Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: [N-]=[N+]=NCc1cncc2cccnc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cncc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.1 g (5.9 mmol) 8-azidomethyl-1,6-napthyridine in 20 mL THF was added 2 mL H2O and 3 g PPh3. The resulting solution was allowed to stir overnight at room temperature, then concentrated in vacuo. Purification by flash chromatography (50×140 mm silica gel, linear gradient 5-20% (10% NH4H in MeOH):CH2Cl2) yielded 8-aminomethyl-1,6-napthyridine. 1H NMR (CDCl3, 400 MHz) δ9.22 (s, 1H); 9.13 (dd, 1H, J=4.3 and 1.8 Hz); 8.70 (s, 1H); 8.32 (dd, 1H, J=8.24 and 1.83 Hz); 7.61 (dd, 1H, J=8.24 and 4.3 Hz); 4.40 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:29][CH2:28]5)[C:23]([F:26])([F:25])[F:24])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:4][N:3]=1.[OH:42]O>CC(O)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([OH:42])=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:28][CH2:29]5)[C:23]([F:26])([F:24])[F:25])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:6][N:7]=1
Reactant: OO
Reactant: CC1(C)OB(c2cc3c(cc2-c2cnc(N)nc2)[nH]c2c(C(N)=O)cnc(N[C@H](C4CC4)C(F)(F)F)c23)OC1(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3cnc(N)nc3)c(O)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 7-(2-aminopyrimidin-5-yl)-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-pyrido[4,3-b]indole-4-carboxamide (218 mg, 0.38 mmol) in AcOH (7.7 mL) was added hydrogen peroxide (30%, 0.20 mL, 1.9 mmol) at 0° C. The reaction was left to stir at room temperature for 3 h, diluted with EtOAc, and washed with water. The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 11.38 (s, 1H); 9.25 (s, 1H); 8.42 (s, 2H); 7.97 (s, 1H); 7.90 (br s, 1H); 7.75 (s, 1H); 7.60 (s, 1H); 7.22 (br s, 1H); 6.63 (m, 2H); 4.86 (m, 1H); 1.45 (m, 1H); 0.72 (m, 1H); 0.60 (m, 1H); 0.53 (m, 1H); 0.36 (m, 1H). LRMS (APCI) calc'd for (C21H18F3N7O2) [M+H]+, 458.1. found 458.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=2[S:24]1(=[O:37])=[O:36]>>[O:37]=[S:24]1(=[O:36])[C:25]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=c1ccc2ccccc2n1C1CCNCC1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2S(=O)(=O)N1CCCCBr
Product: O=C1c2cc([N+](=O)[O-])ccc2S(=O)(=O)N1CCCCN1CCC(n2c(=O)ccc3ccccc32)CC1

Procedure:
From the hydrochloride salt of 1-(4-piperidyl)-2(1H)-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-5-nitro-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 8.88 (d, J=1.9 Hz, 1H), 8.73 (dd, J=8.36, 1.71 Hz, 1H), 8.15 (d, J=8.36 Hz, 1H), 7.79 (br m, 1H), 7.62 (d, J=3.47 Hz, 1H), 7.51 (m, 2H), 7.20 (m, 2H), 6.66 (d, J=9.33 Hz, 1H), 3.91 (t, J=7.33 Hz, 2H), 2.85 (br m, 2H), 2.48 (t, J=8.27 Hz, 2H), 2.21 (t, J=10.65 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:25])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:24])([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:15])[CH2:6][CH2:5]2.[O:26]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O.CCOC(C)=O>[OH:26][C:7]([CH3:24])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:25])[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCc1ccccn1)O2
Agent: CC(=O)C#N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCc2ccccn2)=C(C)C1=O

