Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](I)[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F-].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1cc(I)cc(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(OC)cc(OC)c2)c1
Yield: 88.7 %

Procedure:
To a mixture of 600 mg (4.0 mmol) of 3-methoxyphenylboronic acid, 792 mg (3.0 mmol) of 3,5-dimethoxyiodobenzene, 34 mg (5 mol %) palladium(II)acetate, 182 mg (20 mol %) of tri-o-tolylphosphine, and 3.6 g (24 mmol) of cesium fluoride was added 10 mL of anhydrous dioxane. The reaction was stirred at reflux under N2 for 50 min, then poured into 30 mL of water and extracted with diethyl ether (3×10 mL). The combined ether layers were back extracted with saturated aqueous NaHCO3 solution (1×10 mL), then brine (1×10 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 10%, ethyl acetate:hexanes to provide the titled compound (650 mg, 89%).
Reaction SMILES: C(OCC)C.[Cl:6][SiH:7]([Cl:9])[Cl:8].[Cl:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]Cl>C(N(CC)CC)C>[Cl:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][Si:7]([Cl:9])([Cl:8])[Cl:6]
Reactant: Cl[SiH](Cl)Cl
Reactant: ClC/C=C\CCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: ClC/C=C\C[Si](Cl)(Cl)Cl
Reaction time: 8 h
Yield: 54 %

Procedure:
In a 1-L three-neck round-bottom flask equipped with an efficient reflux condenser, a tru-bore mechanical stirrer equipped with a Teflon paddle and a pressure-equalizing addition funnel was placed cuprous chloride (0.65 g, 6.5 mmol), triethylamine (73.9 g, 0.73 mol) and diethyl ether (500 mL). Trichlorosilane (98.2 g, 0.73 mol), 1,4-dichloro-cis-2-butene (80.6 g, 0.65 mol) and diethyl ether (60 mL) were placed in the addition funnel. This solution was added to the vigorously stirred greenish suspension of cuprous chloride and triethylamine over a period of 4 h. The reaction mixture was stirred overnight. The triethylammonium hydrochloride salts were removed by filtration under argon. These were washed several times with pentane. The solvents were removed from the combined filtrate by distillation through a 15 cm vacuum-jacketed Vigreux column at atmosphere pressure. The residue was transferred to a 250-mL round-bottom flask. The product was purified by fractional distillation under reduced pressure. A fraction with b.p. 72°-73° C./2.8 mmHg, 78.2 g, 54% yield was isolated. It had the following spectral properties.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=O)=[CH:16][N:15]=1>N1C=CC=CC=1>[F:13][C:14]1[N:15]=[CH:16][C:17]([C:18]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: N#Cc1cccc(C(N)=NO)c1
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2noc(-c3ccc(F)nc3)n2)c1
Temperature: 25 °C

Procedure:
3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved in pyridine 10 mL and 6-fluoronicotinoyl chloride (Frontier Scientific, 0.160 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled product. 1H NMR (300 MHz, DMSO-d6) δ 7.56-7.52 (m, 1 H), 7.85 (t, J=7.9 Hz, 1 H), 8.15-8.12 (m, 1 H), 8.43-8.41 (m, 1 H), 8.49 (m, 1 H), 8.8-8.74 (m, 1 H), 9.11-9.0 (m, 1 H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.S(=O)(=O)=O.N1C=CC=CC=1.C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
A solution of the sub-title product of step (i) (17.9 g) in DMSO (100 mL) was added dropwise over 15 minutes to a solution of pyridine sulphur trioxide (44.7 g) and triethylamine (39.3 mL) in DMSO (200 ml) at 0° C. (slight exotherm to 5C). The mixture was warmed to RT after 5 minutes and stirred for 16 hours. The mixture was poured into ice/water and extracted twice with ethyl acetate. The combined organics were washed with brine, dried over is sodium sulfate and concentrated in vacuo to give crude product. The crude product was purified by flash silica chromatography, elution 100% dichloromethane. Pure fractions were evaporated to dryness to afford the sub-title product (17.9 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: COc1ccc(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1

