Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1)([O-:3])=[O:2].C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CC#N>[CH3:24][N:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[CH2:8][O:7][C:6]1[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1CCC[C@@H]1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) was dissolved in CH3CN (20 mL) and formaldehyde (2.4 mL, 37% aqueous) was added. NaBH3CN (607 mg) was added, an exotherm was observed. The pH was monitored every 15 min and adjusted to ˜7 with AcOH. After 45 min, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with 6 N NaOH, 1 N NaOH, and 2 N HCl (3×). The acid washings were combined, adjusted to ˜pH 10 with solid Na2CO3 and extracted with EtOAc (2×). The EtOAc fractions were combined, dried with Na2SO4, and purified with flash chromatography (SiO2, 95:5:0.5 CH2Cl2:MeOH:NH4OH) to afford the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:6]1.CO>C1COCC1>[CH3:3][O:4][CH:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:6]1
Reactant: CO[C@@H]1C[C@@H](COc2cccnc2)N(C)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC1C[C@@H](COc2cccnc2)N(C)C1

Procedure:
To the compound from step 47a above, dissolved in 4 mL of THF, was added 3.39 mL of BH3 and the mixture was heated at reflux for 2 hours. Methanol was added to the reaction mixture and evaporated. The residue was dissolved in anhydrous ethanol. Cesium fluoride was added, and the resultant solution was stirred under reflux for 16 hr. Evaporation of the solvent provided a white solid which was purified on a silica gel column. MS (DCI/NH3) m/e: 223 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.34 (m, 1H), 8.23 (t, J=3 Hz, 1H), 7.22 (m, 1H), 3.93-4.10 (m, 3H), 3.44-3.54 (m, 1H), 3.32 (s, 3H), 3.03-2.87 (m, IF), 2.51 (s, 3H), 2.44-2.33 (m, 11H), 2.11-1.92 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([OH:33])[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CS(C)=O.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([O:33][C:11]2[C:10]([F:14])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=2)[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)COc1ncc(O)cc1Cl
Reactant: CCOC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(Oc2cnc(OCC(C)C)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2,4,5-trifluorobenzoate (135 mg, 0.661 mmol) and potassium carbonate (156 mg, 1.129 mmol) were dissolved in DMSO (3.0 mL). 5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 127.5 mg, 0.632 mmol) was added portion wise and the mixture was stirred at room temperature for 2 hours. The reaction was diluted in EtOAc (10.0 mL) and washed with brine (3×10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0 to 10% EtOAc in heptane to yield the title compound as a clear oil that solidified upon standing (155 mg, 35%):
Reaction SMILES: [Sn].[CH:2](=[O:6])[CH2:3][CH2:4][CH3:5].[CH2:7]([C:9](=CCCC)[CH:10]=[O:11])[CH3:8].C([Sn](=O)CCCC)CCC>>[CH2:2]([O:6][C:10](=[O:11])[CH2:9][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC=C(C=O)CC
Reactant: CCCC=O
Agent: CCCC[Sn](=O)CCCC
Agent: [Sn]
Product: CCCCOC(=O)CCC
Yield: 45 %

Procedure:
Tin metal supported on silica gel is described as a vapor phase aldol catalyst by Swift, Bozik, and Massota, in Catalysis 15 407 (1969). Swift also describes the vapor phase reaction of n-butyraldehyde with tin metal supported on silica gel in U.S. Pat. No. 3,542,878. The product of the reaction is 2-ethylhexenal in 95 percent selectivity, at 40 percent n-butyraldehyde conversion. Japanese workers have described the simple Tischenko reaction of aldehydes in Japan Kokai No. 76/39,619 using dibutyltin oxide. The products claimed were simple esters, for example, n-butyraldehyde reacted in the presence of dibutyltin oxide to form butylbutyrate in approximately 45 percent yield. The catalyst and process described by this invention produce only traces of simple esters (less than 1 percent).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[C:19]([CH2:18][NH:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([O:21][CH3:22])=[O:20]
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(Cl)ccc1C#N
Yield: 36.7 %

