Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.[Cl:21][C:22]1[N:27]=[C:26](I)[C:25]([OH:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[Cl:21][C:22]1[N:27]=[C:26]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:25]([OH:29])=[CH:24][CH:23]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Yield: 72026.3 %

Procedure:
To a solution of (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (126 g, 0.45 mol) and 6-chloro-2-iodopyridin-3-ol (96 g, 0.37 mmol) in 1,4-dioxane (1.8 L) and water (0.2 L) were added Pd(PPh3)2Cl2 (13.2 g, 18.6 mmol) and NaHCO3 (94.8 g, 1.13 mol) under nitrogen atmosphere, and the mixture was heated at 90° C. under N2 for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (900 mL), filtered and concentrated. The residue was diluted with H2O (400 mL) and EtOAc (800 mL), and the layer was separated, the aqueous layer was extracted with EtOAc (3*400 mL). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EtOAc=20:1˜3:1) to give 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (70 g, yield: 70.1%). 1H-NMR (MeOD, 400 MHz) δ 7.36 (s, 1H), 7.23˜7.27 (m, 2H), 7.03˜7.11 (m, 2H), 6.63˜6.68 (m, 1H). MS (M+H)+: 263 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH:27]2[CH:34]3[CH2:35][CH:30]4[CH2:31][CH:32]([CH2:36][CH:28]2[CH2:29]4)[CH2:33]3)=[O:25])[CH2:19]1)=[O:17])[CH3:14].[CH3:37][O:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1([CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[O:38][CH3:37])[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH:27]2[CH:28]3[CH2:29][CH:30]4[CH2:31][CH:32]([CH2:33][CH:34]2[CH2:35]4)[CH2:36]3)=[O:25])[CH2:19]1)=[O:17])[CH3:14]
Reactant: COc1ccccc1CBr
Reactant: CCOC(=O)C1CCCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2OC)CCCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a stirred solution of diisopropylamine (6.3 g, 62.7 mmol) in dry THF (120 mL) at −20° C. under N2 was added 2.5 M n-BuLi (25.1 mL, 62.7 mmol). The resulting solution was added dropwise to a stirred solution of 1-(2-adamantyl) 3-ethoxycarbonylpiperidine-1-carboxylate (14.0 g, 41.8 mmol) in dry THF (170 mL) at −70° C. The mixture was stirred for 1 h at −70° C. and 2-methoxybenzyl bromide (10.9 g, 54.3 mmol) was added. The mixture was stirred for 4 h at rt, quenched with brine and extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography to afford the title compound (14.3 g, 75%). LC-MS Method 3 tR=2.04 min, m/z=456.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:45])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:33]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]4[CH:40]=[CH:41][CH:42]=[CH:43][C:34]3=4)=[O:32])=[CH:27][C:26]=2[CH3:44])[CH2:13][C:12]1=[O:46])(C)(C)C.Cl.O1CCOCC1>C1(C)C=CC=CC=1>[CH3:44][C:26]1[CH:27]=[C:28]([C:31]([N:33]2[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3[CH:40]=[CH:41][CH:42]=[CH:43][C:34]2=3)=[O:32])[CH:29]=[CH:30][C:25]=1[CH2:24][NH:23][C:22]([N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:11]([CH2:10][CH2:9][CH2:8][NH2:7])[C:12](=[O:46])[CH2:13]1)=[O:45]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CCCNC(=O)OC(C)(C)C)c2cccc(F)c21
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CCCN)c2cccc(F)c21
Reaction time: 0.5 h

Procedure:
(3-{5-Fluoro-4-[2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)-benzylcarbamoyl]-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl}propyl)carbamic acid tert-butyl ester from Example 15B (90 mg, 0.14 mmol) was added to a solution of 4N HCl/dioxan (10 ml) and the mixture was stirred for 0.5 h. The mixture was diluted with toluene, evaporated in vacuo and azeotroped with toluene to give a pale yellow solid; yield 82 mg, 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])=[CH:4][CH:3]=1.C([NH:29][CH2:30][C:31](O)=[O:32])(OCC1C=CC=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl>C(Cl)(Cl)Cl.CO.[Pd]>[NH2:29][CH2:30][C:31]([NH:18][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:32]
Reactant: CC(N)(Cc1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(F)cc1)(NC(=O)CN)c1ccc(F)cc1
