Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][N:25]([CH3:36])[C:26](=[O:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([N:25]([CH3:36])[CH3:24])=[O:35])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: CN(C)C(=O)CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (6.57 g) and N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (4.68 g) in 2-propanol (60 mL) was added piperidinium acetate (2.81 g). The reaction mixture was stirred at 80° C. for 4 hr and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane). The obtained solid was washed with diisopropyl ether and recrystallized from ethyl acetate/heptane to give the title compound (5.62 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:11]([OH:22])[C:12]1[O:13][C:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][N:16]=1)[CH2:9][CH3:10])(C)(C)C.[ClH:24]>ClCCl.O1CCOCC1>[ClH:24].[NH2:7][CH:8]([CH2:9][CH3:10])[C@@H:11]([C:12]1[O:13][C:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][N:16]=1)[OH:22]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)c1ncc(-c2cccs2)o1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(N)[C@H](O)c1ncc(-c2cccs2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {(S)-1-[hydroxy-(5-thiophen-2-yl-oxazol-2-yl)-methyl]-propyl}-carbamic acid tert-butyl ester (361 mg, 1.07 mmol) in dry dichloromethane (3 mL) is added 4N HCl in dioxane (3.0 mL, XS). The mixture is stirred at room temperature for 16 h, then concentrated in vacuum to afford (S)-2-Amino-1-(5-thiophen-2-yl-oxazol-2-yl)-butan-1-ol hydrochloride as a solid (quant.).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9](Cl)=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1>C1(C)C=CC=CC=1>[OH:13][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[C:9]([NH:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=[O:10]
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1O
Solvent: Cc1ccccc1
Product: O=C(Nc1nnn[nH]1)c1cc([N+](=O)[O-])ccc1O

Procedure:
The 5-nitrosalicyloyl chloride thus obtained was dissolved in dry toluene (40 ml) and treated with anhydrous 5-aminotetrazole (3.4 g) and the mixture was stirred and heated at reflux for 12 hours. The mixture was then allowed to cool and was treated with petroleum ether (b.p. 40°-60° C.; 40 ml). The resulting solid was filtered off, washed with petroleum ether (b.p. 40°-60° C.) and stirred with hydrochloric acid (2N; 100 ml). The undissolved solid was filtered off, washed with hydrochloric acid (2N) and with water, and was then dried and dissolved in glacial acetic acid (750 ml). The solution was filtered hot and was then concentrated to 150 ml volume and was then cooled and filtered to give 2-hydroxy-5-nitro-N-(tetrazol-5-yl)-benzamide (2.2 g), m.p. 271°-272° C. (with decomposition).
Reaction SMILES: [Cl-].[NH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(O)CC>[N:8]1[C:3]2[N:4]([CH2:9][S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:2]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nccc[n+]1CSc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCCO
Product: C1=CN2CSc3ccccc3N=C2N=C1
Yield: 110.3 %

Procedure:
A mixture of 33.2 g of 2-amino-1-[[(o-bromophenyl)-thio]methyl]pyrimidinium chloride, 27.7 g of anhydrous potassium carbonate, 0.8 g of copper bronze, and 750 ml of n-propanol is heated and stirred, under reflux, for 6 days, filtered hot, and the filtrate concentrated to dryness in vacuo. The residue is dissolved in 600 ml of ether, and the ether solution is washed, dried, decolorized with Darco, and concentrated to give about 23.7 g of a yellow solid. Recrystallization from cyclohexane-benzene gives about 17.4 g of the named compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1.C(C1C=C(B(O)O)C=CC=1)=O.BrC1C=CC=CN=1>>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[N:18]=1
Reactant: Cc1ccnc(Br)n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Brc1ccccn1
Agent: O=Cc1cccc(B(O)O)c1
Product: Cc1ccnc(-c2ccc(C=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 12 by substituting 4-formylphenylboronic acid and 2-bromo-4-methylpyrimidine (prepared as described in Helv. Chim. Acta 1992, 75, 1621) for the 3-formylphenylboronic acid and 2-bromopyridine, respectively, of Reference Example 12. MS 199 (M+H)+.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(Cl)(Cl)Cl>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CCCCCCCCCCCCCCCCOc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)OC)cc1
Yield: 89.4 %

