49][CH2:50][CH2:51][Cl:52])[C:46]([NH:1][C:2]1[C:3]([I:40])=[C:4]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C:5]([I:34])=[C:6]([C:32]=1[I:33])[C:7]([N:9]([CH2:21][CH:22]([OH:28])[CH2:23][OH:24])[CH2:10][CH:11]([OH:17])[CH2:12][OH:13])=[O:8])=[O:47])(=[O:43])[CH3:42]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(CC(COC(C)=O)OC(C)=O)CC(COC(C)=O)OC(C)=O)c1I
Reactant: CC(=O)OC(CCCCl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(CCCCl)OC(C)=O)c(I)c(C(=O)N(CC(O)CO)CC(O)CO)c1I
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Amino-3-acetoxymethyl-N,N-bis-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide, 6.85 mmol) was dissolved in dry N,N-dimethylacetamide (10 ml) and the mixture was cooled in an ice-bath. 2-Acetoxy-5-chloropentanoyl chloride (4.36 g, mmol) was then added dropwise. The mixture was stirred at room temperature for 24 h, and then added slowly to aqueous sodium hydrogen carbonate (5%, 600 ml) with efficient stirring. A precepitate was formed and filtered off, redissolved in methylene chloride (250 ml) which was washed with water (6×70 ml), dried Na2SO4) and concentrate in vacuo. The residue was chromatographed on a column of silica gel using heptane/ethyl acetate (3/7) as the eluent Yield: 7.30 g (97%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: O=C=Nc1ccccc1F
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1F)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-fluorophenyl isocyanate (0.139 ml, 1.22 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 146 mg (46.9%) of the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]([CH:28]([CH3:30])[CH3:29])[N:8]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:39]([O:46]S(C(F)(F)F)(=O)=O)([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:31])[C@@H:7]([CH:28]([CH3:30])[CH3:29])[N:8]([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:3])([CH3:4])[CH3:2].[O-:46][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40]
Reactant: CC(C)CCN([C@@H](C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c1ccc2cc(O)ccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCN([C@@H](C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of N-isoamyl-N-(6-hydroxy naphthalene-2-sulfonyl)-D-valine tert-butyl ester (0.18 g, 0.35 mmol) in dichloromethane (10 mL) at 0° C. is added triethylamine (0.099 mL, 0.71 mmol), triflic anhydride (0.089 mL, 0.53 mmol), and 4-dimethylaminopyridine (0.004 g, 0.035 mmol). The reaction is stirred at 0° C. for 1 hour. The solvents are removed in vacuo, and the residue is purified by column chromatography (6% hexanes-ethyl acetate) to afford the title compound (a triflate) as a yellow solid (0.14 g, 68% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[C:12](=[O:31])[NH:13][C:14](=[O:30])[C:15]=3[C:16]3[C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=[CH:25]4)[CH2:21][CH:20]([CH2:28]O)[CH2:19][N:18]5[CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.O>[Br:33][CH2:28][CH:20]1[CH2:21][C:22]2[C:27]3=[C:26]([C:16]([C:15]4[C:14](=[O:30])[NH:13][C:12](=[O:31])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:17][N:18]3[CH2:19]1)[CH:25]=[CH:24][CH:23]=2
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CO)C3)=C1c1c[nH]c2cc(F)ccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CBr)C3)=C1c1c[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 3-(6-fluoro-1H-indol-3-yl)-4-(5-hydroxymethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)pyrrole-2,5-dione (500 mg, 1.2 mmol), carbon tetrabromide (796 mg, 2.4 mmol), and triphenylphosphine (314 mg, 1.2 mmol) in 15 mL of dimethylformamide was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (40 mL). The organic layer was washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC to provide 350 mg (61%) of the title compound.
Reaction SMILES: [C:1]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:5]([O:7][CH2:8][CH3:9])=[O:6])O.O1CCCC1.[H][H]>C(O)C>[CH2:2]([C:1]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(CC(=O)OCC)C(=O)OCC
Yield: 45 %