Yield: 29.8 %

Procedure:
To a stirred solution of 1,2-bis(4-fluorophenyl)-2-propylamine (12.0 g, 0.049 mol) in chloroform (200 ml) under nitrogen was added N-CBZ-glycine (10.16 g, 0.049 mol) and then a solution of dicyclohexylcarbodiimide (11.35 g, 0.055 mol) in chloroform (100 ml) and the mixture stirred for 30 minutes, then filtered and the solvent evaporated. The residue was treated with ethyl acetate (200 ml), filtered, an additional 200 ml of ethyl acetate added, and then washed with cold 1% HCl (200 ml), brine (200 ml), dried, and the solvent evaporated to give a pale yellow oil. This was dissolved in methanol (400 ml) and 10% HCl (35 ml) and hydrogenated at 40 psi in a Parr apparatus over 2.5 g of 5% Pd/C catalyst for 2.5 hours. The catalyst was removed by filtration, solvent evaporated and the residue dissolved in water (300 ml) and chloroform (500 ml), basified to pH 11 with 50% NaOH, shaken and separated. The aqueous phase was extracted with chloroform (2×200 ml) and the combined organic phases washed with water (2×150 ml), brine (150 ml), dried and evaporated to a pale yellow oil which solidified on standing. The solid was recrystallised three times from cyclohexane (150 ml) and ethanol (10 ml) and vacuum dried to give 4.44 g of 2-amino-N-[1,2bis(4-fluorophenyl)-1-methylethyl]acetamide, mp 130°-131° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[N:9]2[CH:24]=[CH:25][CH:26]=[C:8]2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[OH:27][C:7]1[C:8]2[N:9]([CH:24]=[CH:25][CH:26]=2)[N:10]([CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:11](=[O:12])[C:6]=1[C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5]
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc3ccccc3c2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc3ccccc3c2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 4-hydroxy-1-naphthalen-2-ylmethyl-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 392 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N>[O:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 53 %

Procedure:
A mixture of N-(4-bromobutyl)phthalimide) (2.00 g, 7.09 mmol), phenol (0.67 g, 7.09) and K2CO3 (1.96 g, 14.18 mmoml) in dry MeCN (30 ml) was stirred at rt for 66 h. The reaction mixture was then warmed to 50° C. for 20 h before more phenol (0.33 mg, 3.54 mmol) was added and the resulting mixture was warmed at reflux. After 4 h EtOAc was added, the mixture was washed with brine, then 1N NaOH, and brine again before evaporated the organic phase to dryness to give the title compound (1.11 g, 53%) which was used without further purification. 1H NMR (500 MHz CDCl3): δ 7-90-7.83 (m, 2H), 7.76-7.70 (m, 2H), 7.28 (t, 2H), 6.93 (t, 1H), 6.89 (d, 2H), 4.01 (t, 2H), 3.79 (t, 2H), 1.96-1.82 (m, 4H); Mass Spectrum: M+H+ 296.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:6]=2[CH:17]=1.N1CCCCC1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>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.[Cu]I>[NH2:16][C:12]1[N:11]=[C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:32]#[C:31][C:29]([C:25]4[S:24][CH:28]=[CH:27][N:26]=4)([OH:33])[CH3:30])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1nccc(-n2cnc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2ncn(-c3ccnc(N)n3)c2c1)c1nccs1
Temperature: 75 °C
Reaction time: 3.5 h

Procedure:
To a pressure tube was added 4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (70% purity, 790 mg, 1.91 mmol), followed by piperidine (4 mL), tetrakis(triphenylphosphine)palladium (220 mg, 0.19 mmol), copper(I) iodide (36.3 mg, 0.19 mmol)) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (584.04 mg, 3.81 mmol). The reaction was capped and stirred at 75° C. for 3.5 hr. The reaction mixture was concentrated in vacuo and purified by flash chromatography (Isolute column, 2% MeOH in DCM to 3% MeOH in DCM) followed by reverse phase preparative HPLC to give the title compound as a pale yellow solid: 1H NMR (500 MHz, DMSO) δ 1.92 (3H, s), 7.03 (1H, br. s.), 7.08-7.20 (3H, m), 7.38 (1H, dd, J=8.35, 1.58 Hz), 7.69 (1H, d, J=3.15 Hz), 7.74 (1H, d, J=8.35 Hz), 7.78 (1H, d, J=3.31 Hz), 8.38 (1H, d, J=5.52 Hz), 8.56 (1H, d, J=0.95 Hz), 9.08 (1H, s); LC-MS: m/z=+363.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29][O:18][C:15]1[CH:16]=[CH:17][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=3)[CH:8]=2)[C:13](=[O:19])[CH:14]=1
