Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.C(OCC)(=O)C>[CH2:22]([O:29][C:30]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][CH2:2]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCCCCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorohexanoate (10 g) in ethanol (200 ml) is catalytically hydrogenated over 10% palladium-carbon (5 g, 50% wet) at ordinary temperature under atmospheric pressure. After the absorption of hydrogen has ceased, the catalyst is removed by filtration and the filtrate is evaporated in vacuo to yield ethyl 6-(4-piperidyl)hexanoate. This ester is dissolved in a mixture of water (100 ml), ethyl acetate (200 ml) and sodium bicarbonate (10 g). Benzyloxycarbonyl chloride (7.2 ml) is added dropwise at room temperature and the resulting mixture is stirred overnight. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is purified by silica gel column chromatography using hexane-ethyl acetate (4:1) as an eluent to give ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)hexanoate (7.7 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(N(C(C)C)CC)(C)C.CS(C)=O>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[CH:10]=[O:11])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-2-dibenzylamino-3-(2-fluoro-phenyl)-propan-1-ol (1 g, 2.9 mmol) in 2 mL of diisopropyl-ethyl-amine at 10° C. is slowly added a solution of sulfur trioxide pyridine complex (1.4 g, 8.6 mmol) in 5 mL of DMSO. The reaction is allowed to stir at room temperature for 45 minutes after which time the reaction is quenched by addition of ice water. The product is extracted into ether and the combined organic phases are washed with water, 5% citric acid, and brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduce pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:11])=[CH:4][C:3]=1[OH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:53][S:54]([N:57]1[CH2:61][CH2:60][CH:59](O)[CH2:58]1)(=[O:56])=[O:55]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH3:11])=[CH:4][C:3]=1[O:19][CH:59]1[CH2:60][CH2:61][N:57]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:58]1
Reactant: CS(=O)(=O)N1CCC(O)C1
Reactant: C[C@@H](NCc1ccc(Cl)c(O)c1)c1cccc(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(OC2CCN(S(C)(=O)=O)C2)c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenol 96 (150 mg, 506 μmol) in 5 mL of THF under N2 was added triphenylphosphine (146 mg, 557 μmol). The solution was chilled to 0° C. in an ice bath and then diisopropyl azodicarboxylate (108 μL, 557 μmol) was added dropwise to the reaction. After stirring for 15 min 0° C., a solution of 1-(methylsulfonyl)pyrrolidin-3-ol (84 mg, 506 μmol) in THF was added to the reaction. The reaction was allowed to warm to room temperature and it was stirred for 10 h. The reaction was concentrated and diluted with EtOAc. The organic solution was extracted with saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 10% to 80% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (1R)—N-(4-chloro-3-(1-(methylsulfonyl)pyrrolidin-3-yloxy)benzyl)-1-(3-chlorophenyl)ethanamine 99 (83 mg, 37% yield) as a colorless oil and as a mixture of diastereomers. 1H NMR (400 MHz, d4-methanol) δ ppm 1.26 (d, 1H) 1.73 (d, J=6.85 Hz, 3H) 2.25-2.32 (m, 2H) 2.91 (s, 3H) 3.51-3.60 (m, 2H) 3.62-3.66 (m, 2H) 4.00 (d, 1H) 4.20 (d, 1H) 4.50 (m, 1H) 5.08-5.13 (m, 1H) 6.99-7.07 (m, 1H) 7.14-7.18 (m, 1H) 7.43-7.52 (m, 4H) 7.57 (m, 1H). Mass spectrum: calculated for C20H24Cl2N2O3S 443.4. found 444.4 (M++1).
Reaction SMILES: O[CH2:2][CH2:3][C@@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.CS(Cl)(=O)=O.C([N:18](CC)CC)C.[N-]=[N+]=[N-].[Na+]>ClCCl.CN(C)C=O.C(OCC)(=O)C.O=[Pt]=O>[CH3:9][C:6]1([CH3:10])[O:5][C@H:4]([CH2:3][CH2:2][NH2:18])[CH2:8][O:7]1
Reactant: CC1(C)OC[C@@H](CCO)O1
Reactant: CCN(CC)CC
Agent: O=[Pt]=O
Agent: CS(=O)(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](CCN)O1