Procedure:
A mixture of 23 g of product from Example 84, 13.15 g of methyl bromoacetate, 10.45 g of potassium carbonate and 200 ml of acetone is heated at reflux for 24 hours. The reaction is cooled, chloroform added, filtered and concentrated. The residue is recrystallized from hexane to give 25 g of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:27])=[N:9]2)=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cccc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](OCc1cccc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (52 mg) in N,N-dimethylacetamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (20 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (40 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected by filtration from this suspension, and dried under reduced pressure to give the titled compound (37 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]=2[CH2:29][CH2:28]1.[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>CN(C=O)C>[CH3:1][C:2]1[N:6]([C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]=2[CH2:29][CH2:28]1
Reactant: BrCc1ccccc1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CC2CCc3c(c4ccccc4n3Cc3ccccc3)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
A solution of 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-4H-carbazol-4-one (500 mg) in dry DMF (3 ml) was added dropwise to a stirred suspension of sodium hydride (73% dispersion in oil; 38 mg) in dry DMF (1 ml) under nitrogen. After 20 min. benzyl bromide (0.14 ml) was added and the mixture was stirred for 3 h. Water (50 ml) was added and the suspension was extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 850 mg) which was purified by FCC (column made up in ethyl acetate:hexane:triethylamine 79:20:1) eluting with ethyl acetate:hexane (4:1) to give the title compound (265 mg) as a solid, m.p. 78°-80°.
Reaction SMILES: [I:1]I.[NH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:15])[CH:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+].[Ag+]>[NH2:3][C:4]1[C:14]([I:1])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:15])[CH:5]=1
Reactant: CCOC(=O)c1ccc(N)cc1Cl
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)c1cc(I)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
An iodine solution in ethanol was admixed with silver(I) sulphate and ethyl 4-amino-2-chlorobenzoate and then stirred at room temperature for 45 min. The reaction mixture was filtered through a frit and the filtrate was concentrated under reduced pressure. The residue was slurried in EtOAc, and dilute sodium hydrogencarbonate solution was added. Once everything had gone into solution, the aqueous phase was removed and sodium thiosulphate was dissolved therein. The organic phase was washed again with the aqueous phase and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 33% ethyl acetate) gave 1.85 g (74% of theory) of ethyl 4-amino-2-chloro-5-iodobenzoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([F:10])=[C:12]([CH3:18])[CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Cc1cc(N)ccc1F
Reactant: Fc1cnc(Cl)nc1Cl
Product: Cc1cc(Nc2nc(Cl)ncc2F)ccc1F

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-methylaniline were reacted to provide 2-chloro-5-fluoro-N4-(4-fluoro-3-methylphenyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.06 (d, 1H, J=2.4 Hz), 7.48-7.43 (m, 1H), 7.39 (dd, 1H, J=2.7 and 6.3 Hz), 7.03 (t, 1H, J=9.0 Hz), 6.84 (bs, 1H), 2.30 (d, 1H, J=1.8 Hz); 19F NMR (282 MHz, CDCl3): −34285, −44676; LCMS: purity: 95%; MS (m/e): 257 (MH+).
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:7][CH:8]=2)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:7][CH:8]=2
Reactant: O=CC1c2cc(CCCC(=O)O)ccc2-c2c(C(=O)O)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CCCc1ccc2c(c1)C(CO)c1cccc(C(=O)O)c1-2
Reaction time: 2 h

