Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=4[N:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:28])[CH2:3][CH2:2]1.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.O>ClCCl>[CH2:35]([S:36]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:28])[CH2:5][CH2:6]1)(=[O:38])=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)CNC(=O)N3C1CCNCC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c3c(cnc21)CNC(=O)N3C1CCN(S(=O)(=O)Cc2ccccc2)CC1
Yield: 72 %

Procedure:
1-(Piperidin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one (18.5 mg, 0.0460 mmol) in dichloromethane was mixed with phenylmethanesulfonyl chloride (17.5 mg, 0.092 mmol) and triethylamine (12.8 μL, 0.0920 mmol) for 1 hour under cooling with ice. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1 (v/v)) to give the title compound as a pale yellow solid (18.4 mg, yield 72%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:11]O.F>>[C:9]1([OH:11])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1.[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[OH:11].[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OO
Agent: F
Solvent: c1ccc2ccccc2c1
Product: Oc1ccc2ccccc2c1
Product: Oc1cccc2ccccc12
Yield: 0.7 %
Yield: 42.3 %

Procedure:
When carrying out the hydroxylation of naphthalene with a molar excess of H2O2 (90%) in a conventional acid system, such as anhydrous hydrogen fluoride, at temperatures ranging from -10° to 0° C. and at atmospheric or slightly superatmospheric pressure, 42.3% α-naphthol and only 0.7% β-naphthol were obtained, with about 9% of polymeric higher molecular weight product and 48% of naphthalene can be recovered unchanged. The yield of α-naphthol is 81% with an isomeric purity of 98.4%.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][Li]>O1CCCC1>[C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:13])[CH3:14]
Reactant: [Li]C
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Yield: 34.4 %

Procedure:
Quinaldic acid (2.76 grams, 0.017 mole) was dissolved in 100 ml of dried tetrahydrofuran. Then 25 ml of 1.6 M (0.04 mole) of methyl lithium was added using a syringe. Reaction appeared immediate. The solution was stirred and heated under reflux for two hours and then poured into 600 ml of ice water. The ketone (2-acetylquinoline) was extracted with four 25 ml portions of ethyl ether which, after drying, was removed by rotary evaporation to yield ca. 1.0 g (ca. 40%) of 2-acetylquinoline.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[NH2:26]>>[N:12]1([CH2:11][C:8]([NH:26][C:25]2[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: COc1cc(N)cc(OC)c1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Agent: O=C([O-])C(F)(F)F
Product: COc1cc(NC(=O)Cn2cnc3ccccc32)cc(OC)c1

Procedure:
The title compound was synthesized according to a procedure described in Example 98 starting from 3-carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate (Example 92 part B) and 3,5-dimethoxy-aniline. Calculated for C17H17N3O3 m/z: 311.34, found 311.88 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.69 (s, 6 H), 5.14 (s, 2H), 6.23 (t, J=2.3 Hz, 1H), 6.82 (d, J=2.0 Hz, 2H), 7.22 (m, 2H), 7.51 (d, J=7.6 Hz, 1H), 7.66 (dd, J=7.3, 1.3 Hz, 1H), 8.21 (s, 1H), 10.41 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[Br:16]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([CH2:14][Br:16])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(C(=O)OC)c1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(C(=O)OC)c1

Procedure:
4-Methyl-isophthalic acid dimethyl ester (1.06 g, 5.10 mmol), N-bromosuccinimide (1.00 g, 5.61 mmol) and 1,1′-azobis(cyclohexanecarbonitrile)(0.31 g, 1.27 mmol) were suspended in carbon tetrachloride (22 mL) and the resulting mixture was refluxed for 16 hours under N2. The orange solution was concentrated under reduced pressure and the resulting orange residure was purified via column chromatography on silica gel (hexanes;EtOAc, 7:1, v/v). 4-Bromomethyl-isophthalic acid dimethyl ester was isolated as a yellow crystalline solid (1.05 g, 72%). 1H NMR (CDCl3) δ 3.95 (s, 3H), 3.97 (s, 3H), 4.96 (s, 2H), 7.57 (d, 1H, J=9.0 Hz), 8.13 (dd, 1H, J=9.0, 3.0 Hz), 8.62 (d, 1H, J=3.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([C:19]#[N:20])[N:3]=1.[SH2:21].CCN(CC)CC>C(O)(C)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([C:19](=[S:21])[NH2:20])[N:3]=1
Reactant: N#Cc1nc(N)nc2c1ncn2Cc1ccccc1F
Reactant: S
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: NC(=S)c1nc(N)nc2c1ncn2Cc1ccccc1F
Temperature: 50 °C
Yield: 100 %

