Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][N:4]1[CH2:5][CH2:6][N:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: O=C(c1ccccc1)N1CCN([N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: NN1CCN(C(=O)c2ccccc2)CC1
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
A mixture of 11.75 g (0.05 mole) of p-nitrobenzoylpiperazine in 150 ml of absolute methanol and 0.2 g of 10% palladium on carbon is hydrogenated on a Parr apparatus during which the calculated amount of hydrogen is taken up over a 1.5 hour period. The reaction is left to stand overnight at room temperature. The reaction mixture is filtered from the catalyst and the filtrate concentrated in vacuo giving a near white crystalline residue. This residue is re-crystallized from 1-propanol at the boiling point giving 9.51 g of near-white crystals of melting point 194.5°-195.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[CH2:7][CH2:8][C:9]=2[CH:10]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:30])=[C:17]([C@:19]2([CH3:29])[C:25]([F:27])([F:26])[CH2:24][O:23][CH2:22][C:21](=[O:28])[NH:20]2)[CH:18]=1.[B][B][B][B][B][B][B][B][B][B].C([O-])(O)=O.[Na+]>CO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[CH2:8][CH2:7][CH:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([F:30])=[C:17]([C@:19]4([CH3:29])[C:25]([F:26])([F:27])[CH2:24][O:23][CH2:22][C:21](=[O:28])[NH:20]4)[CH:18]=3)[C:5]2=[N:4][CH:3]=1
Reactant: C[C@]1(c2cc(N)ccc2F)NC(=O)COCC1(F)F
Reactant: O=C1CCc2cc(Cl)cnc21
Agent: O=C([O-])O
Agent: [B][B][B][B][B][B][B][B][B][B]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@]1(c2cc(NC3CCc4cc(Cl)cnc43)ccc2F)NC(=O)COCC1(F)F
Temperature: 23 °C
Reaction time: 22 h
Yield: 87.2 %

Procedure:
To a solution of 3-chloro-5,6-dihydro-[1]pyrindin-7-one (28 mg, 167 μmol) in methanol (6 ml) and dichloromethane (750 μl) at 23° C. was added (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (intermediate A21A) (49.9 mg, 182 μmol) followed by decaborane (5.6 mg, 167 μmol) and the mixture was stirred at 23° C. for 22 hours. After completion, the mixture was poured into aqueous NaHCO3 solution, extracted with ethyl acetate, the organic layers were dried over Na2SO4 and the solvent evaporated. The crude material was purified by silica gel flash chromatography with n-heptane/ethyl acetate to give the (5R)-5-(5-(3-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ylamino)-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (62 mg, 87%) as an orange solid. MS (ISP): m/z=426.1 [(M+H)+] and 428.1 [(M+2+H)+].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>O>[CH3:13][N:14]([CH3:18])[C:15](=[O:16])[O:12][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:3])[CH:11]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=O)Oc1ccc(C=O)c(O)c1
Yield: 29.7 %

Procedure:
To a suspension of sodium hydride (5.74 g, 239 mmol), which was prepared free from mineral oil by washing with hexane, in dimethylformamide (100 ml) was added 2,4-dihydroxybenzaldehyde (15.0 g, 109 mmol) at 0° C. with stirring, and the resulting mixture was stirred for 30 minutes at 0° C. under a nitrogen atmosphere. Subsequently, N,N-dimethylcarbamoyl chloride (10.1 ml, 110 mmol) was added at 0° C., and the resulting mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. After stirring, water (300 ml) was added to the reaction mixture, and the resulting mixture was washed with ethyl acetate (200 ml×1). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (200 ml×3). The extract was washed successively with water (300 ml×3) and saturated aqueous sodium chloride solution (200 ml×2), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-1:2) as the eluent to afford the title compound (6.78 g, yield: 30%) as a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20].[CH3:31][CH2:32][N:33](C(C)C)C(C)C.BrCC#N.CCOC(C)=O>C(#N)C>[Cl:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:19]([NH:18][CH:10]1[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]1[NH:8][CH2:31][C:32]#[N:33])=[O:20])=[CH:29]2
Reactant: CCN(C(C)C)C(C)C
Reactant: NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: N#CCBr
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CCNC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 60.3 %