Procedure:
In an argon-purged flask, crude 9-formyl-7-(3-carboxy-propyl)-4-fluorenecarboxylic acid (4.0 g, 0.0123 mol) was dissolved in anhydrous methanol (50 mL). The flask was placed in a room temperature bath and sodium borohydride (2.3 g, 0.0615 mol) was carefully added to the reaction in portions (Caution! Flammable gas evolution.). The reaction was stirred for two hours and another portion of sodium borohydride was added (1.2 g, 0.031 mol). After another six hours the reaction was treated with a small amount of water. The organic solvent was partially removed at reduced pressure and the mixture was acidified with concentrated HCl. Brine was added and the product was twice extracted with ethyl acetate (300 mL and 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product (3.3 g, 83%) was purified by flash chromatography: silica gel 60 Å eluted with 50:50:2 ethyl acetate/chloroform/glacial acetic acid. The purified product was an orange solid (1.7 g, 43%). 1H-NMR (CD3OD): δ (ppm) 8.3 (d, 1H, Ar); 7.8 (m, 2H, Ar); 7.6 (s, 1H, Ar); 7.4 (t, 1H, Ar); 7.2 (m, 1H, Ar); 4.0 (m, 2H, CH2); 3.9 (m, 1H, CH); 2.8 (t, 2H, CH2); 2.4 (t, 2H, CH2); 2.0 (m, 2H, CH2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([CH2:22][CH2:23][OH:24])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:12][C:11]3=[O:25])[CH3:9])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@@](CCO)(c2ccccc2)CC1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@@](CCO)(c2ccccc2)CC1=O
Yield: 11.6 %

Procedure:
A mixture of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-hydroxyethyl)-4-phenyl piperidin-2-one (25 mg, 0.062 mmol), 4-fluorophenylboronic acid (15 mg, 0.093 mmol), Pd(Ph3P)2Cl2 (5 mg), and aqueous Cs2CO3 (0.1 mL, 2M) in 1,4-dioxane (2 mL) was stirred and heated at reflux for 2 hours. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (S)-1-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-4-(2-hydroxyethyl)-4-phenylpiperidin-2-one (3.0 mg, 12%). LC-MS Method 2, tR=2.167 min, m/z=440.1. 1H NMR (CDCl3): δ 1.18 (d, 3H), 1.86 (m, 2H), 2.06 (m, 2H), 2.54 (m, 2H), 2.64 (m, 1H), 3.10 (dd, 1H), 3.31 (m, 1H), 3.46 (m, 1H), 6.04 (q, 1H), 7.02 (m, 2H), 7.20 (m, 4H), 7.32 (m, 2H), 7.46 (m, 4H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH:8]2[O:12]CCO2)[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+].Cl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.CN(C)C=O.O>[CH3:7][C:5]1[S:6][C:2]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][C:4]=1[CH:8]=[O:12]
Reactant: Cc1sc(Br)cc1C1OCCO1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1sc(-c2ccccc2)cc1C=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
To a mixture of 2-(5-bromo-2-methylthiophen-3-yl)-1,3-dioxolane (3.50 g) synthesized above, phenylboronic acid (2.56 g), sodium carbonate (2.96 g), water (10 mL) and N,N-dimethylformamide (50 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane adduct (1.14 g). The reaction mixture was deaerated, and the mixture was stirred at 80° C. for 3 hr under an argon atmosphere. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give a yellow oil. To a solution of the obtained oil in tetrahydrofuran (20 mL) was added 1N hydrochloric acid (10 mL), and the mixture was stirred at room temperature for 1 hr. Tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.72 g, 61%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([C:15]#[N:16])[N:12]=[CH:11]2)[C:7]([C:17]([F:20])([F:19])[F:18])=[CH:6][C:5]=1[N+:21]([O-])=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[C:13]([C:15]#[N:16])[N:12]=[CH:11]2)[C:7]([C:17]([F:18])([F:19])[F:20])=[CH:6][C:5]=1[NH2:21]
Reactant: COC(=O)c1cc(-n2cnc(C#N)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(-n2cnc(C#N)c2)c(C(F)(F)F)cc1N
Yield: 11 %

Procedure:
A solution of 350 mg (1.03 mmoles) of 5-(4-cyano-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester in 100 ml methanol is treated with 22 mg of 10% palladium on charcoal and hydrogenated at room temperature under a pressure of 1 bar for 16 hours. After filtration of the catalyst and evaporation of the solvent the residue is chromatographed on silica gel using dichloromethane and rising quantities of up to 15% of methanol to give 35 mg (0.113 mmol, 11%) of amorphous 2-amino-5-(4-cyano-imidazol-1-yl)-4-trifluoromethyl-benzoic acid methyl ester, ES-MS: m/z 311 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:14](=O)([O-])[O-].[K+].[K+].CI.C(C(C)=O)C>C(OCC)(=O)C>[CH3:14][S:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CC(C)=O)cc1S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccc(CC(C)=O)cc1SC
Yield: 84 %