Procedure:
400 ml of triethyl citrate were hydrogenated at 175° C. and 10 bar together with 1100 ml of tetrahydrofuran and 60 g of catalyst G (4-mm tablets) until the take-up of hydrogen had ceased. The reaction product was freed from ethanol and distilled under reduced pressure, giving 193 g (45%) of triethyl propane-1,2,3-tricarboxylate.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:15]=3)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[F:27][C:28]([CH3:36])([CH2:32][CH2:33][CH2:34][CH3:35])[C:29]([OH:31])=[O:30].[CH:37]1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[F:27][C:28]([CH3:36])([CH2:32][CH2:33][CH2:34][CH2:35][CH3:37])[C:29]([O:31][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:15]=3)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)=[O:30]
Reactant: CCCCCCOc1ccc(-c2ccccc2-c2ccc(O)cc2)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCC(C)(F)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCOc1ccc(-c2ccccc2-c2ccc(OC(=O)C(C)(F)CCCCC)cc2)cc1
Yield: 23.3 %

Procedure:
240 mg (0.7 mmol) of 4-hydroxy-4"-hexyloxyterphenyl, 20 mg (0.7 mmol) of (-)-2-fluoro-2-methylhexanoic acid, 150 mg (0.7 mmol) of N,N'-dicyclohexylcarbodiimide and 10 mg (0.07 mmol) of 4-dimethylaminopyridine were dissolved in 100 ml of dried dichloromethane, which were stirred under reflux for 7 hours. After the completion of the reaction, the precipitate was removed by filtration and then the filtrate was washed with 1 normal hydrochloric acid and further with water, after which the organic phase was dried on anhydrous magnesium sulfate. After the removal of magnesium sulfate by filtration, the filtrate was purified through a column chromatography of silica gel with toluene as a developing solvent and recrystallized from 60 ml of ethanol to obtain 80 mg (yield: 24%) of a white crystal. The thus obtained compound has the aforementioned physical and chemical properties.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([OH:39])[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:51]I>C1COCC1>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:42]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[CH:25]([O:39][CH3:51])[CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of tert-butyl 4-((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(hydroxy)methyl)piperidine-1-carboxylate (62.2 mg, 0.089 mmol) in THF at 0° C. was added sodium hydride (10.7 mg, 0.27 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and methyl iodide (30 μL, 0.5 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with methanol. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in hexanes) to afford the title compound (45.9 mg, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.16 (m, 1H) 1.17-1.29 (m, 2H) 1.43 (s, 9H) 1.58-1.69 (m, 1H) 1.84 (d, J=13.28 Hz, 1H) 2.44-2.58 (m, 2H) 3.04 (s, 3H) 4.04 (d, J=12.45 Hz, 1H) 4.11 (d, J=7.47 Hz, 1H) 4.15 (d, J=7.05 Hz, 1H) 4.20 (s, 3H) 4.68 (d, J=15.77 Hz, 1H) 4.71 (s, 2H) 4.88 (d, J=16.18 Hz, 1H) 7.36 (s, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.57 (d, J=7.88 Hz, 1H) 7.65 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 710.3, Found: 711.6 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH3:2].C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[NH2:10])[CH3:2]
Reactant: CCOc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccccc2C1=O
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 36.6 %

Procedure:
A stirred mixture of 9.2 g (0.03 mole) of 2-(2-ethoxy-4-nitrophenyl)-1H-isoindol-1,3(2H)-dione and 12.8 g (0.23 mole) of iron powder in 50 ml of water was heated at 100° C. During a two hour period 35.1 g (0.58 mole) of glacial acetic acid was added to the hot reaction mixture. After complete addition the mixture was heated at reflux for four hours. The reaction mixture was cooled then made basic by the addition of potassium carbonate. The basic mixture was extracted with 500 ml of methylene chloride. The extract was filtered, and the filtrate extracted with 300 ml of 2N hydrochloric acid. The acidic extract was made basic with cold concentrated ammonium hydroxide. The basic solution was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under the reduced pressure to produce 3.1 g of 3-ethoxy-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)aniline as a solid.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>CO>[CH3:15][N:16]1[CH2:17][CH:18]=[C:19]([C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=3)[NH:11][CH:10]=2)[CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 72 °C
Yield: 46.5 %