Reactant: OCc1cc2ccccc2o1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4cc5ccccc5o4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), 1-benzofuran-2-ylmethanol (58 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (16 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Fc1ccc(SCCCBr)cc1
Reactant: CCCCc1nc2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2ccccc2n1C1CCN(CCCSc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
To a stirred solution of 1-(3-bromopropylsulfanyl)-4-fluorobenzene (0.2 g) and 2-butyl-1-piperidin-4-yl-1H-benzimidazole (0.3 g) in DMF (5 ml) was added K2CO3 (0.6 g) and KI (0.05 g). The mixture was heated at 100° C. for 1 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (9:1 DCM:MeOH) to yield 0.3 g of the title compound as colourless crystals. Mp. 159-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccc(Cl)cc2)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-cyclopentyl]-methanol (319) (12 g, 56.95 mmol) in dichloromethane (110 mL) was added triethyl amine (16 mL, 113.90 mmol) followed by mesyl chloride (5.3 mL, 68.34 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, diluted with dichloromethane (50 mL) and washed with water (100 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic part was dried, concentrated and purified by CombiFlash column (eluted at 10-20% ethyl acetate in hexane) to get methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (320) (14 g, 85%) as a light yellow crystalline solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]([NH:22][CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][CH2:28][CH2:29][C:24]([CH2:23][NH:22][CH2:20][CH3:21])([OH:30])[CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCNCC1(O)CCCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: CCNCC1(O)CCCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 1 with 3-ethylaminomethyl-3-hydroxypiperidine to give 1-cyclopropyl-7-(3-ethylaminomethyl-3hydroxy-1-piperidinyl)-6-fluoro-1,4dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 199°-203° (with decomposition).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]([Cl:16])([Cl:15])[C:11](=N)OC>C(O)(=O)C>[Cl:9][C:10]([Cl:16])([Cl:15])[C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Nc1ccccc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1.0 Gram of an o-phenylenediamine compound [compound (207)] of the formula (XII) in which X is H and Z is CF2CF2O was dissolved in 20 ml of acetic acid. 1.4 Grams of methyl trichloroacetoimidate was added thereto at room temperature. The resulting mixture was stirred for 12 hours. The reaction solution was poured into ice water, and precipitated crystals were filtered off. The crystals were dissolved in ethyl acetate. The resulting solution was washed with water and dried over anhydrous sodium sulfate. Removing the solvent from the dried layer by distillation gave 1.0 g of a 2-(trichloromethyl)benzimidazole compound [compound (107)] of the formula (XI) in which X is H and Z is CF2CF2O.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:24]3[S:25][C:26]4[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:14][CH:15]2[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Clc1nc2ccccc2s1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nc4ccccc4s3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-benzothiazole. MS (ESI) mass calcd. for C26H23N3OS, 425.56; m/z found, 426.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:35][CH2:36][N:32]([CH3:31])[C:33]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 13.6 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 166 and 1-methylimidazolidin-2-one (60 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (35 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:39])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([CH:23]([OH:39])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][CH:30]=2)[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC(Cc1ccc(OCc2ccccc2)cc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
