Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O1C2C(C(Cl)=O)=CC=CC=2CC1.S(Cl)(Cl)=O.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[C:37]([CH3:38])=[C:36]([CH3:39])[S:35][C:34]1=[NH:40].CCN(CC)CC>C1COCC1.CCOC(C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:33]1[C:37]([CH3:38])=[C:36]([CH3:39])[S:35]/[C:34]/1=[N:40]\[C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: COCCn1c(C)c(C)sc1=N
Agent: O=C(Cl)c1cccc2c1OCC2
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc2c1OCC2
Yield: 32.7 %

Procedure:
The 2,3-dihydrobenzofuran-7-carboxylic acid (TCI-US, 0.25 g, 1.4 mmol) was converted to 2,3-dihydrobenzofuran-7-carbonyl chloride with 5 mL of thionyl chloride using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and the fleshly prepared 2,3-dihydrobenzofuran-7-carbonyl chloride in 30 mL THF were processed as in Example 134B. Purification of the crude material via recrystallization with 50% hexanes:EtOAc gave the title compound (0.12 g, 0.36 mmol, 34% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.25 (s, 3H), 2.30 (s, 3H), 3.22 (t, J=8.8 Hz, 2H), 3.31 (s, 3H), 3.81 (t, J=5.3 Hz, 2H), 4.44 (t, J=5.3 Hz, 2H), 4.64 (t, J=8.8 Hz, 2H), 6.86 (t, J=7.5 Hz, 1H), 7.32 (dd, J=7.3, 1.2 Hz, 1H), 7.93 (dd, J=8.0, 0.8 Hz, 1H); MS (DCI/NH3) m/z 333 (M+H)+; Anal. calculated for C17H20N2O3S.0.1H2O: C, 61.09; H, 6.09; N, 8.38. Found. C, 60.99; H, 5.91; N, 8.25.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH3:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:28]>>[CH3:17][C:18]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][C:19]=1[NH:28][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Cc1c(N)cccc1C(F)(F)F
Product: Cc1c(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cccc1C(F)(F)F
Yield: 28.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 2-methyl-3-trifluoromethyl-phenylamine (0.03 mL, 0.33 mmol) to provide 237 (23 mg, 28% yield) as a brown solid. LC-MS (M+H=370, obsd.=370).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(C[Al]CC(C)C)C>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(C)cc1Cl
Agent: CC(C)C[Al]CC(C)C
Solvent: ClCCl
Product: Cc1ccc(CO)c(Cl)c1
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Methyl 2-chloro-4-methylbenzoate (520 mg, 2.82 mmol) was dissolved in Dichloromethane (DCM) (15 mL) and at 0° C. Dibal-H (4.694 ml, 7.04 mmol) was slowly added. The mixture was left at 0° C. for 2H and then at room temperature overnight. Next morning HPLC showed no starting material remaining, reaction was quenched with Rochelle salt, and leaving under stirring for 1 hour and then it was extracted with DCM, dried and concentrated to afford 365 mg of the final compound, pure enough to be used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][N:3]=1.Cl.[CH:11]1([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:11]1([NH:17][C:18]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Reactant: O=Cc1ccnc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCCCC1)C1CCN(Cc2ccnc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
