Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8](=[O:20])[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)=O>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]([C:9]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[CH:12][N:11]=1)=[O:20]
Reactant: COC(=O)C(=O)NCc1ccc(F)cn1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ncc2ccc(F)cn12
Temperature: 105 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
In a round-bottomed flask, N-(5-fluoro-pyridin-2-ylmethyl)-oxalamic acid methyl ester (crude from Step 1) was dissolved in toluene (8 ml) and phosphorus oxychloride (1.5 ml, 16.1 mmol) was added. The reaction mixture was stirred at 105° C. in an oil bath overnight then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-50% EtOAc) to give 230 mg (31%, 2 steps) of 6-fluoro-imidazo[1,5-a]pyridine-3-carboxylic acid methyl ester as a light brown solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.33 (dd, J=5.1, 1.3 Hz, 1H), 7.75 (s, 1H), 7.69 (dd, J=9.8, 5.3 Hz, 1H), 7.09 (ddd, J=9.7, 7.5, 2.1 Hz, 1H), 4.06 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([F:19])=[C:16]([OH:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:13]1[CH:14]=[C:15]([F:19])[C:16]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:17][C:12]=1[NH2:11]
Reactant: Nc1cc(O)c(F)cc1F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 2-chloro-5-nitropyridine (5.55 g, 35 mmol), 5-amino-2,4-difluorophenol (5.08 g, 35 mmol) and potassium carbonate (4.84 g, 35 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from diethyl ether to give the title compound (9.35 g, quantitatively) as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:3]2[C:2]([C:33]3[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][C:34]=3[Cl:36])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Temperature: 100 °C
Yield: 51.5 %

Procedure:
To a degassed solution of 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.02 mmol), 2,4-dichlorophenylboronic acid (8.0 mg, 0.041 mmol) and K2CO3 (8.5 mg, 0.061 mmol) in 1,4-dioxane (0.3 mL) and H2O (0.1 mL) was added Pd(PPh3)4 (2.3 mg, 0.002 mmol) under argon at 20° C. The reaction mixture was heated at 100° C. for 2 h under argon, then allowed to cool to 20° C. The reaction was concentrated in vacuo, and the residue was purified using reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μC18 30×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm) to afford 5.5 mg (55%) of the title compound as a white solid. LC/MS (method B): retention time=2.03 min, [M+H]+=533.2.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:17]1[O:19][C@@H:18]1[C:20]([O:22]CC)=[O:21])=[O:16])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].C(O)C.O.Cl>C(O)C>[OH:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:17]1[O:19][C@@H:18]1[C:20]([OH:22])=[O:21])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl (2S,3S)-3-[[1-(S)-[α-(R)-hydroxybenzyl]-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (558 mg, 1.66 mmol.) in ethanol (4 mL) was dropwise added 0.5N potassium hydroxide/ethanol solution (4.0 mL, 2.0 mmol.) under chilling with ice. The mixture was stirred for 4 hours at room temperature, and made acidic to reach pH 1-2 by addition of water (40 mL) and 2N hydrochloric acid (approx. 2 mL). The acidic mixture was extracted with three portions of ethyl acetate. The three extracts were combined and washed successively with water and an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the titled compound as a white amorphous product (490 mg, yield 96%).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:14]1[CH2:19][C@@H:18]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17][CH2:16][C@H:15]1[CH3:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[CH2:20]([C@@H:18]1[CH2:19][N:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:15]([CH3:27])[CH2:16][N:17]1[C:29]([O:31][CH3:32])=[O:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@@H]1CN[C@H](Cc2ccccc2)CN1Cc1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Pyridine (0.3 mL, 3.7 mmol) was added to a stirring solution of (2R,5R)-1,5-dibenzyl-2-methylpiperazine (0.28 g, 1.0 mmol) and methyl chloroformate (0.10 g, 0.087 ml, 1.1 mmol) in CH2Cl2 (11 ml). After stirring at ambient temperature for 1 day, the reaction was evaporated in vacuo and the residue purified by flash chromatography (SiO2, 5% MeOH in CH2Cl2) to afford pure product (0.17 g, 49% yield over the two steps). MS (ESI) 339 (M+H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:2]1([C:1]([OH:12])=[O:11])[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)C1CCCC(C(=O)O)C1
Yield: 94.9 %