Procedure:
A suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-carbonitrile (680 mg, 1.85 mmol) in isopropanol (50 mL) was treated with H2S gas for 15 min, then treated with Et3N (0.51 mL, 3.7 mmol), heated at 50° C. for 1 h, concentrated in vacuo, diluted with Et2O and filtered to give the title compound (757 mg, 100%) as a yellow solid; NMR δH (400 MHz, DMSO) 5.36 (2H, s), 6.66 (2H, br s), 7.06-7.43 (4H, m), 8.15 (1H, s), 9.81 (1H, br s) and 10.22 (1H, br s).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]=[C:14]1[NH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:15]1.[C:28]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:33]=CC=C[CH:29]=1.C(O)C#C>O.O1CCCC1>[O:13]=[C:14]1[N:18]([CH2:33][C:28]#[CH:29])[C:17]([C:19]([F:20])([F:21])[F:22])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:15]1
Reactant: CCOC(=O)c1oc(=O)[nH]c1C(F)(F)F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: C#CCO
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1c(C(F)(F)F)c(C(=O)OCC)oc1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
5.4 ml of diethyl azodicarboxylate were added at 10 C to a solution of 7 g of ethyl 2,3-dihydro-2-oxo-4-trifluoromethyl-oxazol-5-carboxylate [prepared as in Patent No. EP 027,020], 70 ml of tetrahydrofuran, 8.15 g of triphenylphosphine and 3.3 ml of propargyl alcohol and the mixture was stirred for one hour at 20° C. The mixture was poured into water and was extracted with ethyl acetate, dried, filtered and concentrated. The residue was chromatographed on silica and eluted with a hexane-ethyl acetate mixture (85-15) to obtain 4.6 g of the expected product melting at 72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15](O)=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[C:24]([O:28][C:29](=[O:32])[NH:30][NH2:31])([CH3:27])([CH3:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([NH:31][NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)NNC(=O)OC(C)(C)C)ccc12
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of the compound [97] (73.2 mg) in chloroform (1.1 mL) were added tert-butylcarbazate (222.0 mg), 1-hydroxybenzotriazole monohydrate (113.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161.0 mg) at room temperature, and then the reaction mixture was stirred for 18 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (84.0 mg) as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[CH:20]([Mg]Br)=[CH2:21].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[NH:15][CH:21]=[CH:20]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc2cc[nH]c12
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
A solution of tert-butyl-dimethyl-[2-(2-nitro-phenyl)-ethoxy]-silane (85.6 g, 304 mmol) in THF (1 L) was cooled to −65° C. and a 1.0 M solution of vinyl magnesium bromide in THF (913 mL, 913 mmol) was introduced while maintaining a temperature below −60° C. The reaction was stirred for 15 minutes at −45° C., additional vinyl magnesium-bromide (152 mL, 152 mmol) was added and the reaction was stirred at −45° C. for 30 minutes. The cold reaction was poured into saturated aq ammonium chloride (800 mL) and diluted with EtOAc (500 mL). The two layers were separated and the aqueous layer was extracted with EtOAc(2×200 mL). The organic layers were combined, washed with brine (400 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (95% hexane/EtOAc) gave the title compound (47.1 g, 56%) as a transparent brown oil. 1H NMR (400 MHz, DMSO-d6) −0.11 (s, 6H), 0.80 (s, 9H), 3.03 (t, J=6.8 Hz, 2H), 3.85 (t, J=6.8 Hz, 2H), 6.39 (dd, J=1.2, 3.2 Hz, 1H), 6.86–6.92 (m, 2H), 7.28 (dd, J=3, 3 Hz, 1H), 7.36 (dd, J=4.8, 4.8 Hz, 1H), 11.02 (br s, 1H). MS (electrospray, m/z) 276 (M++1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[CH:8][C:7]3[N:13]=[N:14][N:15]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:6]=3[C:5]=2[N:4]=1.[OH:22][C@H:23]([CH3:27])[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[CH:8][C:7]3[N:13]=[N:14][N:15]([CH:16]4[CH2:21][CH2:20][N:19]([C:24](=[O:25])[C@H:23]([OH:22])[CH3:27])[CH2:18][CH2:17]4)[C:6]=3[C:5]=2[N:4]=1
Reactant: Clc1ccc2ncc3nnn(C4CCNCC4)c3c2n1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine hydrochloride (600 mg, 1.85 mmol) in DMF (15 mL) was added (R)-2-hydroxypropanoic acid (540 mg, 1.85 mmol), HATU (850 mg, 2.21 mmol) and DIEA (0.8 mL, 3.70 mmol). The mixture was stirred at room temperature overnight. Another 3 eq of HATU and 2 eq of DIEA were added because the reaction did not go to completion as shown by HPLC-MS. The mixture was stirred for another 30 min, and was then diluted with water. The resulting mixture was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous Na2SO4, and concentrated to give the crude product, which was subsequently purified by chromatography on silica gel using EtOAc:PE as eluent to afford (R)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one as a yellow solid (136 mg, yield 20.4%). MS (m/z): 361 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:35]1[CH:40]=[CH:39][C:38]([CH2:41]O)=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OCc1ccncc1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2ccncc2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
In a manner similar to that described in Example H, the product from Example G (0.5 g, 1.08 mmol) and 4-pyridylcarbinol (0.12 mL, 1.26 mmol) were converted to the title compound.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:12]=[P:13](Cl)([Cl:15])[Cl:14].C(N(CC)CC)C>CC(OC)(C)C>[P:13]([Cl:15])([Cl:14])(=[O:12])[O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reaction time: 3 h
Yield: 86.3 %