A mixture of 2-bromo-4-formylpyridine (1 g, 5.38 mmol), piperidine-4-carboxylic acid cyclohexylamide hydrochloride J-1 (1.327 g, 5.38 mmol) and DIPEA (2.78 mL, 16.13 mmol) in DCM (25 mL) is treated with sodium triacetoxy borohydride (2.28 g, 10.75 mmol) in 5 portions over 20 min. and the reaction mixture is stirred for 18 h at RT. Aq. sat. NaHCO3 (25 mL) is added and the mixture is stirred for 30 min. The phases are separated and the aqueous phase is extracted twice with DCM (25 mL). The combined organic phases are dried over MgSO4 and evaporated. The crude residue is purified by flash chromatography on silica gel using a gradient of heptane and EtOAc 1:4 to EtOAc 100%. After concentration of the product-containing fractions, the title compound (1.18 g, 58%) is obtained as a colorless solid LC-MS A: tR=0.59 min; [M+H]+=382.15.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]([CH2:19][CH2:20][C:21]#N)[CH3:18])[N:4]=1.[NH3:23]>[Ni].C(O)C>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]([CH3:18])[CH2:19][CH:20]([NH2:23])[CH3:21])[N:4]=1
Reactant: COc1cc2nc(N(C)CCC#N)nc(N)c2cc1OC
Reactant: N
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: COc1cc2nc(N(C)CC(C)N)nc(N)c2cc1OC

Procedure:
100 gms, 0.309 moles of N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride, 100 gms of Raney-Nickel and 1250 ml of solution of 6.9% ammonia in denatured spirit (denatured ethanol) were charged in an autoclave.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C@H:7]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[CH:22]=[N:23][N:24]([CH2:26][CH3:27])[CH:25]=4)[N:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH2:6][CH2:5][NH:4][CH2:3]1.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.Cl[C:46]1[N:51]=[N:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=1>CN(C=O)C.CO>[C:52]([C:49]1[N:50]=[N:51][C:46]([N:4]2[CH2:5][CH2:6][C@@H:7]([NH:8][C:9]3[C:10]4[N:11]([CH:18]=[C:19]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH3:27])[CH:25]=5)[N:20]=4)[N:12]=[CH:13][C:14]=3[C:15]([NH2:17])=[O:16])[C:2]([CH3:28])([CH3:1])[CH2:3]2)=[CH:47][CH:48]=1)#[N:53]
Reactant: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CCNCC4(C)C)c3n2)cn1
Reactant: N#Cc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CCN(c5ccc(C#N)nn5)CC4(C)C)c3n2)cn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of (R)-8-((3,3-dimethylpiperidin-4-yl)amino)-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-7-carboxamide, TFA (13 mg, 0.026 mmol) in DMF (105 μl), DIEA (22.87 μl, 0.131 mmol) and 6-chloropyridazine-3-carbonitrile (4.02 mg, 0.029 mmol) were added. The reaction was heated at 90° C. After 2 hrs, the reaction was diluted with methanol (10 ml), filtered, and concentrated. The crude material was purified via preparative LC/MS (Method A). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound of Example 53 (9.2 mg, 0.019 mmol, 72.4% yield). 1H NMR (500 MHz, methanol-d4) δ 8.33 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.60 (d, J=9.4 Hz, 1H), 7.22 (d, J=9.9 Hz, 1H), 5.77-5.67 (m, 1H), 4.33 (d, J=12.9 Hz, 1H), 4.26 (q, J=7.4 Hz, 2H), 3.49-3.41 (m, 1H), 3.26-3.19 (m, 1H), 2.35-2.27 (m, 1H), 1.91-1.80 (m, 1H), 1.54 (t, J=7.2 Hz, 3H), 1.43-1.38 (m, 1H), 1.14 (s, 3H), 1.10 (s, 3H). LC/MS (Method F): m/z 486.24 ([M+H]+), Rt. 1.400 min.
