Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CS(C)=O>[CH3:17][C:16]1[O:15][C:14]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(N2CCOCC2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of fluoride 48 (103 mg, 0.22 mmol) and morpholine (2 mL) in DMSO (1 mL) was stirred in a sealed tube at 130° C. for 16 h. The solvent was evaporated and the residue was suspended in ice/water (50 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-10%) of MeOH/EtOAc, to give benzamide 50 (83 mg, 71%) as a white powder: mp (EtOAc) 208-210° C.; 1H NMR δ 9.23 (s, 1 H, CONH), 8.57 (br s, 1 H, H-2′), 8.47 (br d, J=4.5Hz, 1 H, H-6′), 8.00 (br d, J=8.5Hz, 2 H, H-2, H-6), 7.91 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.74 (br d, J=7.8Hz, 1 H, H-4′), 7.54 (d, J=9.0Hz, 2 H, H-3″, H-5″), 7.37 (dd, J=7.8, 4.7Hz, 1 H, H-5′), 7.05 (d, J=9.0Hz, 2 H, H-2″, H-6″), 4.49-4.54 (m, 4 H, CH2SO2, CH2N), 3.72 (br t, J=4.8Hz, 4 H, 2×CH2O), 3.27 (br t, J=4.8Hz, 4 H, 2×CH2N), 2.13 (s, 3 H, CH3); 13C NMR δ 165.5, 157.8, 154.2, 149.7, 148.8, 148.0, 135.3, 135.1, 134.8, 129.7 (2), 128.8, 128.0 (2), 126.4, 126.0, 125.4 (2), 123.4, 113.3 (2), 65.6 (2), 53.2, 46.7 (2), 40.4, 9.6; MS m/z 533.7 (MH+, 100%). Anal. calcd for C28H28N4O5S: C, 63.14; H, 5.30; N, 10.52. Found: C, 62.94; H, 5.18; N, 10.51%.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:7]([C:12]([OH:14])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:43][NH:44][O:45][CH3:46]>CN(C=O)C>[CH3:46][O:45][N:44]([CH3:43])[C:12]([C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:4][CH:3]=[C:2]([CH3:1])[N:11]=2)=[O:14]
Reactant: Cc1ccc(Sc2ccccc2)c(Nc2c(C(=O)O)cnc3nc(C)ccc23)c1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnc2nc(C)ccc2c1Nc1cc(C)ccc1Sc1ccccc1
Reaction time: 24 h

Procedure:
The product from Example 11a (50.5 mg, 0.125 mmol) was reacted with 1,1′-carbonyldiimidazole (40.8 mg, 0.215 mmol) in 2 mL of DMF under an atmosphere of N2 for 30 min. Added N,O-dimethylhydroxylamine hydrochloride (25 mg, 0.215 mmol) and stirred ate room temperature for 24 h. The solvent was concentrated under vacuum giving the title compound. After purification of the crude product by HPLC with AA the product was isolated as the free base (12 mg, 21%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.23 (s, 3H) 2.67 (s, 3H) 2.89 (s, 3H) 3.39 (s, 3H) 6.86 (s, 1H) 6.91-7.04 (m, 1H) 7.15-7.35 (m, 7H) 7.44 (d, J=8.46 Hz, 1H) 8.34 (d, J=8.09 Hz, 1H) 8.67 (s, 1H); MS (ESI+) m/z 445 (M+H)+, 467 (M+Na)+, MS (ESI−) m/z 443 (M−H)−.
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24](OCC)=[O:25].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][OH:25]
Reactant: CCOC(=O)C(C)(CCCCCBr)c1ccccc1
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCCCBr)c1ccccc1
Yield: 97.7 %

Procedure:
According to the procedure given for the synthesis of 206e, 205h (60.0 g, 183 mmol) was reduced with LiBH4 (5.96 g, 274 mmol) and methanol (8.55 g, 269 mmol) in anhydrous CH2Cl2 (390 mL). After the typical workup, crude 206h (51.0 g, 98%) was obtained as a yellowish oil, which was used without further purification for the next step. 1H NMR (CDCl3): δ 7.25-7.08 (m, 5H), 3.64 (d, 1H, J=7.2), 3.50 (d, 1H, J=7.2), 3.35 (t, 2H, J=6 Hz), 1.92-0.95 (m, 9H), 1.28 (s, 3H). 13C NMR (CDCl3): δ 144.77, 128.51, 126.76, 126.21, 72.63, 43.45, 38.37, 34.06, 32.73, 28.96, 23.12, 21.59. HRMS (EI): Calcd for C14H21BrO (M+): 284.0776, found: 284.0787.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]([CH2:19][C:20]([O:22]CC)=[O:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]([CH2:19][C:20]([OH:22])=[O:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(c3ccccc3n2CC(=O)O)C1

