Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[C:4](OC(C)(C)C)(=O)C.C(O[C:15]([C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][O:23][C:20]2=[CH:21][N:22]=1)=[O:16])C.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[C:15]([C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][O:23][C:20]2=[CH:21][N:22]=1)(=[O:16])[CH3:4]
Reactant: CCOC(=O)c1cc2ccoc2cn1
Reactant: CC(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)c1cc2ccoc2cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
As 405 mg (7.5 mmol) of sodium methoxide was stirred in 5 mL of toluene, 1.16 g (10.0 mmol) of tert-butyl acetate was added dropwise at room temperature to the solution. Then, 956 mg (5.0 mmol) of 5-ethoxycarbonylfuro[2,3-c]pyridine dissolved in 5 mL of toluene was added dropwise at room temperature to the above solution. After all the solution had been added, the reaction mixture was heated to 60° C., a reaction was carried out for 3 hours. The resulting reaction mixture was then neutralized with 450 mg (7.5 mmol) of acetic acid, the solution was stirred for 30 minutes, 1.5 mL (7.5 mmol) of 5 N hydrochloric acid was then added, and the solution was stirred for 5 hours at 60° C. to carry out a reaction. The solution was then returned to room temperature, the organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator. The resulting solids were recrystallized from a mixed solvent of toluene-hexane, giving 580 mg (72% yield) of 5-acetylfuro[2,3-c]pyridine in a purity of 99% by HPLC.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2[NH:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16]>ClCCl.C(O)(C(F)(F)F)=O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2[NH:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)CNc1cnnc2ccc(C(F)(F)F)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNc1cnnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl 2-(6-(trifluoromethyl)cinnolin-4-ylamino)acetate (as prepared in the previous step, 200 mg, 0.61 mmol, 1.00 equiv) in dichloromethane (5 mL) and CF3COOH (0.2 mL). The reaction mixture was stirred overnight at room temperature, and then was concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]1(=[O:15])[NH:9][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[K]>CN(C=O)C.C(OCC)C>[CH2:1]([N:9]1[C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]2[C:5]1=[O:15])[C:2]#[CH:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#CCBr
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
Propargyl bromide (1.3 mL, 17.4 mmol) is dissolved in DMF (30 mL) and potassium phtalimide (3.4 g; 18.4 mmol) is added. The mixture is refluxed for 5 h. After cooling at room temperature the mixture is diluted with diethyl ether, washed with water (3×50 mL), dried over Na2SO4 and evaporated under vacuum to give N-propargyl phtalimide as white solid (3.15 g; 17 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:14]2([OH:24])[CH:21]3[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)[N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1.[C:25]([OH:34])(=[O:33])[C@H:26]([C@@H:28]([C:30]([OH:32])=[O:31])[OH:29])[OH:27]>CO.C(#N)C>[C:30]([CH:28]([CH:26]([C:25]([OH:34])=[O:33])[OH:27])[OH:29])([OH:32])=[O:31].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:14]2([OH:24])[CH:15]3[CH2:23][CH:19]4[CH2:18][CH:17]([CH2:22][CH:21]2[CH2:20]4)[CH2:16]3)[N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: OC1(C(c2cccc(Cl)c2)n2ccnc2)C2CC3CC(C2)CC1C3
Solvent: CO
Solvent: CC#N
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