Reaction SMILES: [NH2:1][C@H:2]([CH2:4]O)[CH3:3].C(N(CC)CC)C.[CH2:13]([O:15][P:16](Cl)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].ClCCl.CO.[NH4+].[OH-].C(Cl)(Cl)Cl.CO.[NH4+].[OH-].[O-][Mn](=O)(=O)=O.[K+].CS(Cl)(=O)=O.[OH-].[K+]>ClCCl>[CH2:13]([O:15][P:16]([N@:1]1[CH2:4][C@@H:2]1[CH3:3])(=[O:17])[O:18][CH2:19][CH3:20])[CH3:14]
Reactant: CCOP(=O)(Cl)OCC
Reactant: C[C@H](N)CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)[N@]1C[C@@H]1C
Temperature: 41 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A 12 L 3-neck flask fitted with an overhead mechanical stirrer and 1 L pressure equalizing addition funnel was charged with L-alaninol (250.0 g, 3.33 mol), triethylamine (578 mL, 4.16 mol, 1.25 equiv) and dichloromethane (2.5 L). The stirred solution was cooled to +2° C. and diethoxyphosphoryl chloride (531 mL, 3.661 mol, 1.10 equiv) was added over 1.5 hour while maintaining an internal temperature <+8° C. The reaction mixture was stirred an additional 1 hour at which point the reaction was complete by TLC analysis (silica gel plate, 93:6:1 dichloromethane/MeOH/NH4OH and 6/3/1 CHCl3/MeOH/NH4OH; KMnO4 stain). Additional triethylamine (510 mL, 3.65 mol, 1.10 equiv) was added to the reaction mixture and methanesulfonyl chloride (297 mL, 3.82 mol, 1.15 equiv) was added drop-wise over 1.5 hours while maintaining an internal temperature <+10° C. The resulting reaction mixture was stirred for 1.5 hours at which time TLC analysis (see above methods) indicated the reaction was complete. Potassium hydroxide solution (3 M solution, 4.40 L, 13 mol, 4.0 equiv) was slowly added to the stirred reaction mixture while maintaining an internal temperature <+16° C. The reaction was stirred for 6 hours, after which time the aqueous layer was separated. Saturated NaHCO3 solution (700 mL) was added and the biphasic mixture was heated to 40-42° C. Distillation was started and a first fraction of 1.8 L of dichloromethane was collected. When the batch temperature reached 50° C., a second fraction was collected until the batch temperature was 65° C. The mixture was heated at 65° C. for another 1 hour and then cooled to ambient temperature. Dichloromethane (1.8 L) was added and the mixture stirred for 10 minutes before separation. The organic layer was concentrated under reduced pressure and heptane (250 mL) was added to the concentrate. The resulting mixture was concentrated under reduced pressure. The resulting 4b was obtained as a light yellow liquid (518.5 g, 80.6% yield, 98.90% GC purity). A colorless sample was prepared by short path distillation at 66-67° C., 0.9 mm Hg. Optical rotation c=1.01, ethanol, 22.5° C., +28.8°. 1H NMR (300 MHz, CDCl3) δ 4.15 (dq, J=8.0, 7.1 Hz, 4H), 2.64-2.45 (m, 1H), 2.33 (ddd, J=17.9, 5.9, 1.3 Hz, 1H), 1.91-1.81 (m, 1H), 1.34 (dt, J=7.1, 0.9 Hz, 6H), 1.28 (dd, J=5.4, 1.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:26](=[O:28])=[O:27]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([F:15])=[C:13]([CH:14]=1)[C:26]([OH:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: Fc1ccc(OCc2ccccc2)c(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of 1-benzyloxy-2,3,4-trifluorobenzene (19.89 g, 83.6 mmol) in anhydrous THF (120 mL) was added lithium diisopropylamide (2.0 M in THF, 42.6 mL, 85.2 mmol) at −78° C. under nitrogen atmosphere. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice (20.0 g, 454.5 mmol). The mixture was stirred overnight at ambient temperature. The reaction was quenched with 10% aqueous HCl (300 mL). The mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with 5% sodium hydroxide (300 mL). The aqueous layer was acidized to pH 1 with concentrated HCl (aq.) and extracted with ethyl acetate (200 mL×3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (white solid, 19.33 g, 82% yield). 1H NMR (400 MHz, CDCl3): δ 14.01 (s, 1H), 7.42 (6H, m), 5.16 (2H, s).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:31])([CH3:30])[CH:8]1[O:13][C:12]2=[CH:14][S:15][C:16]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:21][CH:20]=3)=[C:11]2[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN(C)[CH:39]=[O:40]>O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:30])([CH3:31])[CH:8]1[CH2:9][O:10][C:11]2=[C:16]([CH:17]=[CH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:23][CH:24]=3)[S:15][C:14]([CH:39]=[O:40])=[C:12]2[O:13]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)c1ccc(C=Cc2scc3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C=Cc2sc(C=O)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