Procedure:
A stirred solution of ethyl (2-tert.-butoxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate (15 mg, 0.039 mmol) in THF (0.6 ml) is treated with 0.2 N aqueous NaOH (0.29 ml, 0.058 mmol) at rt for 15 min. The reaction mixture is diluted with water (2 ml) and washed with diethyl ether (2 ml), then neutralized with conc. HCl (58 μl), and extracted with dichloromethane. The solvent is evaporated and the crude product is recrystallized from acetonitrile to afford pure compound as a yellow solid: tR (LC-1) 2.16 min; ESI-MS (positive ion): m/z 353.32 [M+Na]+ (calcd 330.38 for C18H22N2O4).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1>[C:1]([O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)c1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nicotinic chloride (1.78 g, 10 mmoL) was added to phenol (1.29 g, 12 mmoL) in 10 mL of tetrahydrofuran (THF). Triethylamine (5 mL) and pyridine (5 mL) were then added to the mixture, which was then stirred at room temperature overnight. After THF was evaporated, the mixture was washed with ethyl acetate in water for three times. The ethyl acetate (EtOAC) layer was then purified with silica column (Hexane: EtOAC=4:1) to give pure product. 1H NMR (400 MHz, CDCl3): δ=9.40 (s, 1H), 8.86 (d, 1H), 8.46 (d, 1H), 7.45 (m, 3H), 7.32 (d, 1H), 7.24 (m, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[S:7][C:8]([S:15]([CH3:17])=O)=[CH:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2].[Na+].[I-].FC(F)(F)C(OC(=O)C(F)(F)F)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.C(Cl)Cl>[CH2:1]([NH:3][C:4]([C:6]1[S:7][C:8]([S:15][CH3:17])=[CH:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2]
Reactant: CCNC(=O)c1sc(S(C)=O)cc1[Si](C)(C)C
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: CCNC(=O)c1sc(SC)cc1[Si](C)(C)C
Temperature: 0 °C
Yield: 88.2 %

Procedure:
To a solution of the compound of Example 260 (0.6 g) and NaI (0.8 g) in 10 mL acetone was added slowly 0.4 mL trifluoroacetic anhydride at 0° C. and the mixture was stirred at 0° C. for an additional hour. Then CH2Cl2 and aq sat sodium meta-bisulfite were added. The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue with 10% ethyl acetate-hexane gave 0.5 g of the title compound as a white solid. m.p. 58-61° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CS(O[CH2:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:19]1([CH2:18][CH2:17][O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)OCCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCC2CC2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 6 h
Yield: 84.2 %

Procedure:
A suspension of 4-methyl-3-nitrophenol (3 g), 2-cyclopropylethyl methanesulfonate (3.22 g) and potassium carbonate (2.71 g) in DMF (100 mL) was stirred at 80° C. for 6 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was extracted with ethyl acetate and water, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (NH, hexane/ethyl acetate) to give the title compound (3.65 g).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]1=[O:12].[CH3:13][C:14]1([CH3:29])[C@H:16](/[CH:17]=[C:18](\[CH3:25])/[CH:19]=[N:20][O:21][CH2:22][C:23]#[CH:24])[C@H:15]1[C:26](O)=[O:27].C(Cl)(Cl)Cl.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.[Cl-].[Na+].O>[CH3:13][C:14]1([CH3:29])[C@H:16](/[CH:17]=[C:18](\[CH3:25])/[CH:19]=[N:20][O:21][CH2:22][C:23]#[CH:24])[C@H:15]1[C:26]([O:1][CH2:2][N:3]1[C:7](=[O:8])[CH2:6][N:5]([CH2:9][C:10]#[CH:11])[C:4]1=[O:12])=[O:27]
Reactant: C#CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C#CCN1CC(=O)N(CO)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: C#CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OCN2C(=O)CN(CC#C)C2=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.12 g of 3-hydroxymethyl-1-(2-propynyl)imidazolidine-2,4-dione, 0.17 g of (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-(2-propynyloxyimino)-1-propenyl]cyclopropanecarboxylic acid, catalytic amount of 4-dimethylaminopyridine and 3 ml of anhydrous chloroform was added 0.16 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the mixture was stirred at room temperature overnight. Thereafter, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 2,5-dioxo-3-(2-propynyl)imidazolidin-1-ylmethyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-(2-propynyloxyimino)-1-propenyl]cyclopropanecarboxylate (hereinafter, referred to as the present compound (6)) represented by the formula (6):
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][NH2:13].[C:14]([N:19]=[C:20](OCC)[CH2:21][CH2:22][CH2:23][CH3:24])(OCC)=[O:15].C(Cl)Cl>CO>[CH2:21]([C:20]1[NH:19][C:14](=[O:15])[N:12]([C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[Cl:1])[N:13]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=NC(=O)OCC)OCC
Reactant: COC(=O)c1ccc(Cl)c(NN)c1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)[nH]1
Yield: 37 %