Procedure:
1-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-(4-methoxy-phenyl)-urea was prepared starting from intermediate D and 4-(methoxy)-phenylisocyanate. MS calcd. for C24H21ClN3O3 [(M+H)+] 434.1, obsd. 434.0.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1CC(O)=O>CN(C)C=O.C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (38 ml) and a few drops of N,N-dimethylformamide was added to a solution of (2-chlorophenyl)acetic acid (50 g) in CH2Cl2 (300 ml). The mixture was stirred at room temperature for 3 hours, and then concentrated under reduced pressure. The residue was distilled under reduced pressure to give (2-chlorophenyl)acetyl chloride (41.24 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=[CH:26][C:27]2=3)=[O:11])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: CC(C(=O)O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a mixture of 2-[4-chloro-3-(trifluoromethyl)phenyl]propanoic acid (47 mg, 0.184 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (40 mg, 0.184 mmol) in DMF (1 mL) was added Hunig's base (59 mg, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (77 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, and then was partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine and dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (24 mg, 29%). 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.48-7.42 (m, 4H), 7.16-7.11 (m, 2H), 4.11 (m, 1H), 3.76 (m, 1H), 3.52 (m, 1H), 2.77 (m, 2H), 1.96 (m, 1H), 1.80 (m, 1H), 1.55 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C22H18ClF4N3O [M+H]+ 452.1, found 452.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([OH:19])[CH:16]=[CH:17]3)=[C:12]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]=2[CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:9])=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[N:42]=[C:41]([CH2:43]O)[CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:43][C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[N:42]=4)[CH:16]=[CH:17]3)=[C:12]([C:20](=[O:25])[C:21]([CH3:23])([CH3:24])[CH3:22])[C:11]=2[CH2:26][C:27]([CH3:33])([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(O)ccn2c1C(=O)c1ccc(Cl)cc1
Reactant: COc1cccc(CO)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3cccc(OC)n3)ccn2c1C(=O)c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a cold (0° C.) solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (100 mg, 0.21 mmol), (6-methoxy-pyridin-2-yl)-methanol (35 mg, 0.25 mmol), and triphenylphosphine (65 mg, 0.25 mmol) in THF (5 mL) is added DIAD (48 μL, 0.25 mmol). The reaction is allowed to gradually warm to 23° C. and then stirred overnight. Silica gel is added and the mixture is concentrated in vacuo then purified by flash chromatography (SiO2, hexanes to 15% EtOAc in hexanes) to give ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-[(6-methoxypyridin-2-yl)methoxy]indolizin-2-yl}-2,2-dimethylpropanoate (20 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.C(O)(=O)C.[N:21]([O-])=[O:22].[Na+]>O>[N:21]([C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:22]
Reactant: O=N[O-]
Reactant: Nc1cc(OCc2ccccc2)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=O)c(OCc2ccccc2)n1

Procedure:
To a solution of 16 g 2,4-diamino-6-benzyloxy-pyrimidine (7) in 250 mL of warm 30% acetic acid is added a solution of 7g sodium nitrite in 25 mL H2O. The sodium nitrite solution is held at 70°-80° C. and is added dropwise while being stirred continuously. The sodium nitrite solution is added until potassium-iodate starch paper shows a positive reaction. The violet-red precipitate is cooled, suctioned off and then recrystallized from ethanol or acetone to yield 8.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][C:8]1[C:13]2[C:14]3[C:23](=[C:24]([CH3:27])[C:25](=[O:26])[C:12]=2[CH:11]=[CH:10][CH:9]=1)[S:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=3.CI.CCOC(C)=O>CN(C=O)C.O>[CH3:1][O:7][C:8]1[C:13]2[C:14]3[C:23](=[C:24]([CH3:27])[C:25](=[O:26])[C:12]=2[CH:11]=[CH:10][CH:9]=1)[S:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=3
Reactant: CC(C)(C)[O-]
Reactant: Cc1c2sc3ccccc3nc-2c2c(O)cccc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)c(C)c3sc4ccccc4nc-3c12
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
Potassium tert.-butoxide (500 mg) was added to a suspension of 1-hydroxy-6-methyl-5H-benzo[a]phenothiazin-5-one (from Example 32) (500 mg) and methyl iodide (2 ml) in DMF (20 ml). After 30 minutes at room temperature, EtOAc (250 ml) was added followed by water (200 ml). The aqueous layer was decanted and the organic layer was dried and evaporated to dryness. The residue was treated with ether, filtered and air-dried to afford the desired product (420 mg), m.p. 170°-171° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][C:17]([O:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:16]1.[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:12])[F:14])=[CH:4][C:3]=1[N:15]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]([O:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[N:16]1
Reactant: CCOC(=O)c1cc(OCC(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C(=O)O)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
0.95 g of ethyl 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxylate was dissolved in 20 mL of ethanol. To this solution, a solution having 0.42 g of potassium hydroxide dissolved in 10 mL of water was added, followed by stirring at room temperature for 30 minutes. Concentrated hydrochloric acid was added to adjust the pH to 2, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 0.90 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1.CCN(C(C)C)C(C)C>CCO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(c2ccncc2[N+](=O)[O-])C1
Yield: 95 %

