Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[N:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33].[NH:44]1[CH2:49][CH2:48][CH:47]([N:50]2[CH2:56][CH2:55][C:54]3[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=3[NH:52][C:51]2=[O:61])[CH2:46][CH2:45]1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[N:24][N:25]=[C:20]2[C@H:19]([NH:31][C:32]([N:44]2[CH2:45][CH2:46][CH:47]([N:50]3[CH2:56][CH2:55][C:54]4[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=4[NH:52][C:51]3=[O:61])[CH2:48][CH2:49]2)=[O:33])[CH2:18][CH2:17]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 60 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
Triethylamine (50 μL, 0.358 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (60 mg, 0.143 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.25 mmol) in tetrahydrofuran (3 mL) at 0° C. After 25 min, the hydrochloride salt of 3-piperidin-4-yl-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one (40 mg, 0.143 mmol) and dichloromethane (3 mL) were added and the mixture was heated to 60° C. After 16 h, the reaction mixture was allowed to cool to ambient temperature and concentrated. Purification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (53 mg). MS 618.2572 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>O1CCOCC1>[CH3:22][N:23]([CH3:24])[S:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3](=[O:4])[C:2]([F:20])([F:19])[F:1])[CH2:6]2)=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A mixture of 2-trifluoroacetyl-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (400 mg, 1.22 mmol, J. Med. Chem. 1980, 23, 837), dimethylamine hydrochloride (150 mg, 1.83 mmol), and triethylamine (0.50 mL, 3.66 mmol) in dioxane (10 mL) was refluxed with stirring for 30 min, cooled to room temperature, concentrated, and purified by flash column chromatography (10→50% ethyl acetate/hexanes) to give 337 mg (82%) of the title compound of Example 247, Step A as a yellow oil. 1H NMR (CDCl3, 300 MHz, 9:5 mixture of rotamers) δ7.67-7.52 (c, 2H), 7.36 (t, 1H), 4.87 (s, 1.3H), 4.81 (s, 0.7H), 3.96-3.86 (c, 2H), 3.08-3.02 (d, 2H), 2.72 (s, 6H); MS (TS) 337 (MH+).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([F:10])[C:5]([O:8][CH3:9])(F)F.[CH2:11]([Mg]Br)[CH3:12].C([O:17]CC)C>>[F:10]/[C:4](=[CH:3]\[CH2:2][CH2:11][CH3:12])/[C:5]([O:8][CH3:9])=[O:17]
Reactant: CCOCC
Reactant: CC[Mg]Br
Reactant: COC(F)(F)C(F)=CCBr
Product: CCC/C=C(\F)C(=O)OC
Yield: 48 %

Procedure:
1.0 g (4.5 mmol) of 4-bromo-1-methoxy-1,1,2-trifluoro-2-butene was treated with ethylmagnesium bromide (3M, 1.6 mL, 4.8 mmol) in diethyl ether according to the same procedure as Example 4 to give 0.29 g (48%) of methyl (Z)-2-fluoro-2-hexenoate. 1H-NMR (300 MHz, CDCl3): δ 0.92(3H, t), 1.46(2H, q), 2.20(2H, dq, J=2, 8 Hz), 3.80(3H, a), 6.11(1H, dt, J=8, 33Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([C:21]1[CH:22]=[C:23]2[NH:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:24]2=[N:25][CH:26]=1)([F:20])[CH3:19].Cl[CH2:33][C:34](Cl)=[O:35].CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[N:11]([CH2:33][C:34]([N:29]2[C:23]3[C:24](=[N:25][CH:26]=[C:21]([C:18]([F:20])([F:17])[CH3:19])[CH:22]=3)[C:27]([CH3:31])([CH3:30])[CH2:28]2)=[O:35])[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Reactant: CC(F)(F)c1cnc2c(c1)NCC2(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(C(C)(F)F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Yield: 60.9 %

Procedure:
The title compound was prepared following methods similar to those described in Preparation 203 starting from (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.74 g, 7.5 mmol), 6-(1,1-difluoro-ethyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (1.1 g, 5.0 mmol), chloroacetyl chloride (490 μL, 6.1 mmol) and DIPEA (3 mL, 16.6 mmol) to give the title compound (1.47 g) as an orange semi-solid. MS: [M+H]+=483.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[C:5]([OH:16])[CH:4]=1.[CH2:17](O)[CH3:18]>>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:17][CH3:18])=[O:12])=[O:8])=[C:5]([OH:16])[CH:4]=1
Reactant: CCO
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1O
Agent: Cl
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1O