Procedure:
Step A In a manner similar to the method described in Example 3a Step A to C, (4R)-(−)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich) (4.91 g, 33.6 mmol) was reacted with methanesulfonyl chloride (3.12 mL, 40.3 mmol) and triethylamine (9.34 mL, 67 mmol) in dichloromethane, then reacted with NaN3 (10.7 g, 0.16 mol) in N,N-dimethylformamide, then treated with PtO2 and H2 (50 psi) in ethyl acetate to give 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine as a brown oil (4.4 g, 90% for three steps).
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:12]1[CH2:14][CH2:13]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH:12]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[OH:4])[CH2:14][CH2:13]1
Reactant: CC(=O)Oc1c(C)cccc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cccc(C2CC2)c1O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 67.6 %

Procedure:
A 500 ml three-necked round-bottomed flask was equipped with a magnetic stirrer bar, a thermometer and a drying tube. A solution of 2-cyclopropyl-6-methylphenyl acetate (18.3 g, 96.2 mmol) in methanol (100 ml) was added thereto. Potassium carbonate (26.5 g, 192 mmol) was added thereto at once and the mixture was stirred at room temperature for 75 minutes. After water (300 ml) was added to the reaction mixture, the resulting mixture was concentrated by an evaporator to remove most of methanol. The obtained mixture was cooled to 0° C. and 4M hydrochloric acid (100 ml) was added thereto such that the temperature of the mixture did not exceed 25° C. This was extracted with a 10% ethyl acetate-90% hexane (V/V) solvent mixture (3×200 ml). The organic layer was combined and successively washed with water (2×200 ml) and a saturated aqueous NaCl solution (50 ml), followed by drying with anhydrous sodium sulfate (90 g). After the solid was removed by filtration and the filtrate was concentrated to obtain 13.8 g of a crude product of 2-cyclopropyl-6-methylphenol as a brown oil. The crude product was distilled (7.6-7.8 mmHg, 94-98° C.) to obtain 9.64 g of 2-cyclopropyl-6-methylphenol as a light purple oil.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:32][CH3:33])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([NH2:31])=[O:30])[CH:23]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([NH2:31])=[O:30])[CH:23]=2)[C:15]([O:32][CH3:33])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(F)c(C(N)=O)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1ccc(F)c(C(N)=O)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (23 mg, 0.12 mmol), 3′-(1-aminoethyl)-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxamide (36 mg, 0.11 mmol), and N,N-diisopropylethylamine (0.037 mL, 0.21 mmol) in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H21ClFN6O2 (M+H)+: m/z=455.1. found: 455.1.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([O:10][C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[CH:14]=[C:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>C(Cl)Cl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([O:10][C:11]3[CH:30]=[CH:29][CH:28]=[C:13]([CH:14]=[C:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[CH:12]=3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(C4CC4)cn3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=C1CCNCC1)c1cccc(Oc2ccc(C3CC3)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of tert-butyl 4-(3-(5-cyclopropylpyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (350 mg, 0.861 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (2 mL, 25.8 mmol). The reaction was stirred at RT overnight. The reaction was concentrated to give an oil. CH2Cl2 was added and the mixture was concentrated again to give the title compound as an oil (253 mg, 70% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[F:24][CH:25]([F:28])[CH2:26][NH2:27]>>[F:24][CH:25]([F:28])[CH2:26][NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: NCC(F)F
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(F)F)cn1
Yield: 80 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2,2-difluoroethylamine instead of methylamine, to the title compound (96 mg, 80%) which was obtained as an off white solid. MS: m/e=374.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][N:3]1[CH2:7][C:8](Cl)=[O:9].[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>O1CCCC1.C(Cl)(Cl)Cl>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:8](=[O:9])[CH2:7][N:3]3[C:2](=[O:1])[CH2:6][S:5][CH2:4]3)[CH2:12][CH2:13]2)=[CH:18]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C(Cl)CN1CSCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CN1CSCC1=O)N1CCC(c2c[nH]c3ccccc23)CC1
Yield: 27.5 %