Procedure:
Dissolve 2-amino-4-chlorobenzonitrile (12.9 g, 85 mmol) in anhydrous dimethylformamide (15 mL). Add potassium carbonate (7.6 g, 90 mmol) and methyl bromoacetate (7.8 mL, 90 mmol) and stir at 70° C. for 5 days. Add additional methyl bromoacetate (78 mL, 90 mmol) and continue heating for 1 day. Dilute with ethyl acetate (300 mL), wash with water, separate the organic phase and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography (25% ethyl acetate/hexane). Recrystallize (hexane) to give the title compound (7 g, 36%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].[I:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]#[N:23])=[CH:15]2>CN(C=O)C>[I:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][C:16]([C:22]#[N:23])=[C:15]2[O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCCO
Reactant: N#Cc1cnc2ccc(I)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOc1c(C#N)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
To the solution of diethylene glycol monomethyl ether (0.75 mL, 6.4 mmol) in DMF (10 mL) was added sodium hydride (0.26 g, 6.4 mmol). After stirring at room temperature for 30 min, 6-iodo-quinoline-3-carbonitrile (example 14c) (1.0 g, 3.18 mmol) was added to the mixture. After further stirring at room temperature for 30 min, ice water was slowly added to the reaction. The reaction was extracted with methylene chloride. The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-45% ethyl acetate in hexanes in 30 min) afforded 6-iodo-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (0.59 g, 46%) as a light yellow solid. LC-MS m/e 399 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc2N(C)C1=O
Yield: 156.8 %

Procedure:
A mixture of 0.03 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.014 g (0.0001 mole) of 4-aminobenzoic acid, 0.3 mL of ethanol, 0.8 mL of water, and 1 drop of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.062 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-benzoic acid (I-5) as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](=[NH:18])OC)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:19].[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24].C>CO>[ClH:19].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C:15]([NH2:18])=[N:24][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(CN)OC
Reactant: COC(=N)c1ccc(-c2ccc(C(C)=O)cc2)o1
Agent: C
Agent: Cl
Solvent: CO
Product: COC(CN=C(N)c1ccc(-c2ccc(C(C)=O)cc2)o1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 30 g (0.12 mole) of methyl 5-(4-acetylphenyl)-2-furimidate and 500 ml of saturated ethereal/HCl was stirred for 2 hrs. at room temperature and the resulting solid filtered. A mixture of this solid, 12.6 g (0.12 mole) of aminoacetaldehyde dimethyl acetal and 500 ml of methanol was refluxed for 3 hr. with the resulting solution being treated with Darco and filtered hot. The filtrate was taken to dryness on the Calab evaporator yielding a residual solid. This solid was dissolved in refluxing methanol (Darco), filtered and the filtrate cooled to room temperature. The filtrate was diluted with ether and the resulting solid filtered and air dried to yield 24 g (57%) of 5-(4-acetylphenyl)-N'-2,2-dimethoxyethyl-2-furamidine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[O:24]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25]1.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:29][CH:26]2[CH2:27][CH2:28][O:24][CH2:25]2)[CH:12]=3)[CH:7]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: NC1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC3CCOC3)cc21
Temperature: 180 °C
Yield: 24.8 %