Procedure:
A solution of 6-hydroxy-2,5,7,8-tetramethyl-N-(pyridin-2-ylmethyl)chroman-2-carboxamide (104 mg, 0.307 mmol) in 4 mL AcCN was chilled to 0° C. and CAN (370 mg in 2 mL H2O) added followed by 8 mL EtOAc, 4 mL 1.0 M NaHCO3 and 250 mg K2CO3. The emulsion was extracted 5×4 mL EtOAc and the combined organics washed 2×4 mL saturated NaCl, dried over Na2SO4 and concentrated to yellow oil. Flash chromatography yielded 2-hydroxy-2-methyl-N-(pyridin-2-ylmethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:9]([CH3:10])[C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:6]1)=[O:4].COC([C@H]1[C@H](C)C(=O)N(CC2C=CC(OC)=CC=2OC)C1)=O.C[O-].[Na+].O>CO>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:8](=[O:11])[C@@H:9]([CH3:10])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)[C@@H]1CN(Cc2ccc(OC)cc2OC)C(=O)[C@@H]1C
Agent: COC(=O)[C@@H]1CN(Cc2ccc(OC)cc2OC)C(=O)[C@H]1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CN2C[C@@H](C(=O)O)[C@H](C)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of a mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester (14.2 g) in methanol (150 ml) was added sodium methoxide (about 5M solution in methanol, 28 ml), and the mixture was stirred at room temperature for 16 hours, and then heated to 55° C. and stirred for 3 hours. To this reaction solution was added sodium methoxide (about 5M solution in methanol, 10 ml), and the mixture was stirred at 55° C. for additional 2 hours. This reaction solution was cooled to room temperature, and then water (50 ml) was added thereto, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure to remove methanol. To the resulting residue was added a 2M aqueous solution of hydrochloric acid (105 ml), and the mixture was extracted with ethyl acetate (300 ml). The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the titled compound (14.0 g).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])=[CH:7][C:6]=1[F:18])(=O)C.Cl.C(=O)([O-])O.[Na+]>>[F:18][C:6]1[CH:7]=[C:8]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(OC(F)(F)C(F)F)cc1F
Yield: 81 %

Procedure:
0.60 Gram of 4-acetylamino-3-fluoro-1-(1,1,2,2tetrafluoroethoxy)benzene and 10 ml of a 20% aqueous hydrochloric acid were added to a reactor and stirred under reflux for 2 hours. After cooling the reaction solution, a 5% aqueous sodium hydrogencarbonate solution was added to make the solution weakly alkaline. The reaction solution was then extracted with two 100-ml portions of diethyl ether. The ether layers were combined, dried and concentrated to obtain a yellow oily product as a residue. This oily product was subjected to chromatography on silica gel to obtain 0.40 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)aniline.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([NH:24][C:3]([C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NN1CCCCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NN2CCCCC2)on1
Yield: 65.6 %

Procedure:
As described for example 18, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.33 mmol) was converted, using 1-aminopiperidine (127 mg, 1.27 mmol) instead of N,N-dimethylhydrazine, to the title compound (83 mg, 68%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=9:1 to 7:3). MS: m/e=384.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([OH:20])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]2[O:20][C:23]([CH3:25])([CH3:24])[O:18][C:17]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)OC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)O1
Yield: 87.7 %

Procedure:
(S)-3-(4-Benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g, 7.34 mmol), 2,2-dimethoxypropane (18.63 g, 0.179 mol) and pyridinium p-toluene sulfonate (0.92 g, 3.66 mmol) in chloroform (80 mL) was heated to reflux for 40 minutes under N2. The mixture was cooled, diluted with water, and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated in vacuo to give crude product that was purified by flash chromatography using 10:1 hexanes:acetone to afford the title compound (2.01 g, 88%). 1H-NMR (400 MHz, CDCl3) δ 7.43–7.29 (m, 5H), 7.17 (d, 2H, J=8.80 Hz), 6.91 (d, 2H, J=8.80 Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.12 (dd, 1H, J=14.617 Hz, J=4.40 Hz), 2.99 (dd, 1H, J=14.67 Hz, J=6.36 Hz), 1.49 (s, 3H), 1.36 (s, 3H). MS (ES+) m/z calc'd for C19H20O4 (M+NH4) 330. Found m/z 330.
Reaction SMILES: [CH3:1][N:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[C:3]1=[O:13].C1C(=O)N([Br:21])C(=O)C1.CC(=O)OCC>CC#N>[Br:21][C:11]1[C:5]2[O:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[C:3](=[O:13])[N:2]([CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccc2c(c1=O)NC(=O)CO2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(Br)c2c(c1=O)NC(=O)CO2
Reaction time: 2 h
Yield: 78 %