Procedure:
The method of Example 1 was followed using 4-chloro-3-nitropyridine (1.0 eq), tert-butyl pyrrolidin-3-ylcarbamate (2.0 eq), and DIEA (2.0 eq) in EtOH yielding tert-butyl 1-(3-nitropyridin-4-yl)pyrrolidin-3-ylcarbamate (95%) LCMS (m/z): 309.1 (MH+); LC Rt=1.922 min.
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.[CH:36](=O)[CH3:37].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:36][CH3:37])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc(C)cc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(C)cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-(4-methylbenzylamino)hexyl)-piperidin-4-yl)methyl)benzamide (0.77 g) as starting compound, acetaldehyde (0.1 ml) and sodium cyanoborohydride (0.23 g) were reacted and treated in the same manner as in Example 136 to give 0.42 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-(4-methylbenzyl)amino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.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.C(O)(=O)C.[NH2:62][C@H:63]([C:66]1[O:70][C:69]([C@@H:71]([NH:75][C:76](=[O:82])[O:77][C:78]([CH3:81])([CH3:80])[CH3:79])[CH:72]([CH3:74])[CH3:73])=[N:68][N:67]=1)[CH2:64][OH:65].[C:83]([OH:89])([C:85]([F:88])([F:87])[F:86])=[O:84]>CN(C=O)C.C(#N)C.O>[F:86][C:85]([F:88])([F:87])[C:83]([OH:89])=[O:84].[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([NH:62][C@H:63]([C:66]3[O:70][C:69]([C@@H:71]([NH:75][C:76](=[O:82])[O:77][C:78]([CH3:79])([CH3:81])[CH3:80])[CH:72]([CH3:73])[CH3:74])=[N:68][N:67]=3)[CH2:64][OH:65])=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nnc([C@@H](N)CO)o1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)N[C@@H](CO)c3nnc([C@@H](NC(=O)OC(C)(C)C)C(C)C)o3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
124 mg (0.37 mmol) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A were initially charged together with 184 mg (0.49 mmol) of HATU and 0.52 ml (3.00 mmol) of N,N-diisopropylethylamine in 1.24 ml of DMF, and the mixture was stirred at room temperature for 10 min. Subsequently, 175 mg (0.49 mmol) of tert-butyl [(1S)-1-{5-[(1S)-1-amino-2-hydroxyethyl]-1,3,4-oxadiazol-2-yl}-2-methylpropyl]carbamate acetate from Example 173A were added to the reaction solution and the mixture was stirred at RT for 1 h. Then the mixture was diluted with acetonitrile and water, admixed with TFA and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). 211 mg of the target compound were obtained (73% of theory, 94% purity).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](N)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.S(=O)(=O)(O)[OH:23]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:23])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: O=S(=O)(O)O
Reactant: CC(C(N)=O)c1ccc2c(c1)CCc1ccccc1C2=O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(5-oxo- 10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionamide (15 g.) in a mixture of sulphuric acid (d = 1.36; 50 cc.) and water (60 cc.) is heated with vigorous stirring for 3 hours at 110°C. After cooling, the product which precipitates is filtered off and then added to N sodium hydroxide solution (55 cc.). The alkaline solution, clarified by filtration, is acidified by adding N hydrochloric acid (60 cc.). The product which precipitates is filtered off, dried and then recrystallised from carbon tetrachloride (170 cc.) to give 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten2-yl)propionic acid (7.4 g.) melting at 122°C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[O:14][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:17](=[O:19])[CH:18]=2)=[CH:7][CH:6]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:2][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[O:14][C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][C:17](=[O:19])[CH:18]=2)=[CH:7][CH:6]=1
Reactant: O=c1cc(C=Cc2ccc([N+](=O)[O-])cc2)oc(-c2ccccc2)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=Cc2cc(=O)cc(-c3ccccc3)o2)cc1

