Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1COCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: Brc1ccccn1
Reactant: NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCCOc1ccccn1
Yield: 42.8 %

Procedure:
3-Aminopropan-1-ol (0.28 ml, 3.64 mmol) was added to a mixture of NaH 60% dispersion in mineral oil (16 mg, 4.11 mmol) in dry THF (8 ml) at rt. The resulting mixture was heated at reflux for 35 mins and cooled to rt before 2-bromopyridine (0.50 g, 3.16 mmol) was added. The mixture was then refluxed for 2 h 20 mins and stirred at rt for another 17 h before more NaH (127 mg, 3.16 mmol) was added and the mixture heated at reflux for 3 h. The mixture was evaporated to dryness, water was added, and the mixture was acidified to pH5 with 1N HCl and washed with DCM. The aqueous phase was then basified to pH4 and extracted again with DCM. The organic extracts were combined and evaporated to give the title compound (0.206 g, 43%) as an oil. 1H NMR (500 MHz CDCl3): 8.17-8.12 (m, 1H), 7.58-7.53 (m, 1H), 6.67-6.63 (m, 1H), 6.72 (d, 1H), 4.39 (t, 2H), 2.88 (t, 2H), 1.93 (quintet, 2H). 13C NMR (125 MHz CDCl3): 164.1, 147.1, 138.7, 116.8, 111.3, 63.8, 39.5, 33.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]([CH:13]=[O:14])[CH:3]=1.[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15]
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: Nc1cc(C=O)nc(C2CCC2)c1F
Solvent: CC#N
Product: Nc1c(F)c(C2CCC2)nc(C=O)c1Cl
Yield: 0.1 %

Procedure:
Using the procedure for Example 15, 4-amino-6-cyclobutyl-5-fluoropicolinaldehyde (0.5 g, 2.57 mol), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.279 g, 1.416 mol) and CH3CN (26 mL) gave 4-amino-3-chloro-6-cyclobutyl-5-fluoropicolinaldehyde (289 mg, 45.7%) as a red foam: 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 4.77 (d, J=9.4 Hz, 2H), 3.87 (ttdd, J=9.3, 8.3, 2.3, 1.1 Hz, 2H), 2.49 (m, 2H), 2.30 (m, 2H), 2.10 (m, 1H), 1.95 (tddd, J=13.4, 7.1, 3.5, 2.1 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −140.24; 13C NMR (101 MHz, CDCl3) δ 191.04, 149.06, 147.71, 145.14, 142.84, 139.20, 115.84, 35.24, 26.86, 18.62; EIMS m/z 228.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][N:5]([CH2:12][CH2:13][C:14](=O)[CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[CH3:4][N:5]([CH2:12][CH2:13][C:14](=[N:2][OH:3])[CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: CC(=O)CCN(C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(CCN(C)c1ccccc1)=NO
Reaction time: 72 h

Procedure:
Add hydroxylamine hydrochloride (4.9 g=70 mmol) in 20 ml water to a solution of 4-(N-methylanilino)-2-butanone (12.4 g=70 mmol) and sodium carbonate (8.6 g=80 mmol) in 60 ml 50% ethanol. Stir for three days, concentrate and extract with ethyl acetate. Dry, concentrate and recrystallize from ether-hexane to obtain product having a melting point 46°-49° C.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6](C)=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=2[CH:15]=[CH:14]1)(=[O:12])=[O:11].[F:24]C1C=CC(S(N2C3C(=C(C=C)C=CC=3)C=C2)(=O)=O)=CC=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O.O1CCOCC1.O>[F:24][C:7]1[CH:6]=[CH:5][C:4]([S:10]([N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:23])[C:16]=3[CH:15]=[CH:14]2)(=[O:12])=[O:11])=[CH:3][CH:8]=1
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(F)cc1
Reactant: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(C=O)cccc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(F)cc1

Procedure:
The procedure for Intermediate 8 was followed using OsO4 (15 mg, 0.058 mmol), 1-[(4-fluorophenyl)sulfonyl]-4-vinyl-1H-indole (347 mg, 1.15 mmol; Intermediate 12), 2,6-lutidine (268 μL, 2.3 mmol), dioxane (15 mL), sodium periodate (0.984 g, 4.6 mmol) and water (5 mL). The title compound (360 mg, 103%, still some dioxane according to HNMR) was obtained as a black sticky oil. MS (ESI+) for C15H10FNO3S m/z 304 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:22])[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1>CO>[CH3:22][N:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C(=O)c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CO
Product: CN(C(=O)c1ccccc1)[C@@H]1CCNC1