Procedure:
By the procedure of Example 4, Step C, the title compound was prepared from methyl 4-chloro-3-hydrazinobenzoate (from Step B) and ethyl N-carbethoxyvalerimidate (from Example 4, Step B) in 37% yield as an orange gum (TLC in 95:5 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 310 (M+1)+.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)nc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccnc1
Product: Cn1c(-c2ccc(C(F)(F)F)nc2)nc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(6-trifluoromethyl-pyridin-3-yl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 116) was reacted with pyridine-3-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 485.4 (MH+).
Reaction SMILES: C([N:4](O)[C:5]([C:7]1[CH:44]=[CH:43][C:10]([O:11][C:12]2[C:17]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:16][CH:15]=[C:14]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=[NH:42])[N:37](O)C(=O)C)=[CH:32][CH:31]=3)[N:13]=2)=[CH:9][CH:8]=1)=[NH:6])(=O)C>CO.[Pd]>[C:5]([C:7]1[CH:44]=[CH:43][C:10]([O:11][C:12]2[C:17]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]4[C:24](=[CH:5][CH:7]=[CH:8][CH:9]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:16][CH:15]=[C:14]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36](=[NH:42])[NH2:37])=[CH:32][CH:31]=3)[N:13]=2)=[CH:9][CH:8]=1)(=[NH:6])[NH2:4]
Reactant: CC(=O)N(O)C(=N)c1ccc(Oc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Oc3ccc(C(=N)N(O)C(C)=O)cc3)n2)cc1
Agent: [Pd]
Solvent: CO
Product: N=C(N)c1ccc(Oc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)c(Oc3ccc(C(=N)N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10% Pd/C (0.1 g) was added under an atmosphere of nitrogen gas to 2,6-bis-(4-(N-acetylhydroxycarbamimidoyl)-phenoxy)-3-(4-fluorobenzene-sulphonamido)-pyridine 0.3 g (0.44 mmol) dissolved in 50 ml methanol. 30 mg of 10% Pd/C was added under nitrogen atmosphere and the reaction mixture was stirred under hydrogen pressure (balloon) at room temperature for 3 h. The reaction mixture was passed through celite, washed with methanol and concentrated under reduced pressure. The concentrate was purified using reverse-phase preparative HPLC column to afford 0.06 g. of the required product. Percentage purity (HPLC): 85.01%, (LCMS): 82.73%. 1H NMR (DMSO-d6): 6.75 (2H, d), 6.9 (1H, d), 7.3 (2H, d), 7.5 (2H, d), 7.65 (2H, m), 7.8 (3H, d), 8.0 (4H, m), 8.35 (1H, s), 9.03 (4H, d), 9.2 (4H, s), 10.2 (1H, s).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:4][C:5]2[C:6]([N:17]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][OH:16])[O:8]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[NH:4][C:5]2[C:6]([N:17]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][O:16][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[O:8]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCc2ccc3[nH]c(C(F)(F)F)nc3c2O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Yield: 86.9 %

Procedure:
A solution of (2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclo-penta[a]naphthalen-8-yl)-methanol (400 mg, 1.47 mmol) and p-toluenesulfonyl chloride (344 mg, 1.76 mmol) in anhydrous pyridine (50 mL) was stirred for 12 hours and then the solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and washed with water (3×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent removed in vacuo to a residue. The residue was purified by chromatography (20% CH2Cl2-hexanes) to give 545 mg (87%) of the title compound as a solid: mp 160° C.; 1H NMR (400 MHz, CDCl3): [tautamer a]:δ1.95 (m, 1H), 2.05 (m, 1H), 2.44 (s, 3H), 2.90 (m, 2H), 4.30 (m, 2H), 4.40 (m, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.3 Hz, 2H), 10.35 (bs, 1H). [tautamer b]: δ1.95 (m, 1H), 2.05 (m, 1H), 2.44 (s, 3H), 2.90 (m, 2H), 4.25 (m, 2H), 4.40 (m, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 9.95 (bs, 1H); IR: 3400, 3080, 2970, 1600, 1550, 1500, 1080 cm−1; MS 427 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH3:13])[C:5]=1[Br:14].[OH-].[Na+]>C(O)C>[Br:14][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
To a solution of 2-bromo-3-methyl-5-nitro-benzoic acid methyl ester ((Example 295: step d) 5.04 g) in ethanol (50 mL) was added a solution of aq NaOH (4M, 1.62 g, 40.5 mmol) and stirred at ambient temperature for 16 h. The resulting red colored solution was concentrated to dryness, dissolved in a minimum amount of H2O, and acidified with 1 N HCl to pH 3–4. The solid was filtered, washed with H2O (3×50 mL) dried under high vacuum to afford the title compound (4.5 g, 94% yield) as a pale yellow solid. 1H NMR (DMSO) δ 8.36–8.35 (m, 1H), 8.24–8.23 (m, 1H), 2.53 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].CCCCCC.C([Li])CCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[Cl-].[NH4+]>O1CCCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([OH:34])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
2-Bromoanisole (5.0 g, 27 mmol) was dissolved in anhydrous tetrahydrofuran (60 ml) to which, while stirring, was subsequently added dropwise n-butyl lithium hexane solution (17 ml, 27 mmol) spending 20 minutes at −78° C. in an atmosphere of argon. After additional 30 minutes of stirring, to this was added dropwise anhydrous tetrahydrofuran solution (40 ml) of 1-t-butoxycarbonyl-4-piperidone (5.3 g, 27 mmol) spending 40 minutes. After additional 3.5 hours of stirring, to this was added saturated ammonium chloride aqueous solution (200 ml). The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then 5.2 g of the aforementioned compound of interest (17 mmol, 63% in yield) was obtained by evaporating the solvent under a reduced pressure.
Reaction SMILES: N[C:2]1[C:3]([I:16])=[C:4]([C:13]([OH:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[OH-].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+].[C-:28]#[N:29].[K+]>O.[Cu]Cl>[C:28]([C:2]1[C:3]([I:16])=[C:4]([C:13]([OH:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])#[N:29]
Reactant: [C-]#N
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Yield: 78.1 %