Procedure:
To a suspension of isophthalic acid (5.0 g, 30.1 mmol) in 45 ml of acetic acid was added a slurry of 0.1 g of platinum oxide in 5 ml of acetic acid. The resulting mixture was stirred under 50 psi of hydrogen at 25° C. for 16 hours. NMR analysis (DMSO-d6) at this time showed complete reduction of starting material. The reaction mixture was filtered through Celite and the filter cake was rinsed with methanol. The combined filtrate and washes were concentrated under reduced pressure, using heptane to azeotropically remove residual acetic acid. Trituration of the resultant semi-solid with heptane and filtration of the precipitate provided 4.92 g (95%) of the title compound as a white powder. mp: 163-165° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH3:26][S:27]([OH:30])(=[O:29])=[O:28]>CCO>[S:27]([OH:30])(=[O:29])(=[O:28])[CH3:26].[NH:12]([C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncnc2cccnc12
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc(Nc2ncnc3cccnc23)cc1
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A solution of 4-chloropyrido[3,2-d]pyrimidine (84 mg, 0.5 mmol), aniline (56 mg, 0.6 mmol) and triethylamine (62 mg, 0.6 mmol) in EtOH (2 mL) are refluxed under N2 with stirring for 2 h. The crude reaction mixture is purified on a preparative tlc plate (silica), eluting once with 3% MeOH in CHCl3. The major band is extracted, and evaporated to dryness under reduced pressure, and the residual solid is dissolved in acetone, (5 mL), filtered, and methanesulfonic acid (32 μL, 0.5 mmol) is added slowly with swirling. The precipitate is collected by suction filtration, rinsed with acetone and dried in a vacuum oven to give 4-anilinopyrido[3,2-d]pyrimidine mesylate (91 mg, 57%) as dull yellow needles. 1H NMR (DMSO) δ 11.75 (1H, slbrs), 9.11 (1H, dd, J=1.5, 4.3 Hz), 8.97 (1H, s), 8.32 (1H, dd, J=1.5, 8.4 Hz), 8.12 (1H, dd, J=4.3, 8.5 Hz), 7.88 (2H, d, J=8.2 Hz), 7.49 (2E, t, J=8.0 Hz), 7.32 (1H, t, J=7.0 Hz), 2.34 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CC(C)=O>[C:29]([NH:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][C@H:6]1[C:19]([OH:21])=[O:20])=[O:4])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)NCC(=O)N1C[C@H](NC(=O)c2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a solution of (2S4R)1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid (0.05 g, 0.17 mmol) and triethylamine (Aldrich) (0.19 mL, 1.37 mmol, 8 equivalents) in acetone (3 mL) was slowly added acetic anhydride (0.13 mL, 1.37 mmol, 8 equivalents) with stirring at room temperature under nitrogen atmosphere. The mixture was stirred for 3 hours while monitored by LCMS. Upon completion, the volatiles were removed in vacuo and the residue was purified by preparative HPLC (column: Xterra MSC18 50×250 mm, 10 u) using 40/60 to 90/10 methanol/water gradient (0.1% formic acid in methanol and 0.1 formic acid in water) to afford 0.020 g (35% yield) of the desired product as white solid with limited solubility in organic solvents.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][SH:14]>>[CH3:9][O:10][C:11](=[O:15])[CH2:12][CH2:13][S:14][CH2:2][C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1
Reactant: COC(=O)CCS
Reactant: Nc1nc(CCl)cs1
Product: COC(=O)CCSCc1csc(N)n1
Yield: 59.7 %