Procedure:
At room temperature, to the title compound of step 1 (90 mg, 0.5 mmol) in anhydrous CH3CN (1 mL) was added NBS (89 mg, 0.5 mmol). After stirring about 2 h, additional NBS (75 mg, 0.4 mmol) was added and the reaction was complete within 20 min. EA extractive work up and silica gel chromatography gave the title compound (51 mg, 0.39 mmol) in 39% yield.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20]1COCC1>>[CH3:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C:11]1=[O:19]
Reactant: C1CCOC1
Reactant: O=C1CC(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)CC(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N2 at 0° C. was added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0° C. for 10 minutes, then Mel (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO3 (1×100 mL), brine (1×100 mL), then dried over MgSO4, filtered, concentrated, and the residue purified by flash chromatography eluting with CH2Cl2/EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].CC(O[Si](C(C)C)(C(C)C)C(C)C)(C)CN1C2C(=CC=CC=2)C=C1C(O)=O.[C:46]([CH:48]([NH:53][C:54]([CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]1[NH:62][C:63]([C:65]1[N:66]([CH2:74][C:75]([OH:78])([CH3:77])[CH3:76])[C:67]2[C:72]([CH:73]=1)=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])=[O:55])[CH2:49][CH:50]([CH3:52])[CH3:51])#[N:47]>C1COCC1>[C:46]([C@@H:48]([NH:53][C:54]([C@@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:57]1[NH:62][C:63]([C:65]1[N:66]([CH2:74][C:75]([OH:78])([CH3:76])[CH3:77])[C:67]2[C:72]([CH:73]=1)=[CH:71][CH:70]=[CH:69][CH:68]=2)=[O:64])=[O:55])[CH2:49][CH:50]([CH3:52])[CH3:51])#[N:47]
Reactant: CC(C)CC(C#N)NC(=O)C1CCCCC1NC(=O)c1cc2ccccc2n1CC(C)(C)O
Agent: CC(C)[Si](OC(C)(C)Cn1c(C(=O)O)cc2ccccc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CC(C)(C)O

Procedure:
Proceeding as described in Example 11, followed by treatment with 1M TBAF in THF at 50° C. for 12 h, 1-(2-Methyl-2-triisopropylsilanyloxy-propyl)-1H-indole-2-carboxylic acid (100 mg, 0.25 mmol) was concerted to 1-(2-hydroxy-2-methyl-propyl)-1H-indole-2-carboxylic acid [2-(1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide (80 mg; SiO2 PTLC: 50% ethyl acetate/hexanes; mp: 101.5-105.5° C.; MS: M+H=453).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8]C(=O)OC(C)(C)C)[O:5][CH:6]=1.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>ClCCl>[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19].[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[O:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)co1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cc(Br)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, a solution of tert-butyl [(4-bromo-2-furyl)methyl]carbamate (15.3 g, 55.4 mmol) in dichloromethane (86 mL) at 0° C. was treated with trifluoroacetic acid (43 mL) over 15 minutes. The reaction mixture warmed to room temperature over 30 minutes. The solvent was removed in vacuo and chased with toluene (3×50 mL). The product was lyophilized for 18 hours to give the desired product as a brown solid (13.0 g, 81%). LCMS calculated for C5H4BrO (M-NH2)+: m/z=158.9, 160.9. 1H NMR (400 MHz, DMSO-d6): δ 8.34 (br s, 3 H), 8.01 (s, 1 H), 6.70 (s, 1 H), 4.08 (s, 1 H).
Reaction SMILES: Cl.N[C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[C:8]([O:15][CH3:16])[CH:7]=2.C[O-].[Na+].B.Cl.[OH-].[Na+]>N1C=CC=CC=1.CO>[NH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:4]2[CH:3]=[CH:12][C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[CH:10]=3)[N:5]=2)[CH2:7]1
Reactant: COc1cc2cc(N)cnc2cc1OC
Agent: B
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc2ccc(C3CCCC(N)C3)nc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 115 %