Procedure:
112 g of 5-amino-2,4,6-triiodoisophthalic acid is suspended in 1100 ml of water and dissolved by adding 10 g of sodium hydroxide. The solution is then cooled to 0° C. after adjusting same to pH 2.5 with sulfuric acid, and, under cooling, a solution of 20 g of sodium nitrite in 60 ml of water is added dropwise, the reaction temperature being maintained at 0-5° C. Then the pH value of the reaction mixture is again adjusted to 2.5 by the dropwise addition of dilute sulfuric acid, and the mixture is stirred under ice cooling for one to two hours. The thus-obtained precipitate is dissolved by gradual dropwise addition of dilute sodium hydroxide solution at pH 4.5. Subsequently the neutralized diazonium salt solution is poured into a solution of 99 g of copper(I) chloride and 172 g of potassium cyanide in 800 ml of water, heated to 30° C.; during this step, strong frothing occurs. The mixture is stirred for 15 minutes at 30° C. The reaction mixture is then acidified with dilute sulfuric acid to pH 2.8-3, and the precipitated copper salt is vacuum-filtered. The filtered solution is then brought to pH 0.5-1 by the further addition of dilute sulfuric acid. The thus-produced precipitate is vacuum-filtered after stirring for several hours in an ice bath, washed with water, and dried at 50° C. For purifying purposes, the crude product is suspended in 400 ml of water, dissolved by adding sodium hydroxide solution, the solution treated for 30 minutes with 10 g of active carbon, and the filtered solution is combined with an excess of a mineral acid. After stirring for several hours in an ice bath, the precipitate is vacuum-filtered, washed with water, and dried at 50° C., thus obtaining 89 g (78% of theory) of 5-cyano-2,4,6-triiodoisophthalic acid as a white powder, having a decomposition point of above 300° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:34])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][CH3:33])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[CH2:32]([O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[O:34])[CH:24]=1)[CH3:33]
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
4-[6-(2-Ethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (IX) (1.47 g, 3.19 mmol) was dissolved in methanol (20 ml) and 10% Pd/C (0.81 g) was added under an atmosphere of nitrogen. The reaction was stirred at room temperature under hydrogen balloon pressure for 18 hours. The catalyst was filtered from the reaction mixture through a celite bed and the filtrate was evaporated to dryness to obtain piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.61 g, 58%).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:10]1[C:31]([CH3:32])=[CH:30][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][N:26]=[C:25](Cl)[CH:24]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)(=O)C(C)(C)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[C:41]([O:40][C@@H:9]([C:10]1[C:31]([CH3:32])=[CH:30][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)[CH:24]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:8][OH:7])([CH3:43])([CH3:44])[CH3:42]
Reactant: CN1CCNCC1
Reactant: Cc1cc2nc(-c3cccc(-c4ccnc(Cl)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(-c3cccc(-c4ccnc(N5CCN(C)CC5)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 120 °C

Procedure:
The reaction mixture of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(3-(2-chloropyridin-4-yl)phenyl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (16 mg, 0.025 mmol), 1-methylpiperazine (1 mL) was heated at 120° C. overnight. Then the reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated. To the residue was added THF, MeOH, 2N NaOH, the mixture was heated at 45° C. After the reaction finished, the reaction was washed by sat NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C36H39ClN4O2S: 627.2 (M+H+); Found: 627.3 (M+H+).