2 g (3.9 mmol) of recrystallized 1-(3,5-dibenzyloxyphenyl)-2-(4-benzyloxyphenyl)ethanone prepared according to Example 5 are introduced into a 100 ml round-bottomed flask and are dissolved in 30 ml of methanol and 25 ml of THF. Approximately 0.147 g of sodium borohydride is added in small fractions at ambient temperature over 1 hour. The medium is kept stirred for 1 h and concentrated, 30 ml of water are added and the medium is extracted with 60 ml of MTBE. The MTBE phase is concentrated to produce 2 g of a light yellow oil which crystallizes over time. 5 ml of methanol are added to this product, the mixture is kept stirred for 1 h and then the white precipitate obtained is filtered off. After drying at vacuum at 35° C., 1.3 g of 1-(3,5-dibenzyloxyphenyl)-2-(4-benzyloxyphenyl)ethanol are recovered in the form of a white solid with a melting point of 80-81° C., i.e. a yield of 65% with respect to the starting ketone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:33][C@@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:33][C@@H:34]1[CH2:38][CH2:37][O:36][CH2:35]1
Reactant: COc1ccc(-c2ccnn2-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1O[C@@H]1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccnn2-c2ccc(N3CCNCC3)cc2)cc1O[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
Into a vial was added tert-butyl 4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate (20.0 mg, 0.0384 mmol) and 1 mL of a 20% (v/v) solution of TFA in CH2Cl2. The reaction was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. The residue was dissolved in 10 mL of ethyl acetate and washed once with 10 mL of saturated aqueous NaHCO3. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give 13 mg (0.0309 mmol, 80%) of 1-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine as a yellow oil. LC/MS (EI) tR 2.02 (Method C), m/z 421.2 (M++1). 1H NMR (CDCl3 300 MHz) δ 1.9 (m, 4H); 3.0 (d, 4H); 3.1 (d, 4H); 3.7-3.9 (m, 3H); 3.8 (s, 3H); 4.6 (m, 1H); 6.4 (s, 1H); 6.5 (s, 1H); 6.8 (m, 3H); 7.0 (d, 1H); 7.2 (d, 2H); 7.7 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[S:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[OH:36])[CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[O:16]=[C:15]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:36][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:35]=2[S:26][CH2:27][CH2:28][CH2:29]3)[C:7](=[O:17])[CH2:8][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:14]1
Reactant: Oc1cccc2c1SCCC2
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCOc1cccc2c1SCCC2

Procedure:
2 g (6.62 mmol) of 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione, 2.5 g (18.04 mmol) of potassium carbonate and a catalytic amount of potassium iodide are added, with stirring, to 1 g (6.015 mmol) of 8-thiochromanol dissolved in 10 cm3 of N,N-dimethylformamide.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:37]([C:36]2[CH:40]=[CH:41][C:33]([N:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][CH2:29]3)=[N:34][CH:35]=2)=[O:38])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Reactant: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methanamine 84-2 (53 mg, 0.195 mmol), 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid 46-1 (16 mg, 0.195 mmol), and HATU (81.5 mg, 0.214 mmol) were added N,N-diisopropylethylamine (DIEA, 52 μL, 0.298 mmol) and DMF (1.0 mL). The solution was stirred overnight at room temperature and was subjected to silica gel column chromatography with 1:1 ethyl acetate/hexanes as eluent to give tert-butyl 4-(5-(((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate 46-2.