Procedure:
3-(2-Amino-thiazol-4-ylmethylsulfanyl)-propionic acid methyl ester (0.75 g, 60%) was prepared from 4-chloromethyl-thiazol-2-ylamine (1.00 g, 5.41 mmol) and 3-mercapto-propionic acid methyl ester (0.97 g, 8.11 mmol) according to procedure Z.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 2.4 g, 14.36 mmol) in DMF (100 mL) was added 4-amino-1-bocpiperidine (Aldrich; 3.15 g, 15.72 mmol) and DIPEA (7.5 mL, 43.06 mmol). The resultant solution was carefully treated portionwise (2-3 portions) with HATU (6.88 g, 18.09 mmol) and the resultant mixture was stirred, under nitrogen, at ambient temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([CH:15]([NH2:18])[CH2:16][CH3:17])[CH3:14]>CS(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CCC(N)CC
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (250 mg, 1.21 mmol) and 1-ethyl-propyl amine (105 mg, 1.21 mmol) in DMSO (4 ml) was stirred at room temperature for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 280 mg of yellow oil. The oil was purified through silical gel column chromatography using 65% chloroform in hexane as eluent to give 110 mg (35%) of the title compound as a yellow crystal, mp 82-84° C. 1H NMR (CDCl3) δ 6.57 (d, 1H), 6.46 (s, 1H), 3.39 (m, 1H), 2.42 (s, 3H), 1.4-1.8 (m, 4H), 0.94 (t, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][CH2:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23](N(CC)CC)[CH3:24].ClC(OCC)=O.C(O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:23][CH3:24])=[O:9])=[C:6]([O:11][CH2:12][C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(OC)nc(COc2cccc(Cl)c2C(=O)O)n1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(Cl)cccc1OCc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.0 g of 6-chloro-2-[(4,6-dimethoxy-2-pyrimidyl)methyloxy]benzoic acid was dissolved in 20 ml of tetrahydrofuran and cooled with ice. 0.35 g of triethylamine dissolved in 1 ml of tetrahydrofuran and 0.40 g of ethyl chloroformate dissolved in 1 ml of tetrahydrofuran were added thereto, and the mixture was stirred under ice cooling for about 30 minutes. Then, a solution of 1 g of ethanol and 0.35 g of triethylamine in 2 ml of tetrahydrofuran was added, and the temperature was raised up to room temperature in about one hour. After the removal of the solvent, the residue was purified using column chromatography to obtain 1.0 g of ethyl 6-chloro-2-[(4,6-dimethoxy-2-pyrmidyl)methyloxy]benzoate (yield 92%).
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.[Cl-].[CH3:28][Zn+]>C1COCC1.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>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:10]4[C:2]([CH3:28])=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: C[Zn+]
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2nc(C)n3c2c1OCC3c1ccccn1
Temperature: 150 °C
Yield: 49 %

Procedure:
A mixture of 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (45 mg, 0.12 mmol), 2.0 M methylzinc chloride in THF (310 μL), and tetrakis(triphenylphosphine)palladium(0) (7 mg, 0.006 mmol) in THF (2 mL) under nitrogen was heated in a microwave at 150° C. for 5 min. Purification by preparative LCMS using pH 10 buffer gave the title compound (21 mg, 49%). LCMS calc. for C20H19N4O2 (M+H)+: m/z=347.1. found: 347.2. 1H NMR (300 MHz, CD3OD) δ 8.58 (d, J=4.8 Hz, 1H), 7.69 (td, J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=7.1, 5.3 Hz, 1H), 7.05 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.1 Hz, 2H), 6.59 (d, J=7.9 Hz, 1H), 6.03 (s, 1H), 4.55 (dd, J=11.5, 2.8 Hz, 2H), 4.29-4.09 (m, 1H), 4.00-3.71 (m, 2H), 3.63-3.50 (m, 3H), 3.40 (dd, J=9.8, 4.6 Hz, 1H), 2.23 (s, 3H), 2.23-2.11 (m, 1H), 2.08 (s, 3H), 1.98-1.83 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH2:21][N:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[S:23]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[C:27]=2[OH:34])(=[O:25])=[O:24])[CH:20]=1)[CH2:5][N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:33][C:28]1[C:27]([OH:34])=[C:26]([S:23]([N:22]([CH2:21][C:19]2[CH:18]=[C:4]([CH2:5][NH:6][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:3]=[C:2]([Cl:1])[CH:20]=2)[CH2:35][CH:36]([CH3:37])[CH3:38])(=[O:25])=[O:24])[CH:31]=[C:30]([Cl:32])[CH:29]=1
Reactant: CC(C)CN(Cc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNCc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of tert-butyl 3-chloro-5-((3,5-dichloro-2-hydroxy-N-isobutylphenylsulfonamido)methyl)benzyl(isobutyl)carbamate (0.23 g, 0.38 mmol) in methylene chloride (5 mL) was added TFA (0.87 mL, 11.3 mmol). The reaction mixture was stirred at rt for 2 h., concentrated and the residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the desired product as white solid (0.18 g, 92%). 1H NMR (CD3OD): δ 7.45 (d, J=2.8 Hz, 2H), 7.40 (s, 2H), 7.37 (s, 1H), 7.31 (d, J=2.8 Hz, 1H), 4.57 (s, 2H), 4.07 (s, 2H), 3.04 (d, J=7.2 Hz, 2H), 2.80 (d, J=7.2 Hz, 2H), 2.00 (m, 1H), 1.68 (m, 1H), 1.00 (d, J=6.6 Hz, 6H), 0.76 (d, J=6.6 Hz, 6H); MS (ESI): (M+H)+=507.22, 509.21.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[CH:7][C:8]=2[CH3:12])[N:3]=1.[Br:14]Br.OS([O-])=O.[Na+].N>C(O)(=O)C.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([CH3:13])=[C:7]([Br:14])[C:8]=2[CH3:12])[N:3]=1
Reactant: BrBr
Reactant: Cc1cc(C)c2ccc(N)nc2n1
Agent: N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2nc(N)ccc2c(C)c1Br
Temperature: 60 °C
Yield: 52.4 %