Procedure:
N-[1-Amino-2,3-dihydro-1H-inden-2-yl]-5-chloro-1H-indole-2-carboxamide trifluoroacetic acid salt (Method 4, 220 mg, 0.5 mmol), DIPEA (260 μL, 1.5 mmol) and bromoacetonitrile (37 μL, 0.55 mmol) in acetonitrile (5 mL) were heated in a microwave to 180° C. for 1 min. EtOAc (30 mL) was added and the mixture washed with water,(2×10 mL), brine (10 mL), dried (MgSO4) and evaporated. The residue was purified by column chromatography (EtOAc:Hexane 1:1) to afford the title compound (110 mg, 60%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=O)[O:30][CH:31]([CH2:32][CH3:33])[C:25]=2[C:24]=1[Cl:35].Cl>C1COCC1>[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[O:30][CH:31]([CH2:32][CH3:33])[C:25]=2[C:24]=1[Cl:35]
Reactant: CCC1OC(=O)c2cnc(Cl)c(Cl)c21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)c(Cl)c21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (1.44 g, 9.52 mmol.) in THF (10 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (19 mL of a 1 M solution in THF, 19.0 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and then warmed room temperature. A solution of 6,7-dichloro-1-ethyl-1H-furo[3,4-c]pyridin-3-one (1.47 g, 6.33 mmol) in THF (9 mL) is added dropwise to the reaction mixture and the reaction mixture is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (200 mL). The resulting mixture is heated to 100° C. for 2 h and then stirred at room temperature for 36 h. The precipitate which formed is collected by filtration, washed with small volumes of ethyl acetate (10×3 mL) and dried under vacuum to give the title compound as a yellow solid (810 mg, 35%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:46]([CH3:48])[CH3:47])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:39][CH2:38][C:33]3(OCC[O:34]3)[CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH:46]([CH3:48])[CH3:47])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:31][CH2:32][C:33](=[O:34])[CH2:38][CH2:39]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccc3)CCC3(CC2)OCCO3)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccccc3)CCC(=O)CC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.6 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-ylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (271) (500 mg, 0.74 mmol) in tetrahydrofuran (30.0 mL) was added 2.1N aqueous HCl (6.0 mL) and stirred at room temperature for 7 h while silica thin layer chromatography was performed (only ethyl acetate; Rf=0.25). The reaction mixture was concentrated in vacuum and diluted with ethyl acetate (50 mL), washed with aqueous NaHCO3 solution (20 mL) and brine (30 mL) and dried and concentrated in vacuum to get a crude mass which was purified by CombiFlash using a gradient eluent mixture of methanol and dichloromethane to get pure 5-benzyloxy-6-hydroxy-2-(4-oxo-1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (272) (255 mg, 66.6%) as a white sticky solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23](O)=O)=[C:19]([CH3:28])[C:18]=1[CH3:29]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][C:17]([O:16][CH3:15])=[C:18]([CH3:29])[C:19]=3[CH3:28])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1ccc(C=CC(=O)O)c(C)c1C
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3C)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.5 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.9 g (13.9 mmol) of 4-methoxy-2,3-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 0.80 g (yield of Compound 72 as white crystals.
Reaction SMILES: [OH:1]O.[O-]Cl=O.[Na+].[Br:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([F:17])[CH:9]=1.Cl>O.CC#N>[Br:7][C:8]1[C:15]([CH3:16])=[CH:14][C:11]([C:12]([OH:1])=[O:13])=[C:10]([F:17])[CH:9]=1
Reactant: OO
Reactant: Cc1cc(C=O)c(F)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(=O)O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.3 %