Procedure:
Hydrogen chloride was bubbled into a gently boiling solution of 3-(4-chloro-2-hydroxybenzoyl)propionic acid (12.0 g, 0.053 mole) in dry ethanol (21.2 cc) until esterification was complete. The product crystallised from ether to give ethyl 3-(4-chloro-2-hydroxybenzoyl)-propionate (13.29 g, 98% m.p. 68°-69° ) (Found: C, 56.07; H, 5.06; Cl, 13.69; M+, 256/258. C12H13ClO4 requires: C, 56.15; H, 5.10; Cl, 13.81%; M, 256/258).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-:44]>O>[F:44]/[C:2](/[C:19]1[CH:24]=[N:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[CH:1]\[N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2
Reactant: COc1ccc(Br)cn1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: COc1ccc(/C(F)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 80 °C

Procedure:
5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (285 mg, 0.00127 mol) and 5-bromo-2-methoxy-pyridine (200 mg, 0.001063 mol), dichlorobistriphenylphosphine palladium (II) (20 mg, 0.0000285 mol) and TBAF.3H2O (1 g, 0.00317 mol) were charged in a microwave tube. The reaction mixture was heated at 80° C. for 5 min in microwave. It was then cooled to RT. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (100 mL) and the compound extracted with EtOAc (3×30 mL). The combined organic layers were washed with water, dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified on neutral alumina (Eluent: 0-20%, Hexane/EtOAc). 2 mg of pure product was obtained as a liquid. 1H NMR (CDCl3, free base) δ (ppm): 8.22 (s, 1H), 7.92 (d, 1H), 7.36 (d, 1H), 7.20 (s, 1H), 7.04 (d, 1H), 6.80 (d, 1H), 5.70 (d, 1H), 3.68 (s, 2H), 3.92 (m, 2H), 3.88 (m, 2H), 2.60 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:5])[CH3:4].F[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[C:20]([Cl:32])[CH:19]=1)=[N:10][CH:11]=[N:12]2>>[NH2:1][CH2:2][C@H:3]([CH3:4])[O:5][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[C:20]([Cl:32])[CH:19]=1)=[N:10][CH:11]=[N:12]2
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: C[C@H](O)CN
Product: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 46 %

Procedure:
The procedure described in Example 1 (preparation of starting materials) was repeated using (S)-(+)-1-amino-2-propanol and 5-fluoro-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine in 46% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.96 (m, 2H), 4.79 (m, 1H), 5.28 (s, 2H), 7.17 (d, 1H), 7.21 (d, 1H), 7.29 (d, 1H), 7.35 (m, 1H), 7.56 (d, 1H), 7.64 (dd, 1H), 7.70 (t, 1H), 7.86 (dt, 1H), 8.20 (d, 1H), 8.48 (s, 1H), 8.58 (d, 1H), 10.60 (bs, 1H); Mass Spectrum MH+ 435.
Reaction SMILES: [F:1]C1C=C2C(C(C=O)=CN2)=CC=1.C(O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31])C=C>>[F:1][C:25]1[CH:24]=[C:23]2[C:19]([C:20]([N:29]=[C:30]=[O:31])=[CH:21][N:22]2[C:26]([NH2:28])=[O:27])=[CH:18][CH:17]=1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Product: NC(=O)n1cc(N=C=O)c2ccc(F)cc21

Procedure:
was prepared from 6-fluoro-1H-indole-3-carbaldehyde [2795-41-7] using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].C([O-])([O-])=[O:14].[K+].[K+].C(N)(N)=O.OO.C(Cl)Cl>CC(C)=O.O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]([NH2:6])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: NC(N)=O
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-fluoro-4-nitrobenzonitrile (15 g, 90.3 mmol) and K2CO3 (25.03 g, 181.1 mmol) in 100 mL of acetone/water (4:1) was added urea hydrogen peroxide adduct (16.99 g, 180.6 mmol) and the reaction stirred overnight at ambient temperature. DCM (100 mL) and water (500 mL) were added to the reaction mixture, the solution partitioned and the organic layer separated. The aqueous layer was extracted with DCM (3×100 mL) and the combined organic portions, washed with brine (100 mL), filtered through Celite and passed through a PTFE separation frit. The solvent was concentrated in vacuo and the title compound obtained as an orange solid (10 g, 60% yield) after recrystallisation from EtOAc/petroleum ether (40-60° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][C:11](=[CH:12]2)C1=O.[CH:20]([NH2:23])([CH3:22])[CH3:21].C[C:25](C)=[O:26]>>[CH:20]([NH:23][C:25](=[O:26])[C:16]1[CH2:17][CH2:18][CH2:11][CH2:12][C:13]=1[C:14]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[F:1])=[O:15])([CH3:22])[CH3:21]
Reactant: CC(C)N
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1ccc(Cl)cc1F
Reactant: CC(C)=O
Product: CC(C)NC(=O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In acetone (40 ml) was dissolved N-(2-fluoro-4-chlorophenyl)-3,4,5,6-tetrahydroisophthalimide (2.8 g) and while stirring at room temperature, isopropylamine (0.6 g) was added. The mixture was allowed to stand for 10 hours, after which time the precipitate was recovered by filtration and washed with acetone. Yield 3.0 g.; m.p. 188°-189° C.
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:30])[O:11]1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CO>C1COCC1>[OH:1][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:30])[O:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1COCCN1c1ccc2c(c1)OC[C@H]1[C@H](CO)OC(=O)N21
Temperature: 0 °C
Yield: 70.8 %