Procedure:
A solution of 4-oxo-3-thiazolidinylacetyl chloride (1.75 g) in tetrahydrofuran (5.00 ml) was added dropsise to a suspension of 3-(4-piperidyl)indole (2.00 g) and triethylamine (4.10 ml) in a mixture of tetrahydrofuran (15.0 ml) and chloroform (5.00 ml) at 4° to 7° C. with stirring. After the mixture was allowed to stir for 1 hour with ice-bath cooling, the resultant precipitate was removed by filtration and the solvent was evaporated in vacuo. The residue was mixed with saturated aqueous sodium hydrogen carbonate (10.0 ml) and the mixture was extracted with chloroform (20.0 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of methanol and acetone to give 4-(3-indolyl)-1-[(4-oxo-3-thiazolidinyl)acetyl]piperidine (0.92 g) as slightly brown prisms.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([O:36][CH3:37])=[O:35]>CS(C)=O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36][CH3:37])=[O:35])[CH:7]=1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cccc32)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cccc32)c1
Temperature: 170 °C
Yield: 24.9 %

Procedure:
A mixture of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 35 mg, 0.12 mmol) and methyl 3-(4-amino-1H-indazol-1-yl)benzoate (Intermediate 9) (32.7 mg, 0.12 mmol) was heated by microwave (250 W) at 170° C. for 45 minutes. The crude product was cooled, dissolved in DMSO/MeOH and purified by mass-directed autopreparation. The appropriate fractions were evaporated, dissolved in DCM, washed with aqueous sodium bicarbonate, passed through a hydrophobic frit and evaporated to give the title compound (16.7 mg).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH:12]1([C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH2:14][CH2:13]1.[Cl-].[NH4+]>C1COCC1>[CH:12]1([C:15]([CH:17]2[CH2:19][CH2:18]2)([OH:16])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH2:14][CH2:13]1
Reactant: O=C(C1CC1)C1CC1
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(O)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of trimethylsilylacetylene (5 mL, 35.4 mmol) in THF (100 mL) cooled at −78° C., a 1.6M n-butyllithium in hexanes (22.1 mL, 35.4 mmol) was added dropwise. The solution was stirred for 30 min before dicyclopropyl ketone (4.06 mL, 35.4 mmol) was added. The temperature was then slowly raised to room temperature and the reaction was stirred overnight. The reaction was then poured into a saturated ammonium chloride solution and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 4.14 (s, 1H), 1.22-1.10 (m, 2H), 0.65-0.55 (m, 2H), 0.50-0.30 (m, 6H), 0.14 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:12][CH2:13][O:14][CH3:15])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:18][CH3:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[N:6]([CH2:12][CH2:13][O:14][CH3:15])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:18][CH3:19])=[N:22][CH:23]=1
Reactant: COCCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3CCOC)ncc1Cl

Procedure:
Analogous to procedure Example 101b, 7-Amino-6-methoxy-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (50 mg, 0.190 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (55 mg, 0.185 mmol) were converted to the desired product 12X (26 mg, 27%), purified by ISCO chromatography. 1H-NMR (CDCl3) δ 11.09 (s, 1H), 8.65 (d, J=8.3 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.14 (s, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 712 (t, J=7.5 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.21 (br s, 1H), 3.80 (s, 3H), 3.54 (br m, 2H), 3.28 (s, 3H), 3.05 (d, J=5.0 Hz, 3H), 2.32 (br m, 2H), 1.0-2.5 (low, broad m's, 6H); LC/MS (ESI-pos) m/z 525.37 (M+H). M.P.=205-207° C.
Reaction SMILES: [C:1](=[O:3])=O.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl>[C:5]1([N:4]=[C:1]=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccccc1
Reactant: O=C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C=Nc1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (20 mL) solution containing aniline (Ph--NH2) (0.02 mol, 1.86 g) and triethylamine (0.06 mol, 6.0 g) at -10° C. (ice and salt bath) for 40 min at a pressure of 0 psig. The reaction mixture was transferred rapidly via cannula under carbon dioxide to the precooled solution of phosphorus oxychloride (0.02 mol, 3.2 g) in 20 mL dichloromethane. After stirring for ca. 30 min at -10° C. a white ppt. formed. The ppt. was filtered off and the filtrate concentrated in vacuo. The residue was extracted with 3×20 mL diethyl ether. The ether layers were concentrated and the residue was distilled under vacuum (ca. 0.1-0.3 torr) collecting product, phenyl isocyanate, at 71°-73° C. (1.45 g, 61%) of 99% purity as judged by GC. IR (neat) 2266 cm-1. 1H NMR (CDCl3) δ 7.30 (t, 2H, J=7.8), 7.17 (t, 1H, J=7.5), 7.07 (d, 2H, J=6.7) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1Cl)[N:15]([NH:20][CH3:21])[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]2=[O:25].[B:26]([F:29])([F:28])[OH:27]>CS(C)=O>[F:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[N:15]([NH:20][CH3:21])[CH:14]=[C:13]([C:22]([OH:24])=[O:23])[C:12]2=[O:25].[B:26]([F:29])([F:28])[OH:27]
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN1CCNCC1
Agent: OB(F)F
Solvent: CS(C)=O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 6.87 g of 4-methyl-piperazine and 7.26 g of an anhydride of 6-fluoro-7-chloro-1-methylamino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and difluoroboric acid formed with 36 ml of dimethyl sulfoxide is stirred at 110° C. for 3 hours. As the reaction proceeds yellow crystals precipitate gradually from the reaction mixture. The anhydride of 6-fluoro-1-methylamino-7-(4-methyl-piperazino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and difluoroboric acid thus formed is hydrolyzed without isolation from the reaction mixture as follows:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:21]([F:22])=[CH:20][C:19]2[N:18]=[CH:17][C:16]3[N:23]([CH3:33])[C:24](=[O:32])[N:25]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:15]=3[C:14]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[F:22][C:21]1[C:12]([C:5]2[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][C:14]2[C:15]3[N:25]([CH:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[C:24](=[O:32])[N:23]([CH3:33])[C:16]=3[CH:17]=[N:18][C:19]=2[CH:20]=1
Reactant: Cn1c(=O)n(C2CCOCC2)c2c3cc(Br)c(F)cc3ncc21
Reactant: OB(O)c1ccc(F)nc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)n(C2CCOCC2)c2c3cc(-c4ccc(F)nc4)c(F)cc3ncc21
Temperature: 80 °C
Yield: 88.2 %