Procedure:
In a 22 L 3-neck flask equipped with a mechanical stirrer, an internal thermocouple, a cooling bath of dry/acetone, an additional funnel and a nitrogen inlet was placed 1-naphthol (780 g, 5.41 mol, 491 g used from Aldrich, ≧99% grade, Product No N1000 and 289 g used from Alfa Aesar 99% grade, Product No A11862) in 10 L of MTBE at room temperature. POCl3 (495 mL, 5.41 mol, ReagentPlus® 99%, Product No 201170, Aldrich) in an additional funnel was dropwise added in 5 min (note: no exothermic observed) under nitrogen pressure. To this solution at −25° C. (an internal temperature) was slowly added by triethylamine (754 mL, 5.41 mol, ≧99.5% grade, Product No 471283, Aldrich) for one h (note: exotherm observed) and then the cooling bath was removed after the addition was completed. The reaction mixture was aged for 3 h at room temperature under nitrogen pressure. The triethylamine hydrochloride salt was filtered off using a 3 L sintered funnel (Medium size) and the filtrate was concentrated to dryness under reduced pressure at <20° C. of water bath to give desired product as clear dark yellow oil (1219 g, 86.3%) which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH2:3][C:4]([OH:6])=[O:5].Cl.[CH3:16][CH2:17]O>>[CH2:16]([O:5][C:4](=[O:6])[CH2:3][C@H:2]([NH2:1])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH3:17]
Reactant: CCO
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1Cl
Agent: Cl
Product: CCOC(=O)C[C@H](N)Cc1ccccc1Cl

Procedure:
(R)-3-Amino-4-(2-chloro-phenyl)-butyric acid (10 g, 50 mmol) was dissolved in absolute EtOH (250 mL). Concentrated HCl (2 mL) was added and the mixture was heated to reflux overnight. The product was vacuumed to dryness and azeotroped with toluene (4×50 mL), then placed under high vacuum overnight to yield the title compound as a white solid (10 g).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH2:45][CH2:46][O:47][CH3:48])[CH3:44])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: COCCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CCOC)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.9 mg) was obtained.
Reaction SMILES: CCOC(C)=O.[CH3:7][C:8]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:9]=1[C:10]([NH:12][C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1)=[O:11].[H][H]>CO.[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:8]([CH3:7])=[C:9]([CH:19]=1)[C:10]([NH:12][C:13]1[CH:18]=[N:17][CH:16]=[N:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cncnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1C(=O)Nc1cncnc1