60 mL of dry tetrahydrofuran is added via syringe to 3.4 g (0.0074 mole) of 4 contained in a nitrogen purged round bottom flask. The solution is cooled to 0° C. The solution is stirred at 0° C. for 60 minutes, at which point 3.2 mL of 2.5 M BuLi in hexanes is added dropwise. The solution is allowed to stir for 15 min at 0° C., followed by the addition of 0.697 mL (0.009 mole) of anydrous dimethylformamide. The solution is warmed to room temperature, where it was stirred overnight. The tetrahydrofuran is removed under reduced pressure, and the resulting material is taken up in 500 mL of chloroform. The organic layer is washed with water three times, dried over MgSO4, and solvent is then removed under reduced pressure. The compound is purified on a silica column with a hexane/ethyl acetate mobile phase.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:22]O.CC([O-])=O.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]#[N:22])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(C#N)ccc3o2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A mixture of 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (4.46 g), hydroxylamine hydrochloride (3.96 g) and sodium acetate anhydrous (5.0 g) in acetic acid (40 ml) was stirred at ambient temperature for 3 hours. Subsequently, acetic anhydride (13 ml) was added to the mixture. After being stirred for 30 minutes at the same temperature, the reaction mixture was stirred at 120° C. for 2 hours. After being cooled, the mixture was poured into water, followed by collecting by filtration. The precipitates were washed with water and air-dried at ambient temperature. The crude products were washed with petroleum ether to give 4-tert-butyl-2-(5-cyanobenzofuran-2-yl)thiazole (4.44 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:12][C:13]([NH2:15])=[NH:14].[H-].[Na+].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([C:4]([NH2:5])=[N:14][C:13]([NH2:15])=[N:12]2)=[CH:6][CH:7]=1
Reactant: N=C(N)N
Reactant: N#Cc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2ccc(F)cc2n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
2,4-Difluorobenzonitrile (2.78 g, 1 eq), guanidine hydrochloride (7.15 g, 3.74 eq), and sodium hydride (3.6 g, 7.6 eq) are added to dimethylacetamide (50 mL) and the resulting mixture is stirred at 150° C. for overnight. Then the reaction mixture is poured into sat'd NaHCO3 aq. solution (300 mL), extracted by EtOAc (3×200 mL). The combined organic layers is dried over Na2SO4, filtered, concentrated. The crude product is purified by flash chromatography to give 7-Fluoro-quinazolin-2,4-diamine (1 g, 28% yield). LC/MS m/z=179 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[C:12]([CH3:21])=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][C:16]=2[CH3:17])=[CH:5][CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 125 °C
Reaction time: 20 h
Yield: 6 %

Procedure:
To a solution of 4-methoxyphenol (6.70 g, 53.9 mmol) and 4-chloro-3,5-dimethyl nitrobenzene (10 g, 53.9 mmol) in N-methylpyrrolidinone (50 mL) at room temperature was added potassium carbonate (8.19 g, 59.3 mmol). The reaction mixture was heated to 125° C. and stirred for 20 hours. The solution was cooled to room temperature, diluted with water (500 mL), and extracted with methylene chloride (3 times 300 mL). The combined organic extracts were washed with potassium hydroxide (0.1N, 3 times 500 mL), water (500 mL), brine (500 mL), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in a mixture of ether (20 mL) and petroleum ether (30 mL) and the title compound was crystalized as a brown solid (6.84 g). The mother liquor was concentrated and purified by column chromatography (20% methylene chloride in hexane to 27.5% methylene chloride in hexane) to give an additional product (0.88 g) and the unreacted starting material (3.4 g). 1H NMR (400 MHz, CDCl3) δ7.97 (s, 2H), 6.78 (d, 2H), 6.64 (d, 2H), 3.74 (s, 3H), 2.18 (s, 6H).