Procedure:
Analogously to Method B, 0.774 g of (R)—N-(1-benzylpyrrolidin-3-yl)-N-methylbenzamide in methanol is used to prepare the title compound. Rf=0.08 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=2.04.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[N:21]=[C:22]2[N:27]([C:28](=[O:38])[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:25][O:24][C:23]2([CH3:40])[CH3:39])=[O:19])(=O)=O.[CH3:41][NH:42][CH3:43]>C(#N)C.O1CCCC1.C(OCC)(=O)C>[CH3:41][N:42]([CH3:43])[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[N:21]=[C:22]2[N:27]([C:28](=[O:38])[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:25][O:24][C:23]2([CH3:39])[CH3:40])=[O:19]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCOS(C)(=O)=O)c(OCc1ccccc1)c2=O
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)CC#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of intermediate 183, 3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynyl methanesulfonate (0.100 g, 0.18 mmol) in acetonitrile (5 ml) was treated at 22° C. with 0.3 ml (0.6 mmol) of a 2 M solution of dimethylamine in tetrahydrofuran and the resulting mixture was stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.080 g (88% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 2.43 (6H, s, 2×NCH3), 3.58 (2H, broad s, CH2), 4.05 (4H, m, 2×CH2), 4.70 (2H, d, J=6.0 Hz, NCH2), 5.30 (2H, s, OCH2), 7.01 (1H, m, aromatic), 7.18 (1H,dd, J=3 Hz and J=9.1 Hz, aromatic), 7.32-7.38 (4H, m, aromatics), 7.50-7.53 (2H, m, aromatics), 7.79 (1H, broad t, NH). HRMS (ESI+) calculated for C29H32FN4O4 [M+H+]: 519.2408; found: 519.2407.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:9][CH:10]=1)=[N+]=[N-].C(OCC)(=O)C.C(N(CC)CC)C.[C:43](=O)([O:49]C(C)(C)C)[O:44][C:45]([CH3:48])([CH3:47])[CH3:46]>ClCCl.[C].[Pd].CCCCCC.C(O)C>[C:45]([O:44][C:43](=[O:49])[NH:1][CH2:4][C:5]1[CH:10]=[N:9][C:8]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[CH:7][CH:6]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reaction time: 0.75 h
Yield: 28.9 %

Procedure:
The 5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine (230 mg, 0.529 mmol) obtained in Example 62 and palladium carbon (46 mg) were added to a mixture of ethyl acetate (15 ml) and ethanol (15 ml). The resulting mixture was stirred for 45 minutes under a hydrogen atmosphere of 1 atmospheric pressure. The reaction mixture was filtered. The filtrate was then concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane (5 ml). To the resulting solution were added triethylamine (70 μl, 0.499 mmol) and di-t-butyl carbonate (174 mg, 0.996 mmol). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography, and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (78 mg, 0.153 mmol, 37%) as a colorless amorphous substance.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:11])[NH2:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:1]1(=[N:10][N:9]([CH3:11])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: CN(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CN(C)N=C1CCCCC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 87.4 %

Procedure:
To solution of cyclohexanone (2.00 g, 20.4 mmol) and N,N-dimethylhydrazine (1.50 ml, 20.4 mmol) in ethanol (20 ml) was added a catalytic amount of toluene-4-sulfonic acid monohydrate. The reaction mixture was stirred at 70° C. for 72 h. The solvent was evaporated, and the residue was purified by Kugelrohr distillation (60-80° C., 5 mbar) to give the title compound (2.50 g, 87%) as colorless oil. MS m/e: 141 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:37](=[O:38])[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH:29]([CH3:30])[CH3:31])=[CH:41][CH:40]=3)[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(OC(C)C)cc3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-isopropoxy-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-isopropoxybenzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown oil. MS m/e: 575.2 [M+H]+.
Reaction SMILES: CC(OC1C([N+]([O-])=O)=CC=CC=1)=O.[CH3:14][CH2:15][C:16]1[C:25]2[CH2:26][N:27]3[C:32](=[O:33])[C:31]4[CH2:34][O:35][C:36]([C@:38]([OH:41])([CH2:39][CH3:40])[C:30]=4[CH:29]=[C:28]3[C:24]=2[N:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([O:42]C(N1CCC(N3CCCCC3)CC1)=O)[CH:20]=[CH:21]2)=[O:37].C1N(CCO)CCN(CCS(O)(=O)=O)C1>>[CH3:14][CH2:15][C:16]1[C:25]2[CH2:26][N:27]3[C:32](=[O:33])[C:31]4[CH2:34][O:35][C:36]([C@:38]([OH:41])([CH2:39][CH3:40])[C:30]=4[CH:29]=[C:28]3[C:24]=2[N:23]=[C:22]2[C:17]=1[CH:18]=[C:19]([OH:42])[CH:20]=[CH:21]2)=[O:37]
Reactant: CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: CC(=O)Oc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Product: CCc1c2c(nc3ccc(O)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Reaction time: 0.5 h