Procedure:
Compound (3R,3aS)-3-((t-butyldimethylsiloxy)methyl)-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1 (3H)-one (3.6 g, 8.295 mmol) prepared as above in (a) was dissolved in 50 ml of THF, cooled to 0° C., to which was slowly added tetra-n-butylammonium fluoride (1M, 10 ml). The resulting mixture was raised to room temperature and reacted for 2 h. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, THF was evaporated. The resulting mixture was washed with ethyl acetate/n-hexane=1/1 under stirring, filtered under reduced pressure, and dried to afford 1.88 g of white solid, yield 70.86%.
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].Cl.CN.[CH3:60][NH:61][CH2:62][CH2:63][N:64]1[CH:68]=[N:67][CH:66]=[N:65]1>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:61]([CH3:60])[CH2:62][CH2:63][N:64]1[CH:68]=[N:67][CH:66]=[N:65]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CNCCn1cncn1
Agent: CN
Agent: Cl
Product: CN(CCn1cncn1)S(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with N-methyl-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]amine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 427.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].F[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=[O:15])[CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCC(=O)Nc1ccc(O)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)Nc1ccc(Oc2ccccc2[N+](=O)[O-])cc1C(=O)OC
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A mixture of 5-hydroxy-2-propionylamino-benzoic acid methyl ester (1.0 g, 4.5 mmol) and potassium carbonate (0.62 g, 4.5 mmol) was stirred in DMF (5 mL) for 10 minutes. 2-fluoronitrobenzene (0.63 g, 4.5 mmol) was then added and stirring was continued at room temperature overnight. Water (10 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried under vacuum to give pure 2-propionylamino-5-(2-nitro-phenoxy)-benzoic methyl ester (1.16 g, 3.4 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:12]=[N:13]O)[C:5]([CH:19]([CH3:21])[CH3:20])=[C:4]([Cl:22])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(#N)C.CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:12]#[N:13])[C:5]([CH:19]([CH3:20])[CH3:21])=[C:4]([Cl:22])[N:3]=1
Reactant: Cc1cc(C=NO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a stirred solution of (70) (4.4 g, 12.93 mmol) in acetonitrile (40 ml), was added triphenylphosphine (13.56 g, 51.73 mmol) and carbon tetrachloride (2.5 ml, 25.86 mmol). After 30 min., carbon tetrachloride (5 ml) was added and the mixture was stirred for 1 hr. The mixture was diluted with ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:4)) to afford 3.82 g (94%) of a white solid. m.p. 143-144° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.45 (3H, s), 3.60 (1H, m), 7.18 (1H, m), 7.25 (1H, m), 7.40 (1H, m).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[C:24]=1[C:25](Cl)=[O:26].[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:17]([CH:5]([CH2:4][CH2:3][CH2:2][CH3:1])[CH2:6][N:8]1[C:7]2[C:15](=[CH:16][C:17]([C:25](=[O:26])[C:24]3[C:23]([CH3:22])=[CH:31][C:30]([CH3:32])=[CH:29][C:28]=3[CH3:33])=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]3=2)[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([C:41](=[O:42])[CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:13]=2)[CH3:16]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccc(C(=O)Cc3ccccc3)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 159.5 %