43.0 g (125.4 mmol) of (3-chlorophenyl)-(2-hydroxy-2-adamantyl)-(1-imidazolyl)-methane and 18.83 g (125.4 mmol) of D(-)-tartaric acid were dissolved in a mixture of 67 ml of methanol and 440 ml of acetonitrile at the boiling point. When the solution was slowly cooled to room temperature, crystallization occurred. After 2 days, the crystals were filtered off under suction and washed with acetonitrile and ether and dried for 3 hours at 98° C./3-6 mbar. 23.50 g of (3-chlorophenyl)-(2-hydroxy-2-adamantyl)-(1-imidazolyl)-methane hydrogen tartrate ([α]D : (+) 4.26° (c=1.0, CH3OH)) were obtained. This product was dissolved in a boiling mixture of 33 ml of methanol and 193 ml of acetonitrile and allowed to crystallize out at room temperature. After isolation as described above, 18.00 g of product [α]D22 : (+) 5.30° (c=1.0, CH3OH)) were obtained. These 18.00 g were recrystallized in an analogous manner from 26 ml of methanol and 151 ml of acetonitrile. 14.2 g of product [α]D22 : (+) 5.53° (c=1.0, CH3OH)) were obtained. A further recrystallization from 20 ml of methanol and 116 ml of acetonitrile gave 11.7 g of product ([α]D22 : (+) 5.90° (c=1.0, CH3OH)). Further recrystallization of this substance from 16 ml of methanol and 95 ml of acetonitrile in 9.60 g of (3-chlorophenyl)-(2-hydroxy-2-adamantyl)-(1-imidazolyl)-methane hydrogen tartrate ([α]D22 : (+) 6.18° (c=1.0, CH 3 OH)) as a pure diastereomeric salt of melting point 112°-113° C. (decomposition). The mother liquors from the 3rd, 4th and 5th recrystallizations were combined and evaporated down in vacuo, and the remaining residue (8.20 g) was recrystallized from 11.5 ml of methanol and 66.5 ml of acetonitrile in a manner analogous to that described above. 5.4 g of product ([α]D22 : (+) 5.81° (c=1.0, CH3OH)) were obtained, and this product was recrystallized twice more from appropriate methanol/acetonitrile mixtures in an analogous manner. Thereafter, a further 3.60 g of pure diastereomeric hydrogen tartrate ([α]D22 : (+) 6.20° (c=1.0, CH3OH)) were obtained at this point. A total of 13.20 g (=42.7% of theory) of pure (+)-(3-chlorophenyl)-(2-hydroxy-2-adamantyl)-(1-imidazolyl)-methane hydrogen tartrate were obtained in this manner (starting from D(-)-tartaric acid).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](Cl)=[O:31].O>N1C=CC=CC=1>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:31]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cnc(N2CC3CN(C(=O)c4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a suspension of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.156 g, 0.59 mmol) in pyridine (2 ml) was added 2-naphthalene carbonyl chloride (0.136 g, 0.71 mmol). The mixture was stirred for 3 h, then water (10 ml) was added and the product collected by filtration. The product was washed with further water and then dried overnight under vacuum to yield the title compound (0.217 g, 71%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:38]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:30][C:31]3[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:38])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1cccc(C)c1CBr
Product: Cc1cccc(C)c1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-(3-Benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and 2-Bromomethyl-1,3-dimethyl-benzene following the procedure of Example 478: MS m/z 498; HRMS: calcd for C32H26F3NO+H+, 498.20392; found (ESI, [M+H]+), 498.2038.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])O[C:2]1=[O:11].[CH2:12]1[C@@H:15](C(O)=O)[NH:14][CH2:13]1>CN(C)C=O.C(O)(=O)C>[S:9]1[C:5]2[C:4](=[O:10])[N:14]3[CH2:15][CH2:12][C@H:13]3[C:2](=[O:11])[NH:1][C:6]=2[CH:7]=[CH:8]1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2ccsc2C(=O)N2CC[C@@H]12
Yield: 42.7 %