Procedure:
A solution of KOH (12 g, 213.21 mmol) in methanol (100 mL) was added to 5-nitro-1H-indole (15 g, 92.04 mmol) in a 250 mL flask. 1-methylpiperidin-4-one (13.7 g, 120.46 mmol) was then added dropwise with stirring, while cooling the reaction to 20° C. The resulting solution was stirred for 4 hours, while the temperature was maintained at 72° C. The reaction mixture was then cooled to 15° C., and the product was precipitated by the addition of water (100 mL). Filtration, followed by recrystallization of the residue from ethanol afforded 11 g (46%) of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole as a yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH3:37][N:38]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[N:39]1.C(N(CC)CC)C>C(#N)C.CO>[CH3:37][N:38]1[CH:42]=[CH:41][C:40]([S:43]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[CH:12]=[C:11]([C:13]4[CH:36]=[CH:35][C:16]5[N:17]([C:20]6[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=6)[CH:18]=[N:19][C:15]=5[CH:14]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)(=[O:45])=[O:44])=[N:39]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1ccc(S(=O)(=O)N2CCC(n3cc(-c4ccc5c(c4)ncn5-c4cccc(NC(=O)NCC(F)(F)F)c4)cn3)CC2)n1

Procedure:
To a solution of N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt (20.0 mg, 0.0385 mmol) in acetonitrile (1 mL) was added 1-methyl-1H-pyrazole-3-sulfonyl chloride (10. mg, 0.058 mmol, Maybridge, Cat. No. CC48303) and triethylamine (16 μL, 0.12 mmol), the solution was stirred at r.t. overnight. The reaction solution was diluted with MeOH and then purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=628.2.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1[CH2:36]COCC1.C(N(CC)CC)C.C(Cl)(Cl)=O.[NH2:48][CH:49]1[CH2:52][CH2:51][CH2:50]1>C1(C)C=CC=CC=1>[CH:49]1([NH:48][C:36]([NH:18][C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][N:26]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:20][CH:19]=2)=[O:31])[CH2:52][CH2:51][CH2:50]1
Reactant: NC1CCC1
Reactant: C1COCCO1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ccncn1)C2
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CCC3)cc2)nc2c1CCN(c1ccncn1)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (0.0700 g, 0.000173 mol) in dry 1,4-Dioxane (1.50 mL, 0.0192 mol) was added Triethylamine (0.0266 mL, 0.000191 mol) followed by 20% Phosgene in toluene (1:4, Phosgene:Toluene, 0.100 mL). The reaction mixture was heated at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and then added aminocyclobutane (0.0892 mL, 0.00104 mol). The reaction mixture was stirred overnight. LC-MS shows mostly product. The reaction mixture was concentrated purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.56 (s, 1H), 8.22 (dd, J=16.1, 7.5, 3H), 7.48 (d, J=8.8, 2H), 6.96 (d, J=6.2, 1H), 6.57 (d, J=7.6, 1H), 4.76 (d, J=18.0, 1H), 4.64 (d, J=18.3, 1H), 4.15 (dt, J=15.6, 7.8, 2H), 4.00 (dd, J=16.4, 8.3, 1H), 3.87 (d, J=11.3, 1H), 3.80-3.57 (m, 5H), 2.75 (s, 2H), 2.20 (dt, J=14.1, 5.0, 2H), 2.10 (ddd, J=10.1, 7.6, 3.6, 1H), 1.93-1.79 (m, 2H), 1.73 (dt, J=11.9, 9.7, 1H), 1.56 (m, 2H), 1.26 (d, J=6.6, 3H). LC/MS-m/z+501.3 (M+H)+