Procedure:
CE activity was determined by the spectrophotometric method described above for rabbit CE samples using o-NPA as a substrate. In another assay, activation of CPT-11 was determined by incubating samples of hiCE with either 5 μM or 25 μM CPT-11 in a total volume of 200 μl of 50 mM Hepes pH 7.4 at 37° C. for up to 20 hours. Reactions were terminated by the addition of an equal volume of cold acidified methanol, followed by centrifugation at 100,000×g for 30 minutes. The levels of SN-38 produced in the reaction were quantitated by HPLC.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[CH:15][C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[CH3:17]COC(C)=O.CCCCCC>CS(C)=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:8]2[CH2:17][C@H:9]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 0.05 h
Yield: 46.7 %

Procedure:
To a vigorously stirring mixture of (CH3)3S(I)O (7.76 g, 35.3 mmol) in DMSO (75 mL) was added NaH (0.972 g, 36.5 mmol) in small portions over 5 min. Following complete addition, the reaction was left to stir for 10 min before the rapid dropwise addition of ethyl trans-4-bromocinnamate (2.21 mL, 11.8 mmol), which is commercially available from, for example, Sigma-Aldrich. After 3 h the reaction was partitioned between EtOAc (100 mL) and H2O (200 mL). The aq. phase washed with EtOAc (2×75 mL) wherein the combined organics were washed with H2O (2×50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting solid was absorbed onto Celite® and subjected to flash chromatography (SiO2—40 g; gradient elution: 5% EtOAc/Hexane isocratic for 3 min then 5-30% EtOAc/Hexane over 20 min at 40 mL/min to afford 1.48 g 13Ai as a white solid (46.7% yield). 1H NMR (500 MHz, CDCl3) δ 7.46-7.33 (m, 2H), 6.97 (d, J=8.6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 2.47 (ddd, J=9.2, 6.4, 4.3 Hz, 1H), 1.86 (ddd, J=8.5, 5.4, 4.2 Hz, 1H), 1.59 (dt, J=9.5, 4.8 Hz, 1H), 1.35-1.18 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=2[CH2:21][CH3:22])=[C:4]([F:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35])=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>C1COCC1>[CH2:21]([C:8]1[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:10][CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([NH:1][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)=[O:38])=[CH:3][C:4]=1[F:25])[CH3:22]
Reactant: CCc1c(Oc2ccc(N)cc2F)ccnc1NC(=O)OC(C)(C)C
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1c(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccnc1NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared from tert-butyl 4-(4-amino-2-fluorophenoxy)-3-ethylpyridin-2-ylcarbamate (20 mg, 0.058 mmol) and 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (232 μL, 0.070 mmol) in THF in the same manner as Step D of Example 33. MS(ESI+): m/z 527.31 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([NH:18][CH:16]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])[N:23]=[CH:22][N:21]=1
Reactant: C[C@H](N)c1nc2cccnc2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
A mixture of (S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (0.194 g, 0.81 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.176 g, 1.14 mmol) and DIPEA (0.26 mL, 1.47 mol) in IPA (2 mL) was stirred at 90° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-10% MeOH in EtOAc) to give 302 as a white solid (0.190 g, 66%). LCMS (method K): Rt 3.01 min, [M+H]+ 357. 1H NMR (DMSO-d6): δ 8.25 (1H, dd, J=4.76, 1.48 Hz), 8.12 (1H, dd, J=7.98, 1.48 Hz), 7.87 (1H, s), 7.72 (1H, d, J=7.21 Hz), 7.53-7.52 (4H, m), 7.32 (1H, dd, J=7.99, 4.77 Hz), 7.19 (2H, s), 5.51 (1H, m, J=6.98 Hz), 1.52 (3H, d, J=6.84 Hz)
Reaction SMILES: C(OC1C=CC(C(OC)=O)=CC=1CC=C)(=O)C.C(OC1C=CC(C(OC)=O)=CC=1CC=C(C)C)(=O)C.COCOCOC.COCCl.CCN(C(C)C)C(C)C.NC1C=CC=CC=1.[H][H].[CH3:66][O:67][C:68]1[CH:69]=[C:70]([O:79]COC)[C:71]([CH3:78])=[C:72]([O:74]COC)[CH:73]=1>CN(C)C=O.O1CCCC1.[Pd]>[CH3:66][O:67][C:68]1[CH:69]=[C:70]([OH:79])[C:71]([CH3:78])=[C:72]([OH:74])[CH:73]=1
Reactant: [H][H]
Reactant: COCOc1cc(OC)cc(OCOC)c1C
Agent: [Pd]
Agent: C=CCc1cc(C(=O)OC)ccc1OC(C)=O
Agent: COC(=O)c1ccc(OC(C)=O)c(CC=C(C)C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(O)c(C)c(O)c1