Procedure:
NaH2PO4 (418 mg, 3.48 mmol) in H2O (17.6 ml), a 35% aqueous H2O2 solution (2.5 ml, 25.7 mmol) and NaClO2 (2.23 g, 24.7 mmol) in H2O (34.9 ml) were sequentially added to a mixture of 4-bromo-2-fluoro-5-methyl-benzaldehyde (3.74 g, 17.2 mmol) in MeCN (52 ml) at 0° C. The mixture was stirred at room temperature for 14 hours, and then made acidic (pH 3) with a 10% aqueous HCl solution and extracted with ethyl acetate (3×100 ml). The organic layers were washed with H2O (70 ml), and then dried over MgSO4 and concentrated under reduced pressure to give 4-bromo-2-fluoro-5-methyl-benzoic acid as a pale orange solid (4.02 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH:39][CH3:40])=[O:38])[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH:39][CH3:40])=[O:38])[CH:32]=4)[CH:15]=3)[N:10]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Oc1ccc2nc(Nc3ccc(Br)cc3)ncc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccc(Br)cc4)ncc3c2)ccn1
Yield: 70 %

Procedure:
The mixture containing 2-[(4-bromophenyl)amino]quinazolin-6-ol (1 eq), potassiumbis(trimethylsilyl)amide (4eq) was stirred in dimethylformamide for 10 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methylcarboxamide (1 eq) and Potassium carbonate (1.2 eq) and microwaved for 6 mins at 170° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on preparative chromatography yielded 4-{2-[(4-bromophenyl)amino]quinazolin-6-yloxy}-(2-pyridyl)-N-methylcarboxamide in 70-75% yield.
Reaction SMILES: [C:1]1([CH2:19][OH:20])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][O:20][CH2:19][C:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: CN(C)CCCl
Reactant: OCc1scc2c1-c1ccccc1Oc1ccccc1-2
Agent: Cl
Product: CN(C)CCOCc1scc2c1-c1ccccc1Oc1ccccc1-2

Procedure:
Starting from the alcohol 12 (0.25 mmole) and 2-dimethylaminoethylchloride-hydrochloride (2.5 mmoles), an oily product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16](O)=[O:17])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:44]1[CH2:49][CH2:48][CH:47]([CH2:50][N:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:46][CH2:45]1>CCOCC.CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:44]2[CH2:45][CH2:46][CH:47]([CH2:50][N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)[CH2:48][CH2:49]2)=[O:17])=[CH:19][CH:20]=1
Reactant: C1CCN(CC2CCNCC2)CC1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCC(CN2CCCCC2)CC1
Yield: 53.9 %

Procedure:
The following was added to anhydrous DMF (2 mL) sequentially: 1-(4-fluorobenzyl)-1H-indole-2-carboxylic acid (66.8 mg, 0.248 mmol), Hunig's Base (0.217 ml, 1.240 mmol), EDC (52.3 mg, 0.273 mmol), HOBT (41.8 mg, 0.273 mmol), and 1-(piperidin-4-ylmethyl)piperidine (45.2 mg, 0.248 mmol) (from SJB-2-083.) This was stirred at room temperature for 24 h with 3 Å MS. At this time, a 1:1 solution of EtOAc:Et2O was added and the solution was washed with 10% aq. Na2CO3. The organic phase was dried with MgSO4 and concentrated in vacuo. The residue was then purified by silica gel chromatography (20 g silica, 80% EtOAc/Hexanes) to give 58 mg of the title compound as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[C:3]=1[CH:9]=O.[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][NH2:20])[CH:15]=[C:16]([F:18])[CH:17]=1>CN1C(=O)CCC1>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([I:1])=[C:3]3[CH:9]=[N:20]2)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: NNc1cc(F)cc(Cl)c1
Reactant: O=Cc1c(I)ccnc1F
Solvent: CN1CCCC1=O
Product: Fc1cc(Cl)cc(-n2ncc3c(I)ccnc32)c1
Temperature: 185 °C
Yield: 78.8 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added 4-iodo-2-fluoro-3-formylpyridine (714.6 mg, 2.85 mmol), (3-chloro-5-fluorophenyl)hydrazine (457.6 mg, 2.85 mmol) and anhydrous NMP (8.5 mL). The reaction mixture was flushed with argon, securely capped and heated to 185° C. for 1 h, 45 min. The reaction mixture was worked up according to the procedure described in Intermediate 69A to give 839 mg (76.9%) of the title compound (contains approximately 45% of the hydrazone intermediate) as a dark red solid. LC/MS (Condition B): ret. T=4.8 min, (M+H)+ 373.87.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=3[C:11](=[O:20])[N:10]3[CH2:21][CH2:22][CH2:23][C:24](=O)[C:9]=23)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:27][OH:28]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=3[C:11](=[O:20])[N:10]3[CH2:21][CH2:22][CH2:23]/[C:24](=[N:27]\[OH:28])/[C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(=O)CCC3
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)/C(=N/O)CCC3
Temperature: 25 °C