Procedure:
A solution of 26.9 g (171mmol) of 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (EP 27214) and 16.1 g (171 mmol) of L-azetidine-2-carboxylic acid in 200 ml of dimethylformamide and 40 ml of acetic acid was stirred at 120° for 3 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 15.2 g (43%) of (S)-6,7-dihydroazeto[1,2-a]thieno[3,2-e][1,4]diazepine-5,9(4H,5aH)-dione as a colourless crystallizate of m.p. 274°.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[Br:19]Br>C(O)(=O)C>[Br:19][C:14]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]([NH2:18])[C:8]3[N:7]=[CH:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]=3[C:16]=2[CH:15]=1
Reactant: BrBr
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reaction time: 24 h
Yield: 25.6 %

Procedure:
To a solution of 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 41.6 mmol) in acetic acid (150 mL) was added Br2 (10.0 g, 62.6 mmol), and after 24 h, the resulting solid was collected by filtration and washed with H2O. The orange solid was suspended in a saturated aqueous solution of NaHSO3, after which it was again collected and stirred with a 2 M solution of Na2CO3 for 18 h. The solid was collected by filtration, washed with H2O, and azeotropically dried with toluene on a rotary evaporator. Purification on silica gel (7%-10% methanol in CH2Cl2 gradient) afforded 3.4 g of 8-bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[N+:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)([O-:36])=[O:35].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:40]2[CH:41]=[CH:42][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 0.05 g (0.1 mmol) of above resin-bound 3-(4-bromo-phenyl)-2-(S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester in 2.0 mL of DME was added 50.1 mg (0.3 mmol) of 4-nitrophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated at 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% DCM) to give 28.2 mg of the title compound. LC/MS (m/z): 565 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:14](Cl)(Cl)[Cl:15]>[Cl-].[Zn+2].[Cl-]>[Cl:15][P:14]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13]1
Reactant: ClP(Cl)Cl
Reactant: Oc1ccccc1-c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Product: ClP1Oc2ccccc2-c2ccccc21

Procedure:
reacting o-phenylphenol with phosphorus trichloride in the presence of zinc chloride catalyst to form a 6-chloro-6H-dibenz [c,e][1,2] oxaphosphorin of the following formula (II);
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].C(N(C(C)C)C(C)C)C.[Br:35][CH2:36][C:37](Br)=[O:38]>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][N:16]1[C:37](=[O:38])[CH2:36][Br:35])[CH3:3]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)COc1ccc(F)cc1C1NCCc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(F)cc1C1c2ccccc2CCN1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution under N2 of (±)-[4-fluoro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (2.0 g, 5.2 mmol, 1.0 eq.) in DCM (13 mL), N-ethyldiisopropylamine (2.7 mL, 15.6 mmol, 3.0 eq.) was added. A solution of bromoacetyl bromide (0.5 mL, 5.7 mmol, 1.1 eq.) in DCM (5 mL) was added dropwise. The cooling bath was removed and the brown solution stirred at r.t. for 2 hours. The solution was diluted with AcOEt (170 mL), washed with sat. aq. NaHCO3 soln. (1×90 mL), with sat. aq. NaCl soln. (1×90 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 35 mL/min, heptane to heptane+AcOEt) to yield the title compound as a brown oil.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:6]([F:18])[CH:5]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34](O)=[O:35])[N:25]=1>>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:13][CH2:14][N:15]([C:34](=[O:35])[CH2:33][N:26]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:32]4[C:24]([C:20]4[NH:19][CH:23]=[CH:22][N:21]=4)=[N:25]3)[CH2:16][CH2:17]2)=[C:6]([F:18])[CH:5]=1
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: COc1cc(N2CCNCC2)c(F)cc1Cl
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)c(F)cc1Cl

Procedure:
The title compound was prepared following Protocol A. 1-(4-Chloro-2-fluoro-5-methoxyphenyl)piperazine dihydrochloride and [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 10% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (27 mg): 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H), 8.67 (dd, 0.4H), 8.57-8.55 (m, 1H), 7.31-7.20 (m, 2H), 7.12-7.06 (m, 2H), 6.49-6.45 (m, 1H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 3.86 (s, 0.9H), 3.85 (s, 2.1 H), 3.81-3.75 (m, 4H), 3.15-3.08 (m, 4H); LC/MS m/z (M+H)+ 470.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCc1ccc(Cl)c(Cl)c1
Yield: 84.3 %

Procedure:
To a solution of 3,4-dichlorobenzylamine (3.97 g) and triethylamine (3.5 ml) in chloroform (80 ml) was added a solution of 2-nitrobenzenesulfonyl chloride (5 g) in chloroform (20 ml) at 0° C. with stirring and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed successively with diluted hydrochloric acid and water, and then dried. Evaporation of the solvent gave N-(3,4-dichlorobenzyl)-2-nitrobenzenesulfonamide (6.87 g).
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.C[O:23][C:24]([C:26]1[C:27]([C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[O:42][CH3:43])=[CH:28][CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)=[O:25]>>[Cl:41][C:39]1[CH:38]=[CH:37][C:36]([O:42][CH3:43])=[C:35]([C:27]2[C:26]([C:24]([OH:25])=[O:23])=[CH:31][C:30]([N+:32]([O-:34])=[O:33])=[CH:29][CH:28]=2)[CH:40]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(Cl)ccc1OC
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccc(Cl)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 93.8 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl-5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate (0.83 g, 2.6 mmol) to afford 0.75 g (95%) of 5'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid as a yellow solid. Data for (5'-chloro-2'-methoxy-4-nitro-2-biphenyl)carboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.69 (d,J=2.5, 1H); 8.46 (dd,J=8.3, 2.6, 1H); 7.68 (d,J=8.5, 1H); 7.41 (dd,J=8.9, 2.7, 1H); 7.33 (d,J=2.8, 1H); 7.08 (d,J=8.6, 1H); 3.75 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@@H:5]4[CH2:6][C@H:7]([CH3:8])[C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@H](C)[C@@H](N)C1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from N-[(1R*,3S*,4S*)-3-amino-4-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f68) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH2:24]([CH2:26][NH2:27])[OH:25].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[OH:25][CH2:24][CH2:26][NH:27][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: NCCO
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NCCO)[nH]n1
Temperature: 90 °C
Yield: 27.4 %