Procedure:
To a solution of Example A3 (2.0 g, 5.7 mmol) in NMP (10 mL) was added tetrahydro-furan-3-ylamine (1.5 g, 17.2 mmol) and DBU (1.7 g, 11.4 mmol). Nitrogen was bubbled through the mixture for 5 min and then it was heated in the microwave at 180° C. for 1 h. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydrofuran-3-ylamino)-1,6-naphthyridin-2(1H)-one (0.57 g, 25% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.66 (s, 1H), 7.27 (d, J=6.4 Hz, 1H), 7.18 (d, J=11.2 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H), 6.33 (s, 1H), 5.31 (s, 2H), 4.46-4.42 (m, 1H), 4.08 (q, J=6.8 Hz, 2H), 3.89-3.81 (m, 2H), 3.75-3.69 (m, 1H), 3.55-3.52 (m, 1H), 2.22-2.17 (m, 1H), 1.83-1.79 (m, 1H), 1.20 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C@@H:25]([CH2:33][CH3:34])[CH2:26][NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[C:5]1=[O:35])C=C.CC#N.O.I([O-])(=O)(=O)=O.[Na+].CC[O:49][C:50]([CH3:52])=[O:51]>O.[Ru](Cl)(Cl)Cl>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:6]([C@@H:25]([CH2:33][CH3:34])[CH2:26][NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[C:5](=[O:35])[C@:4]([CH2:52][C:50]([OH:49])=[O:51])([CH3:1])[CH2:9]2)[CH:15]=[C:14]([F:16])[CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cc(F)cc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)CC)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CC[C@@H](CNS(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)ethanesulfonamide (Example 393, Step C, 120 mg, 0.216 mmol) in EtOAc:MeCN:water (1.450 mL) (2/2/3) at rt was added sodium periodate (185 mg, 0.864 mmol) slowly. Then ruthenium chloride hydrate (1.071 mg, 4.75 μmol) was added. The mixture was stirred vigourously at rt for 2 h. Then the mixture was filtered and the solid was washed with EtOAc. The filtrate was extracted with EtOAc 2×. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparatory HPLC (column: Gemini™ Prep C18 5 um column; Phenomenex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[NH:6][C:5](=O)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:5]1[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=1
Reactant: O=c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Cl)n2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (51.5 g, 168 mmol) and phosphoryl chloride (50 mL) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (53.4 g, 98%). MS (ISN) 384.1 [(M+OAc)−], 386.0 [(M+2+OAc)−]; mp 39-40° C.
Reaction SMILES: [C:1]([N:4]1[C:16]2[C:11](=[CH:12][C:13](Br)=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]1=2)(=[O:3])[CH3:2].[C:26]1([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=[C:33]2[C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:16]2[C:11](=[CH:12][C:13]([C:44]3[CH:45]=[CH:46][C:41]([C:33]4[N:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=4)=[CH:42][CH:43]=3)=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]1=2)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: CC(=O)n1c2ccc3ccccc3c2c2cc(Br)c3ccccc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccc3ccccc3c2c2cc(-c3ccc(-c4nc5ccccc5n4-c4ccccc4)cc3)c3ccccc3c21
Yield: 90.9 %

Procedure:
Following the above procedure, Suzuki coupling of 3.4 g of 7-acetyl-12-bromo-7H-dibenzo [a,g]carbazole and 3.8 g of 4-(1-phenyl-1H-benzo [d]imidazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.01 g of tetrakis(triphenylphosphine)palladium, 2.7 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 4.6 g of 7-acetyl-12-[4-(1-phenyl-1H-benzo[d]imidazol-2-yl)phenyl]-7H-dibenzo [a,g]carbazole as a white solid.
Reaction SMILES: C1(C)C=CC(S([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:29])(=O)=O)=CC=1.[C:31]([NH:34][CH:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)(=[O:33])[CH3:32].C(N(CC)CC)C>C(O)C>[C:31]([NH:34][CH:35]1[CH2:39][CH2:38][N:37]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:28])[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:21][CH2:22]3)=[CH:12][C:11]=2[F:29])[CH2:36]1)(=[O:33])[CH3:32]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(S(=O)(=O)c3ccc(C)cc3)c(F)cc2c1=O
Reactant: CC(=O)NC1CCNC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 80.2 %

Procedure:
A mixture of ethyl 7-(p-tolylsulfonyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (800 mg), 3-acetylaminopyrrolidine (300 mg), triethylamine (236 mg), and ethanol (25 ml) was refluxed for 2 hours. After evaporation of the solvent under reduced pressure, the residual crude crystals were recrystallized from ethanol-isopropyl ether to give ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (600 mg), m.p. 246°-248° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](B3OC(C)(C)C(C)(C)O3)[CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[O:41][C:42](Br)=[CH:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:23]1[CH:24]=[C:25]([CH:35]([NH:37][C:38]([C:40]2[O:41][C:42]([C:6]3[CH:7]=[C:8]([CH:10]4[CH2:11][CH2:12]4)[CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=3)=[CH:43][CH:44]=2)=[O:39])[CH3:36])[CH:26]=[C:27]([F:34])[C:28]=1[NH:29][S:30]([CH3:33])(=[O:32])=[O:31]
Reactant: CC(NC(=O)c1ccc(Br)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1(C)OB(c2cc(C3CC3)cc(C3CC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1ccc(-c2cc(C3CC3)cc(C3CC3)c2)o1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 38.4 %