Procedure:
To a solution of 11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione (125 mg) in 4 mL pyridine was added hydroxylamine hydrochloride (51 mg). The reaction was heated to reflux for 5 h, then cooled to room temp and partitioned between ether and water. The aqueous solution was extracted with ether (2×). The combined organic solutions were washed with 1 N HCl (1×), and 10% bicarb (1×), then dried (MgSO4) and concentrated. Flash chromatography (10-70% EtOAc/hexanes) gave the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][C:10]([C:16](OCC)=O)=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]2[C:21]3[CH:22]=[C:23]([C:28](OCC)=O)[CH:24]=[CH:25][C:26]=3[NH:27][C:4]=12.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[C:4]2[NH:27][C:26]3[C:21](=[CH:22][C:23]([CH3:28])=[CH:24][CH:25]=3)[C:5]=2[CH:6]=[C:7]2[C:8]3[CH:9]=[C:10]([CH3:16])[CH:11]=[CH:12][C:13]=3[NH:14][C:15]=12
Reactant: CCOC(=O)c1ccc2[nH]c3c(OC)c4[nH]c5ccc(C(=O)OCC)cc5c4cc3c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c2[nH]c3ccc(C)cc3c2cc2c1[nH]c1ccc(C)cc12
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of diethyl 6-methoxy-5,7-dihydroindolo[2,3-b]carbazole-2,10-dicarboxylate (1.72 g, 4 mmol) in THF (40 mL), with stirring at 0-5° C. and under Ar, was slowly added a solution of LAH in THF (16 mL, 1.0 M). After addition of LAH solution, the mixture was warmed to room temperature and then refluxed 2 h. The reaction mixture was cooled in an ice-water bath and quenched by carefully adding ethyl acetate (20 mL) and water (20 mL). The resultant mixture was extracted with ethyl acetate (3×100 ml); the extracts were combined, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was subjected to chromatography on silica gel to give 6-methoxy-2,10-dimethyl-5,7-dihydroindolo[2,3-b]carbazole (180 mg, 14%), 1H NMR (400 MHz, DMSO-d6) δ ppm 10.97 (s, 2H), 8.45 (s, 1H), 7.91 (s, 2H), 7.33 (d, J=8.0 Hz, 2H), 7.14 (dd, J=1.2, 8.0 Hz, 2H), 4.07 (s, 3H), 2.49 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:29]=3[N:30]=2)[CH2:22]1>>[CH3:19][N:20]([CH3:36])[CH:21]1[CH2:25][CH2:24][N:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([NH:35][C:8](=[O:10])[CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=4)=[CH:31][C:29]=3[N:30]=2)[CH2:22]1
Reactant: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3cc(NC(=O)C=Cc4ccc(F)cc4)ccc3o2)C1
Yield: 69.3 %