Procedure:
A solution of concentrated hydrochloric acid (0.2 ml) in ethanol (20 ml) was added to a stirred refluxing suspension of 2-[2-(4-nitrophenyl)-ethenyl]-6-phenyl-4H-pyran-4-one (8.5 g) and iron powder (4.5 g) in ethanol (80 ml) and water (20 ml). The stirred mixture was heated under reflux for 5 hours, adding further concentrated hydrochloric acid (0.2 ml) after 2 hours. The hot mixture was filtered and the filtrate was evaporated under vacuum. The solid residue was crystallised from chloroform-petroleum ether 60°-80° C. to give 2-[2-(4-aminophenyl)-ethenyl]-6-phenyl-4H-pyran-4-one (mp 192°-194° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][O:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.[Br:22]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([Br:22])[O:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccoc2CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2cc(Br)oc2CC1
Reaction time: 1 h

Procedure:
A solution of the product from step h) (50 mg, 0.21 mmol) in CHCl3 (527 μl) and AcOH (527 μl) was treated with N-bromosuccinimide (38.1 mg, 0.21 mmol) at 22° C. After 1 hour, the contents were poured into sat. NaHCO3 and extracted with EtOAc (2×5 ml). The organic layer was washed with brine (1×5 ml), dried (MgSO4) and purified by preparative TLC (80% hexanes:20% EtOAc) providing 2-bromo-4,5,7,8-tetrahydro-furo[2,3-d]azepine-6-carboxylic acid tert-butyl ester which was directly treated with 4M HCl in dioxane (2 ml). The dioxane was evaporated and the residue was dissolved in MeOH and purified by preparative LC/MS providing 1.3 mg of the title compound. 1H NMR (CDCl3) 6.08 (s, 1H); 3.02-3.07 (m, 4H); 2.89-2.92 (m, 2H); 2.57-2.70 (m, 3H); MS: ESI (positive): 216, 218 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[CH:5][C:4]=1[NH2:16].CS([C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1)=O.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[CH:5][C:4]=1[NH:16][C:20]1[N:21]=[CH:22][C:23]2[CH:29]=[CH:28][C:27](=[O:30])[N:26]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH:34]=[CH:35][CH:36]=3)[C:24]=2[N:25]=1
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Reactant: COc1cc(N2CCN(C)CC2)ncc1N
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C)CC2)ncc1Nc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 85 °C
Yield: 76.9 %

Procedure:
4-Methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-amine (8a; 1.22 g, 5.49 mmol), tert-butyl (3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (52; 1.40 g, 3.50 mmol) were treated with tert-butanol (20 mL) and DIEA (1.53 mL, 8.74 mmol) and heated to 85° C. overnight (20 h) in a 250 mL round-bottomed flask with a reflux condenser. The reaction mixture was concentrated on the rotovap and the crude solid was suspended in Et2O and filtered affording the crude tert-butyl (3-(24(4-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (8b; 1.50 g, 2.69 mmol, 77% yield) as a brownish-yellow amorphous solid. m/z (ESI, +ve ion) 559.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48 (1H, br. s.), 8.65 (1H, br. s.), 8.54 (1H, s), 7.86 (1H, d, J=9.4 Hz), 7.82 (1H, s), 7.43 (1H, d, J=8.0 Hz), 7.37 (2H, br. s.), 6.81 (1H, br. s.), 6.38 (1H, d, J=9.4 Hz), 6.29 (1H, br. s.), 3.73 (3H, s), 3.45 (4H, br. s.), 2.40 (4H, br. s.), 2.24 (3H, s), 1.47 (9H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].N[CH:14]([C:18]([NH2:20])=[O:19])[C:15]([NH2:17])=[O:16].C(O)(=O)C>CO>[C:18]([C:14]1[N:2]=[C:1]([C:3]2[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=2)[NH:17][C:15]=1[OH:16])(=[O:19])[NH2:20]
Reactant: NC(=O)C(N)C(N)=O
Reactant: N#Cc1cc[n+]([O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1nc(-c2cc[n+]([O-])cc2)[nH]c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of 4-cyanopyridine N-oxide (600 g) in ahydrous methanol (250 ml) was added sodium methoxide (1.35 g), and this solution was stirred for 0.5 hour at room temperature. To this solution were added aminomalonamide (3.51 g) and acetic acid, and this mixture was stirred for 2 hours under reflux. After cooling the reaction mixture to 0°-5° C., the precipitated product was separated by filtration, washed with ethanol, isopropylether and dried under vacuum to give yellow crystal of 4-(4-carbamoyl-5-hydroxyimidazole-2yl)-pyridine-N-oxide (5.96 g).