Procedure:
A mixture of 10 g of 3-mercapto-4-methoxyphenylacetone, 9 g of anhydrous potassium carbonate, 42 g of methyl iodide, and 50 ml of methyl ethyl ketone was stirred under refluxing for 20 hours, and after cooling, the reaction mixture was filtered. The filtrate obtained was, then, evaporated to dryness. The residue formed was dissolved in ethyl acetate and after washing the solution obtained with water, ethyl acetate was distilled off and the crude crystals obtained were recrystallized from a mixture of n-hexane and ether to provide 9 g of 3-methylthio-4-methoxyphenylacetone having a melting point of 74°-75° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:28])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[C:5]([CH3:29])=[CH:4][N:3]=1.[CH2:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[CH3:31].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.C1(C)C=CC=CC=1>[CH2:30]([C:32]1[CH:37]=[CH:36][C:35]([C:2]2[N:7]=[C:6]([N:8]([CH3:28])[CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]4)[C:5]([CH3:29])=[CH:4][N:3]=2)=[CH:34][CH:33]=1)[CH3:31]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)ncc3C)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ncc3C)ccc21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a mixture of toluene (12 mL) and 1,4-dioxane (2.5 mL) were added ethyl ((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 342, 205 mg, 0.49 mmol), 4-ethylphenyl boronic acid (294 mg, 1.96 mmol), and PdCl2(dppf).CH2Cl2 (35.9 mg, 0.05 mmol). A flow of argon was passed through the reaction mixture for 30 min, then Na2CO3 (2.45 mL, 4.91 mmol, 2 M aqueous solution) was added, and the reaction was stirred at 75° C. for 18 h. After cooling to rt, the reaction mixture was diluted with EtOAc, and washed with a saturated aqueous solution of NaHCO3. The organic layer was then dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4:1 hexanes/EtOAc) to provide the product (140 mg, 59%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.26-1.32 (m, 6H), 1.73-1.80 (m, 1H), 2.16-2.19 (m, 2H), 2.33 (s, 3H), 2.35-2.42 (m, 2H), 2.67-2.88 (m, 5H), 3.22 (s, 3H), 3.51-3.55 (m, 1H), 3.79 (t, 2H), 4.00 (t, 2H), 4.19 (q, 2H), 6.69 (d, 1H), 6.75 (s, 1H), 7.04 (d, 1H), 7.26 (d, 2H), 8.08 (s, 1H), 8.30 (d, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[C@@H:3]([NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]=2[C:16]2[C:15](=[O:23])[NH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:4]([F:7])([F:6])[F:5].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:24])[C@@H:3]([NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N+:21]([O-:33])=[CH:22][C:17]=2[C:16]2[C:15](=[O:23])[NH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)[C:4]([F:6])([F:5])[F:7]
Reactant: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2cnccc12)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](Nc1nc2cc[nH]c(=O)c2c2c[n+]([O-])ccc12)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one (20 mg, 0.059 mmol) in CH2Cl2 (8 mL) at 0° C. was added m-CPBA (60 mg, 0.268 mmol, 77% max) and allowed to stir for 2 hr. 10% sodium thiosulfate and sat. sodium bicarbonate were added to the reaction solution and stirred for 30 min. The layers were separated, the organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified on reverse phase HPLC 100% H2O to 100% MeCN to afford 6-{[(1R)-2-methyl-1-(trifluoromethyl)propyl]amino}pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one 9-oxide. 1H NMR (600 MHz, CD3OD) δ 10.80 (s, 1H), 8.50 (d, 1H), 8.35 (d, 1H), 7.48 (d, 1H), 6.60 (d, 1H), 5.39 (m, 1H), 2.33 (m, 1H), 1.14 (d, 3H), 1.06 (d, 3H). LRMS (ESI) calc'd for (C16H16F3N4O2) [M+H]+, 353.1; found 353.1.