Reaction SMILES: [Li]CCCC.[Si:6]([C:13]1[O:14][CH:15]=[CH:16][C:17]=1[CH2:18][OH:19])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Cl-].[Li+].CN(C)[CH:24]=[O:25]>CCCCCC.C(COC)OC>[Si:6]([C:13]1[O:14][CH:15]=[C:16]([CH:24]=[O:25])[C:17]=1[CH2:18][OH:19])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)c1occc1CO
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)c1occ(C=O)c1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-BuLi (a 1.6M solution in hexane; 2.7 ml, 4.28 mmol) was added dropwise to a solution of 3-(2-tert-butyldimethylsilyl-furylmethanol (430 mg, 2.0 mmol) in dimethoxyethane (5 ml) at -78 degrees C. under argon. After stirring at 0 degrees C. for 15 minutes, lithium chloride (860 mg, 20.4 mmol), followed by N,N-dimethylformamide (0.35 ml, 4.48 mmol) was added. Stirring continued at 0 degrees C. for 16 hours and the mixture was quenched with ammonium chloride. Extraction with ethyl acetate and evaporation of the dried (magnesium sulfate) extracts gave a solid, which was recrystallized from hexane to give the titled aldehyde.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].OO.[OH-].[Na+].S(=O)(=O)(O)[OH:28]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:21][CH:22]=1)(=[O:28])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CCCCCCCOc2ccc(C(N)=O)cc2)on1
Reaction time: 8 h

Procedure:
A mixture of 4.47 g (0.015 mole) of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole (Example 5), 8 ml of 30% hydrogen peroxide, 8 ml of 95% ethanol and 0.6 ml of 6 N sodium hydroxide was stirred for ten minutes. There was then added 10 ml of 95% ethanol and the reaction mixture was warmed at 40°-50° C. for 4.5 hours, then held at room temperature overnight and treated with 5% sulfuric acid to neutral pH. The mixture was cooled and the solid product collected by filtration to give 4.4 g of 5-[7-(4-carbamylphenoxy)heptyl]-3-methylisoxazole, m.p. 153°-154° C., and recrystallized from methanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([NH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Br:12])[CH:6]=2)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
DCM (20.0 mL) was added to a flask containing ethyl 3-amino-7-bromoquinoline-2-carboxylate (from commercial source, 1.38 g, 4.68 mmol) and pyridine (1.0 mL, 12 mmol). The reaction mixture was cooled to −10° C. Benzyl chloroformate (0.843 mL, 5.61 mmol) was added slowly. The mixture was then allowed to warm gradually to room temperature and stirred for an additional 1 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with MeOH (10 mL) to form a precipitate that was collected by vacuum filtration and washed with cold MeOH to give the sub-title compound (1.73 g, 86%) as a white powder. LCMS calc. for C20H18BrN2O4(M+H)+: m/z=429.2. Found: 429.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:12])=[O:11])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:12])=[O:11]
Reactant: [H][H]
Reactant: C[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NS(=O)(=O)c1ccccc1N)C(=O)N1CCC[C@H]1C(=O)O
Yield: 53.6 %

Procedure:
N-o-nitrobenzenesulfonyl-L-alanyl-L-proline (1.51 g, 4.1 mmole) was dissolved in ethanol (10 ml) and hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 3 hours. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate, diethyl ether and petroleum ether to give N-o-aminobenzenesulfonyl-L-alanyl-L-proline (yield: 0.75 g, 56.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[N:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([F:32])=[CH:27][N:26]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)c1
Yield: 21.1 %

Procedure:
To a solution of tert-butyl {5-[2-(3-aminophenyl)ethyl]pyridin-3-yl}carbamate (0.20 g, 0.64 mmol) (prepared in Example C19, step B) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) in N,N-dimethylformamide (4 mL) was added potassium carbonate (0.430 g, 3.1 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc once. The combined organic layers were washed with water and brine, and then dried (Na2SO4), filtered, and concentrated. The crude was purified by silica gel column chromatography to give the desired product as a light yellow oil (60 mg, 20%). LCMS for C22H24ClFN5O2 (M+H)+: m/z=444.0.
Reaction SMILES: [CH3:1][P:2](Cl)(Cl)=[S:3].[H-].[Na+].[CH:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([OH:17])[CH:9]=1>O1CCCC1>[N+:14]([C:13]1[CH:12]=[CH:11][C:10]([O:17][P:2]([CH3:1])(=[S:3])[O:17][C:10]2[CH:9]=[CH:8][C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=2)=[CH:9][CH:8]=1)([O-:16])=[O:15]
Reactant: CP(=S)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CP(=S)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
The methylphosphonothioic acid O,O-bis-(4-nitrophenyl)ester intermediate is prepared according to procedure E using 536 mg of methylphosphonothioic dichloride, 345 mg of sodium hydride (50% in oil), 1 g of p-nitrophenol and 10 ml of tetrahydrofuran. 1.19 g of expected product are collected.