Procedure:
2-(3,5-Dicyclopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (74 mg, 0.26 mmol) and 5-bromo-furan-2-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (110 mg, 0.26 mmol) was reacted using Pd(PPh3)2Cl2 (14 mg, 0.02 mmol), Cs2CO3 (254 mg, 0.78 mmol) as described above to give the title compound (50 mg, 38%) after purification by flash chromatography on silica gel (% EtOAc in hexane=30%˜70%).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:19]([C:22]1[C:23]([NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1)(=[O:21])[CH3:20]>C1COCC1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:19]([C:22]1[C:23]([NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1)([OH:21])[CH3:20])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(Cl)nc1NC(=O)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(C)(O)c1ccc(Cl)nc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A first intermediate compound, 7-Chloro-4-methyl-1H-[1,8]naphthyridin-2-one, was produced as follows: A solution of tert-butyl acetate (0.6 mL, 4.45 mmol) is added dropwise to a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 4.2 mL, 4.2 mmol) in THF (5 mL) at −78° C. The yellow solution is stirred for 1 hour and N-(3-acetyl-6-chloro-pyridin-2-yl)-2,2-dimethyl-propionamide (0.503 g, 1.97 mmol) in THF (5 mL) is added dropwise to the mixture. The yellow suspension is stirred at −78° C. for 30 minutes and warmed to RT. The suspension clears to a yellow solution and the mixture is stirred at room temperature for 1.5 hours. The mixture is quenched with water and extracted with CH2Cl2. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to a brown liquid. The liquid is purified by column chromatography (2:1 hexanes/ethyl acetate) to afford 3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-butyric acid tert-butyl ester (0.548 g, 75%) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 10.40 (br s, 1H), 7.37 (d, 1H), 6.98 (d, 1H), 5.61 (s, 1H), 3.03 (d, 1H), 2.67 (d, 1H), 1.56 (s, 3H), 1.45 (s, 9H), 1.32 (s, 9H). MS ES: m/z=370.86, 372.56.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>ClCCl>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][CH:10]1[NH:9][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: NC1Cc2ccccc2C1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
200 ml of dichloromethane then 10 ml, i.e. 7.26 g (71.7 mmol) of triethylamine were added to 5 g (29.5 mmol) of 2-aminoindan hydrochloride. The mixture was stirred for 30 min, then 3.4 ml, i.e. 3.84 g (35.4 mmol) of ethyl chloroformate were added dropwise. The mixture was stirred for 30 min, then ice-water and an excess of 1N hydrochloric acid were added. The precipitate was filtered, washed, dried and purified by chromatography on a silica gel column, eluted with an 80:20 mixture of dichloromethane/ethyl acetate. 4.25 g of amorphous solid were isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[CH3:12].[H][H]>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1C
Reaction time: 0.17 h

Procedure:
To the solution of 1-methoxy-2-methyl-4-nitrobenzene (10 g, 60 mmol) in EtOH and EtOAc (250 mL, 3:2) was added 10% Pd/C (2 g). The mixture was stirred for 24 h under one atmosphere of hydrogen. Celite was added and the mixture was stirred for 10 min. The mixture was filtered through a pad of Celite. Concentration under reduced pressure gave 4-methoxy-3-methylaniline. LCMS-ESI+ (m/z): 138.2 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH2:23]([NH2:33])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1>>[O:29]1[C:30]2[CH:31]=[CH:32][C:24]([CH2:23][NH:33][C:4]([C:6]3[N:7]=[C:8]([C:15]4[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=4[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=3[OH:12])=[O:5])=[CH:25][C:26]=2[O:27][CH2:28]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc3c(c2)OCO3)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and piperonylamine (76 mg, 0.5 mmol). The title product was obtained as an off-white solid (18.6 mg, 45% yield). 1HNMR (500 MHz, CDCl3) δ: 12.35 (1H, s), 7.74 (1H, br s), 7.52–7.46 (1H, m), 7.04 (2H, dd, J=8.24, 7.33 Hz), 6.80 (1H, s), 6.78–6.74 (2H, m), 5.93 (2H, s), 4.48 (2H, d, J=6.10 Hz), 3.40 (3H, s). HRMS (ESI) calcd for C20H14F2N3O5 (M−H): 414.0902; found: 414.0900.