Procedure:
(6-Fluoropyridin-3-yl)boronic acid (0.445 g, 3.16 mmol), 8-bromo-7-fluoro-3-methyl-1-(oxan-4-yl)imidazo[5,4-c]quinolin-2-one (1 g, 2.63 mmol) and 2M K2CO3 (3.95 mL, 7.89 mmol) were suspended in dioxane (3 mL) and water (0.75 mL). The reaction was degassed with nitrogen and then dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (0.086 g, 0.13 mmol) was added and the reaction heated to 80° C. for 1 h in the microwave reactor. The mixture was allowed to cool, diluted with water then extracted with DCM (2×100 mL). The combined organic phases were separated and concentrated in vacuo. The crude product was purified by FCC, elution gradient 0 to 10% methanolic ammonia in DCM, to afford the desired material as a beige solid (0.92 g, 88%). NMR Spectrum: 1H NMR (500 MHz, DMSO-d6) δ 1.90 (2H, dd), 2.69 (2H, qt), 3.49-3.59 (5H, m), 3.97-4.06 (2H, m), 5.08 (1H, tt), 7.38-7.45 (1H, m), 7.96 (1H, d), 8.34-8.42 (2H, m), 8.61-8.65 (1H, m), 8.95 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=397
Reaction SMILES: C[O:2][C:3](=[O:28])[C@:4]([NH2:27])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:8][CH:7]=1.[OH-].[Na+].CCOCC>O>[C:23]([O:22][C:20]([C@:4]([NH2:27])([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:10][CH:11]=1)[C:3]([OH:28])=[O:2])=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: COC(=O)[C@@](N)(Cc1ccc(-c2ccccc2OC)cc1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1-c1ccc(C[C@](N)(C(=O)O)C(=O)OC(C)(C)C)cc1

Procedure:
A solution of (S)-2-t-butoxycarbonyl-amino-3-(2'-methoxybiphenyl-4-yl)-propionic acid methyl ester (4.1 g in methanolic 1N sodium hydroxide (60 mL) is stirred at room temperature for 3 hours. Ether (30 mL) and water (30 mL) are added. The aqueous layer is separated and acidified with concentrated HCl, then extracted with ether (2×20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gives (S)-2-t-butoxycarbonyl-amino-3-(2'-methoxybiphenyl-4-yl)-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:46][CH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1CBr
Temperature: 80 °C

Procedure:
The compound of example 220 (5 g, 0.0184 mol) was dissolved in carbon tetrachloride (125 mL). Benzoyl peroxide (250 mg) and NBS (3.6 g, 0.0202 mol) were added and the reaction mixture was refluxed at 80° C. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to yield crude residue containing 85% mono bromo and 10% dibromo product and 5% starting material. The crude title compound obtained was used directly for preparation of compound of example 222.