Procedure:
173 g (1 mol) of 2-amino-5,7-dimethyl-1,8-naphthyridine is suspended in 500 ml of glacial acetic acid. At 60° C. and with stirring, 160 g (1 mol) of bromine is dripped in, the solid going into solution. After all has been added, the mixture is stirred overnight at room temperature (20° C.) and then poured into 1 liter of water. Excess bromine is reduced by adding a small amount of NaHSO3. The pH is brought to 4 with concentrated NH3 solution. The mixture is stirred for about 30 minutes and the precipitate is filtered off and dried under reduced pressure to give 132 g of a pale brown solid.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]([N:45]1[C@H:49]([C:50](O)=[O:51])[CH2:48][S@@:47](=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([N:45]1[C@H:49]([C:50](=[O:51])[NH:10][C@H:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=2)[CH2:48][S@@:47](=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1
Reactant: C[C@@H](N)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
9.47 g (69.11 mmole) of (R)-α-methyl-p-hydroxybenzylamine (prepared as described in Preparation 13), 10.58 g (69.11 mmole) of N-hydroxybenzotriazole monohydrate and 14.26 g (69.11 mmole) of dicyclohexylcarbodiimide were added in that order to a solution of 17.50 g (69.11 mmole) of (1R,4R)-3-benzoyl-1-oxo-thiazolidine-4-carboxylic acid (prepared as described in Preparation 10) in 100 ml of dimethylformamide cooled at 5° C., and the mixture was stirred at a temperature between 3° and 6° C. for 30 minutes and then at room temperature for a further 4 hours. At the end of this time, the reaction mixture was filtered and the insolubles were washed with 100 ml of hot dimethylformamide. The filtrate and the washings were combined and concentrated by evaporation under reduced pressure to leave crystals. These crystals were recrystallized from methanol to give 19.21 g (74.6%) of the title compound in the form of colorless needles melting at 233°-234° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][C:25](Cl)=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[K+].[Br-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:25](=[O:26])[CH2:24][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC

Procedure:
prepared from 3,4-dimethoxyphenethylamine and 3,4-dimethoxyphenylacetyl chloride; mp 125° C. (lit.17 123-125° C.); IR (KBr) 3327, 3064, 3007, 2916, 2840, 1642, 1608, 1591; 1H NMR δ 2.67 (t, 2H), 3.40-3.47 (m, 4H), 3.83 (s, 6H), 3.86 (s, 3H), 3.88 (s, 3H), 5.30 (brs, 1H), 6.52-6.86 (m, 6H); 13C NMR δ 35.6, 41.2, 43.5, 56.3, 56.4, 70.5, 111.7, 112.2, 115.8, 121.1, 127.5, 127.9, 128.5, 129.1, 131.1, 131.6, 137.3, 148.1, 149.5, 158.5, 171.8.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:24][C:25]1[C:26]([NH:40][CH3:41])=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:28]=[N:27][C:26]=1[NH:40][CH3:41]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1Cl

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 0.107 mmol) and [3-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-methyl-amine (stage 146.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.53 min (Method A); M+H=485 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.24-8.21 (m, 1H), 8.15 (s, 1H), 8.06-8.01 (m, 1H), 7.92-7.87 (m, 1H), 7.62-7.57 (m, 1H), 7.40-7.37 (m, 1H), 6.81-6.76 (m, 1H), 3.95 (s, 3H), 3.57 (s, 3H), 2.89 (d, 3H), 1.95 (s, 3H))