Procedure:
A 2L high-pressure vessel was charged with Palladium 10% on carbon wet (50% water) and EtOAc (50 mL). 2-methyl-5-nitro-N-(pyrimidin-5-yl)benzamide 45 (18.79 g) was dissolved in methanol (400 mL) and added to the previous mixture. The reaction vessel was pressurized to 30 psi of H2 and mechanically stirred until the hydrogen intake stopped. The reduction of the nitro group was complete by LCMS and the mixture was filtered off through paper and glass paper. The crude 5-amino-2-methyl-N-(pyrimidin-5-yl)benzamide 46 was obtained as a yellow solid and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([Cl:22])[C:14]=2[Cl:23])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].C(O)(=O)C.C(O)C>[Fe].C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([Cl:22])[C:14]=2[Cl:23])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: Cn1nc(Cc2cc([N+](=O)[O-])cc(Cl)c2Cl)c(Cl)c1OC(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(Cc2cc(N)cc(Cl)c2Cl)c(Cl)c1OC(F)F

Procedure:
At 70—75° C., 2.2 g (5.7 mmol) of 4-chloro-3-(2,3-dichloro-5-nitrobenzyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were added to a mixture of 1.7 g (30 mmol) of iron, 5 ml of acetic acid and 10 ml of ethanol. The mixture was then heated under reflux for 1 hour. The reaction mixture was then admixed with 50 ml of ethyl acetate and filtered through a bed of diatomaceous earth. Finally, the mixture was concentrated. Yield: 2 g;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=2)[CH:34]=[CH:33]1.C(N(CC)CC)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:41]([C:38]2[CH:39]=[C:40]3[C:35]([CH:34]=[CH:33][N:32]3[CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:36][CH:37]=2)=[O:42])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reactant: COCCCn1ccc2ccc(C(=O)O)cc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCCn1ccc2ccc(C(=O)N(C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(C)(C)O[SiH2]C(C)(C)C)C(C)C)cc21

Procedure:
From (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 12.9 mmol), 1-(3-methoxy-propyl)-1H-indole-6-carboxylic acid (4.22 g, 18.1 mmol), BOPCI (4.6 g, 18.1 mmol) and triethylamine (7.2 mL, 51.7 mmol). TLC, Rf (AcOEt)=0.32.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.[C:24]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])#[N:25].C(O)(=O)C>>[C:30]([O:29][C:27](=[O:28])[CH:26]([C:24]#[N:25])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C(C#N)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 50 %

Procedure:
Into a seal vessel, 4-Fluoro-2-methoxy-1-nitro-benzene (15.00 g, 87.65 mmol), 1.00 M of Potassium tert-Butoxide in Tetrahydrofuran (193 mL, 193 mmol), and t-Butyl cyanoacetate (24.7 g, 175 mmol) were added. The reaction mixture was heated at 80° C. for 4 hours. The reaction was cooled to room temperature. Acetic acid (10.96 mL, 192.8 mmol) was added. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc. The collected fractions afforded an orange collected fractions afforded Cyano-(3-methoxy-4-nitro-phenyl)-acetic acid tert-butyl ester as an orange solid (12.8 g, 49%).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=[O:4].[NH2:13][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15].[ClH:20].Cl>O1CCOCC1>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:13][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[O:5].[NH2:1][CH2:2][C:3]([NH:13][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[O:4].[ClH:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)NC(=O)CN
Product: COC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Yield: 137.8 %

Procedure:
Boc-Gly-Ala-OCH3 was prepared by coupling Boc-Gly-OH (35.0 g, 200 mmol) to H-Ala-OCH3.HCl (27.9 g, 200 mmol) using a mixed anhydride procedure. The resulting product (43.5 g, 167 mmol) was deblocked with anhydrous HCl in dioxane. After deblocking, crystallization from dioxane:ether yielded 27.1 g of H-Gly-Ala-OCH3.HCl.