Procedure:
The preparation of intermediate 6 is described and illustrated below. The coumarin phenol 7 was converted to the methoxymethyl ether using methoxymethyl chloride and Hunig's base in Dimethylformamide. The free aniline, liberated through hydrogenolysis with 10% Pd/C and hydrogen in tetrahydrofuran from 7, was coupled with acid chloride 9 to give benzamide 10. Subsequent cleavage of the methoxymethyl ether with 4N hydrochloride in dioxane provided phenol 6 in high yield.
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][C:4](=[N:8][OH:9])[C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:21][CH3:22])(=O)=O>CC(C)=O>[CH2:21]([O:9][N:8]=[C:4]([CH2:3][C:2]([CH3:1])=[CH2:10])[C:5](=[O:7])[CH3:6])[CH3:22]
Reactant: C=C(C)CC(=NO)C(C)=O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(C)CC(=NOCC)C(C)=O
Temperature: 23 °C
Reaction time: 2 h

Procedure:
285.7 g of 5-methylhex-5-ene-2,3-dione 3-oxime from Example 1 were dissolved in 750 ml of acetone and admixed with 335.8 g of potassium carbonate. 362 g of diethyl sulfate in 300 ml of acetone were then added dropwise, and the mixture was stirred at 23° C. for 2 hours. The solvent was then removed under reduced pressure, the residue was taken up in methyl tert-butyl ether/water and the aqueous phase was extracted repeatedly with methyl tert-butyl ether. The combined organic phases were washed with 15% strength ammonia solution and water and dried over sodium sulfate, and the solvent was removed under reduced pressure. This gave 355.4 g of the title compound as a yellow oil.
Reaction SMILES: Cl.Cl[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([CH:11]([CH3:13])[CH3:12])=[N:5][N:4]=1.[CH3:14][NH:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:16])[C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([CH:11]([CH3:13])[CH3:12])=[N:5][N:4]=1
Reactant: CNC
Reactant: CC(C)c1nnc(Cl)n(C)c1=O
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)c1nnc(N(C)C)n(C)c1=O
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
30.0 g (0.15 mole) of 3-chloro-6-isopropyl-4-methyl-1,2,4-triazin-5(4H)-one hydrochloride are suspended in 60 ml of toluene. With gentle cooling, a solution of 20.4 g (0.45 mole) of dimethylamine in 80 ml of toluene is run into the above still just stirrable mixture at about 30° C. over 2 minutes. The cooling is removed and the reaction mixture exotherms to 50° C. The reaction is complete after stirring for 15 minutes. The mixture is thoroughly stirred in 50 ml of cold water and the organic phase is separated, dried over magnesium sulfate and evaporated to dryness, affording a pale beige-coloured, clear oil in quantitative yield. Distillation yields 21.4 g (72.8%) of 3-dimethylamino-6-isopropyl-4-methyl-1,2,4-triazin-5(4H)-one as a clear, colourless oil with b.p. 135° C./0.04 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)=[C:5]2[CH2:19][CH2:20][N:21]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:37]([N:21]([CH2:20][CH2:19][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:46]([N:45]([CH3:49])[CH3:44])=[O:47])[CH:3]=2)[NH:7][C:6]=1[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of N-{4-[4-({2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}benzylamino)butyl]phenyl}methanesulfonamide (15 mg in 1.5 mL of dry methylene chloride) at 0° C. was added dimethylcarbamyl chloride (0.03 mL of a 10% v/v solution in methylene chloride) and diisopropylethylamine (0.053 mL of a 10% v/v solution in methylene chloride) and the mixture warmed to room temperature. After 3 days the reaction was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:1) to give the title compound (17 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48](O)=[O:49].C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:63]([CH3:66])([O-:65])=[O:64].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48](=[O:49])[CH2:66][N+:63]([O-:65])=[O:64]
Reactant: O=C(O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: C[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a anhydrous THF (22 mL) solution of the carboxylic acid 55 (2.97 g, 4.28 mmol) was added 1,1′-carbonyl diimidazole (800 mg, 4.93 mmol) at room temperature. In separate flask, nitromethane (0.92 mL, 17.12 mmol) was added to a THF (9 mL) solution of NaH (200 mg, 4.93 mmol). The resulting white suspension was stirred at room temperature for 3 h. Then the prepared acyl imidazole solution was added to the suspension through a cannula at room temperature. After the transfer, the mixture was heated to 50° C. for 1.5 h. It was cooled to room temperature and quenched with 1.0 M HCl. The organic layer was extracted with ethyl acetate, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography to provide the titled compound (3.13 g, 99%).