Procedure:
To 11H-benzo[a]carbazole (1.06 g, 3.23 mmol) in CH2Cl2 (5 ml) are added AlCl3 (0.510 g, 3.82 mmol) and 2,4,6-trimethylbenzoyl chloride (0.59 g, 3.24 mmol) at 0° C. After stirring at room temperature for 1 hour, AlCl3 (0.51 g, 3.82 mmol) and phenylacetyl chloride (0.52 g, 3.39 mmol) are added at 0° C. The reaction mixture is stirred at room temperature for 2 hours, and then it is poured into ice-water. The crude product is extracted with CH2Cl2, and washed with water and brine. After drying over MgSO4 and concentration, the product is reprecipitated from CH2Cl2 and n-hexane to obtain a white powder (1.53 g, 81%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.79-0.91 (m), 1.18-1.50 (m), 2.19 (s), 2.28 (m), 2.41 (s), 4.38 (s), 4.74 (m), 6.97 (s), 7.22-7.36 (m), 7.56 (d), 7.71 (t), 7.77 (t), 8.14 (d), 8.35 (s), 8.62 (d), 8.63 (s), 9.58 (s).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([N:32]3[CH2:31][CH2:30][NH:29][CH:28]([CH3:27])[CH2:33]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Reactant: CC1CNCCN1
Product: CC1CN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccccc4)c3)cn2)CCN1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.18 mmol) was used in general procedure 3 with 2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 450.1 (M)+
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[C:20](=[O:26])[CH:21]([CH3:25])[CH2:22][CH2:23][OH:24].CCN(CC)CC>C(Cl)Cl>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]([C:20](=[O:26])[CH:21]([CH3:25])[CH2:22][CH:23]=[O:24])=[C:12]([CH3:11])[CH:17]=1
Reactant: COc1ccc(C(=O)C(C)CCO)c(C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)C(C)CC=O)c(C)c1
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
To a 200 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added a solution of 4-bromo-3-methylanisole (2.77 g, 16.3 mmol) in 40 mL of THF under nitrogen. The solution was cooled to −68° C. with a dry ice/acetone bath. To this solution was slowly added t-BuLi (21.0 mL, 1.70 M in pentane, 35.8 mmol) followed by the addition of a solution of α-methyl-γ-butyrolactone (2.30 m L, 24.4 mmol) in THF (10.0 mL). The internal temperature was controlled <−55° C. After 1 h stirring at <−55° C., the reaction mixture was quenched with saturated NH4Cl solution and warmed to room temperature. Water and EtOAc were added and separated. The aqueous layer was extracted with EtOAc (2×). The combined organic solutions was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness to give 3.85 g of 1-(4-methoxy-2-methylphenyl)-4-hydroxy-2-methylbutan-1-one as light yellow oil, which was combined with another batch of material and subjected to column chromatography to give 1.26 g (18%) of clear oil. This material was used for Swern oxidation. To a 100 mL, 3-neck round bottom flask, equipped with an internal temperature controller, was added DMSO (1.75 mL, 24.6 mmol) and CH2Cl2 (20 mL). The solution was cooled to −80° C. with a MeOH/liquid nitrogen bath. To this solution was added oxalyl chloride (1.10 mL, 12.3 mmol) slowly via syringe pump. The mixture was stirred at −80° C. for 15 min followed by the addition of a solution of the above 1-(2-methyl-4-methoxyphenyl)-4-hydroxy-2-methylbutan-1-one (1.23 g) in CH2Cl2 (3.0 mL) slowly via syringe pump. After stirring at <−70° C. for 1 h, to the mixture was added Et3N (7.70 mL, 55.0 mmol). The cooling bath was removed after 5 min and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with hexanes (120 mL) and washed with water. The aqueous layer was extracted with hexanes. The combined organic solutions was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/6 EtOAc/heptane) to give 0.326 g (27%) of light yellow oil as the title compound: compound: 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.82 (d, J=8 Hz, 1H), 6.83 (d, J=3 Hz, 1H), 6.81 (s, 1H), 3.94–3.86 (m, 4H), 3.20–3.13 (m, 1H), 2.62–2.56 (m, 1H), 2.51 (s, 3H), 1.21 (d, J=7 Hz, 3H); MS m/z 221.1 (M++H).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC[C@H](N)C(O)C(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.20 mL, 11 eq, 1.14 mmol) followed by (3RS,4S)-4-amino-2-methyl-hexan-3-ol (28 mg, 2.0 eq, 0.21 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSo4) and evaporated in vacuo. The residue was purified by gradient column chromatography, on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid; Yield: 5.7 mg (14%). (50% de 4S,3R: 50% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.90-1.06 (m, 9H, —NHCH(CH2CH3)CH(CH3)2OH), 1.57 (d, 6H, J=6.79 Hz, —CH(CH3)2), 1.64-1.93 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.24-3.37 (m, 1H, —NHCH(CH2CH3) CH(CH (CH3)2)OH), 3.80-3.95 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.57-4.71 (m, 1H, —CH(CH3)2), 4.84-4.96 (m, 2H, —HNCH2-Pyr), 5.13-5.24 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 6.65-6.80 (m, 1H, —HNCH2-Pyr), 7.12-7.23 (m, 1H, Pyr-H), 7.30-7.40 (m, 1H, Pyr-H), 7.56 (s, 1H, —N═CH—N—), 7.59-7.74 (m, 1H, Pyr-H), 8.61 (d, 1H, J=4.42 Hz, Pyr-H). FABMS m/z (relative intensity): 398 ([M+H]+, 100), 324 (55). Accurate Mass (M+H): Actual: 398.2668, Measured: 398.2654.