Procedure:
To a solution of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and ethanolamine (29 mg, 0.47 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (16 mg, 0.11 mmol) and the reaction was heated at 90° C. under argon overnight. After cooling to room temperature, the mixture was evaporated and purification by chromatography (silica, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (30 mg, 28%), which was obtained as a white solid. MS: m/e=343.2 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[N:4]=[CH:3][CH:2]=1.[C:12]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][CH:2]=[N:1]2
Reactant: Oc1cccc2nccnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2nccnc12
Temperature: 50 °C

Procedure:
To quinoxalin-5-ol (0.43 g) dissolved in DMF (6 ml) was added K2CO3 (2.5 eq.) and KI (0.2 eq.). To this mixture was then added dropwise iodomethane (1.2 eq.). The resulting mixture then heated to 50° C. overnight. The reaction mixture was subsequently partitioned between satd. NaHCO3 and EtOAc, the EtOAc layer backwashed with water and brine, dried over Na2SO4, and concentrated to dryness under vacuum. The crude material was then purified by SGC (MeOH:DCM) affording 5-methoxyquinoxaline. MS (ESI+) for m/z 160 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:15].[O:16]([NH2:18])[CH3:17].C(=O)(O)[O-].[Na+]>C1COCC1.O>[ClH:15].[CH3:17][O:16][N:18]=[C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C1CCNCC1
Reaction time: 0.17 h
Yield: 128.3 %

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g) and methoxylamine hydrochloride (2.93 g) in THF (66 mL) was treated with sodium bicarbonate (2.95 g) dissolved in water (20 mL). The biphasic mixture was stirred vigorously for 10 minutes, diluted with water, and extracted with ethyl acetate (×3). The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 2.12 g of the title compound, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ ppm 1.49 (s, 9H), 2.34 (t, 2H, J=6.07 Hz), 2.57 (t, 2H, J=6.07 Hz), 3.51 (t, 2H, J=6.07 Hz), 3.56 (t, 2H, J=6.07 Hz), 3.85 (s, 3H).
Reaction SMILES: C(=O)=O.[H-].[Na+].[CH2:6]([OH:9])[CH2:7][CH3:8].[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([Si:14]([CH3:17])([CH3:16])[O:9][CH2:6][CH2:7][CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dry-ice cooled suspension of 4.0 g of sodium hydride (60% dispersion in mineral oil) in 80 ml of anhydrous THF was dropwise added a solution of 7.44 ml of 1-propanol in 30 ml of the same solvent, and the mixture was slowly warmed to room temperature with continued stirring for 1 hr under nitrogen. A solution of 15.0 g of t-butyldimethylchlorosilane in 40 ml of THF was slowly added by syringe and continued stirring for 3 hr at room temperature. After distillation of the solvent, house vacuum distillation afforded the pure t-butyldimethyl-n-propoxysilane as a colorless liquid (106° C./house vacuum, 12.0 g, 69.2%). 1HNMR (CDCl3): δ 0.05 (s, 6H), 0.88 (t, J=7.5Hz, 3H), 0.89 (s, 9H), 1.53 (sextet, 2H), 3.56 (t, J=6.6 Hz, 2H). 13C-NMR (CDCl3): δ−5.08 (2C), 10.47 (1C), 18.58 (1C), 26.17 (3C), 26.21 (1C), 65.13 (1 C).