Procedure:
Prepare according to Method C (Example 9), using 4-fluorocinnamic acid (107 mg, 0.643 mmol), oxalyl chloride (300 μL, 3.43 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzooxazol-5-ylamine (97 mg, 0.399 mmol) to afford the title compound (109 mg, 69%). mass spectrum (m/e): 395.3 [M+H], 393.3 [M−H]. 1H NMR (400 MHz, CDCl3): δ 7.68 (m, 1H), 7.53-7.35 (m, 4H), 7.17 (m, 1H), 7.07-6.95 (m, 2H), 6.49 (d, 1H, J=15.4 Hz), 3.94-3.77 (m, 2H), 3.59 (m, 1H), 3.44 (m, 1H), 2.89 (m, 1H), 2.31 (s, 6H), 2.24 (m, 1H), 1.96 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[F:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].CC(C)=O.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]O.C(N(CC)CC)C>C(Cl)(Cl)Cl.S(Cl)(Cl)=O>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([O:19][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[O:18])=[CH:15][C:14]=2[F:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2F)ccc(C(C)=O)c1O
Reactant: CN(C)CCCO
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2F)ccc(C(C)=O)c1O
Yield: 52.2 %

Procedure:
A solution of 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-fluorobenzoic acid (220 mg) in chloroform (2 ml) and thionyl chloride (0.4 ml) was refluxed for 20 minutes, then the solvent was removed under reduced pressure. To the residue was added toluene, and then the solvent was removed under reduced pressure. To the residue thus obtained was added acetone (5 ml), 3-dimethylaminopropanol (70 mg) and triethylamine (0.25 ml), and the mixture was refluxed for 0.5 hour. The precipitated colorless crystals were removed by filtration, and the filtrate was concentrated. The residue was dissolved in chloroform, and the solution was washed once with a saturated sodium hydrogen carbonate, and dried with sodium sulfate. The solvent was removed by evaporation and to the cooled residue was added hexane to give colorless crystals of 3-dimethylaminopropyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-fluorobenzoate (140 mg). m.p. 55°-56° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[N:16]=[C:17]([CH3:20])[O:18][CH:19]=2)[N:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:21]1([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]3[N:16]=[C:17]([CH3:20])[O:18][CH:19]=3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: Cc1nc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)co1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: Cc1nc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)co1
Yield: 32.7 %

Procedure:
A 25 mL round bottom flask equipped with a reflux condenser and a nitrogen line was charged with 4-((3-bromo-4-nitro-1H-indazol-1-yl)methyl)-2-methyloxazole (304 mg, 0.902 mmol), cyclopropylboronic acid (170 mg, 1.98 mmol), palladium acetate (8 mg, 0.036 mmol), potassium carbonate (410 mg, 2.98 mmol), and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (37 mg, 0.072 mmol). To the flask was added a 1,4-dioxane:water mixture (5:1; 6 mL), and the flask was evacuated and refilled with nitrogen three times. The reaction mixture was stirred and heated at reflux for 11 hours. The reaction mixture was cooled, diluted with excess water and extracted multiple times with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated, and subjected to preparative thin-layer chromatography (silica, 1:1 EtOAc/Hexane as eluent) to afford the product (88.1 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@@H:11]([CH3:29])[CH2:10]2)=[C:4]([CH3:30])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C@@H:11]([CH3:29])[CH2:10]2)[C:40](=[O:42])[CH3:41])=[C:4]([CH3:30])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccc(Cl)cc3C)C[C@@H]2C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3C)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of (2S,4R)-N-(4-chloro-2-methylphenyl)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (140 mg, 0.33 mmol, 1 equ.) in acetyl chloride (1.0 mL) was added diisopropylethylamine (58 uL, 0.33 mmol, 1 equ.). The mixture was stirred at room temperature for 5 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride/methanol 99/1) to afford pure N-(4-chloro-2-methylphenyl)-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (140 mg, 92%).