Procedure:
To a MeOH (3 mL) solution of 4 Å powdered molecular sieves (0.11 g) under argon is added 3-amino-6,7-dimethoxy-quinoline hydrochloride (0.17 g, 0.68 mmol) and NaOMe (0.039 g, 0.71 mmol). The reaction mixture is stirred at room temperature for 30 min., and cyclohexahone (0.074 mL, 0.71 mmol), then pyridine.borane (0.072 mL, 0.071 mmol) are added portionwise. The mixture is stirred for 4.5 h, then 5N HCl (1.4 mL, 6.8 mmol) is added portionwise. The reaction mixture is stirred 45 min., then made strongly basic with 5N NaOH. The mix is partitioned between EtOAC and H2O, and the aqueous layer is washed with EtOAc (2×). The combined organic layers are washed with brine, (1×), dried (MgSO4), chromatographed (50% EtOAc/hexanes), and recrystallized from EtOAc/liexanes to obtain 0.112 g light-yellow solid in 57% yield (m.p. 164-165). Anal. calcd for C17H22N2O2: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.45; H, 7.49; N, 9.80.
Reaction SMILES: CN(C(ON1N=NC2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CCCC1.[CH3:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:46]2[CH:47]=[N:48][C:49]([N:52]3[C:60]4[C:55](=[CH:56][CH:57]=[C:58]([C:61](O)=[O:62])[CH:59]=4)[C:54]([S:64][CH3:65])=[CH:53]3)=[N:50][CH:51]=2)[CH:41]=1>CN(C=O)C>[CH3:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:46]2[CH:47]=[N:48][C:49]([N:52]3[C:60]4[C:55](=[CH:56][CH:57]=[C:58]([C:61]([N:15]5[CH2:14][CH2:13][CH2:12][CH2:10]5)=[O:62])[CH:59]=4)[C:54]([S:64][CH3:65])=[CH:53]3)=[N:50][CH:51]=2)[CH:41]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CSc1cn(-c2ncc(-c3cc(C)ccn3)cn2)c2cc(C(=O)O)ccc12
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1cn(-c2ncc(-c3cc(C)ccn3)cn2)c2cc(C(=O)N3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (0.36 g, 0.95 mmol), diisopropylethylamine (0.41 mL, 2.39 mmol) and pyrrolidine (0.079 mL, 0.96 mmol) were added at 0° C. to a solution of the carboxylic acid 269b) (0.3 g, 0.79 mmol) in DMF (2 mL) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then poured onto water and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate and evaporated. The remnant was purified by flash column chromatography [silica; dichloromethane with 1% methanol]. White solid. Yield: 0.33 g (97% of theory)
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[S:21][CH:22]=[C:23]([C:25]([O:27]C)=[O:26])[N:24]=4)=[CH:16][C:15]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=4)=[CH:16][C:15]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:11])=[O:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1csc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(C(=O)O)cs3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
Into 45 mL of methanol was dissolved 954 mg of Compound 69, and 4.0 mL of 1 mol/L sodium hydroxide was added thereto. After 20 minutes of stirring under heating and refluxing, the solvent was removed by evaporation under reduced pressure, and the resulting residue was extracted with ether-water (1/1). To the aqueous layer was added 2 mol/L hydrochloric acid, and the precipitated crystals were washed with ether to obtain 746 mg of the title compound as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)Cl>[CH2:31]([O:30][C:28]([N:15]1[CH:16]2[CH:21]([CH:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][CH2:17]2)[N:12]([C:10](=[O:11])[CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (104.9 mg, 0.26 mmol) was dissolved in absolute CH2Cl2 (13 ml) under N2 and ethyl chloroformate (34.5 mg, 0.32 mmol) was added dropwise. The solution was stirred at room temperature overnight, and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.05, l=18 cm, V=5 ml). A yellow resin was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([O:15][P:16]([C:21]([NH2:24])([CH3:23])[CH3:22])(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14].C(N(CC)CC)C>C(#N)C>[CH2:18]([O:17][P:16]([C:21]([NH:24][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:22])[CH3:23])(=[O:20])[O:15][CH2:13][CH3:14])[CH3:19]
Reactant: CCOP(=O)(OCC)C(C)(C)N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
83 g of 3-nitrobenzoyl chloride in 150 ml of acetonitrile are added dropwise to a solution of 105 g of 2-aminopropane-2-phosphonic acid diethyl ester and 45 g of triethylamine in 300 ml of acetonitrile at 0° C, with good stirring. After completion of the addition, the mixture is stirred for a further 3 hours at 0° C; it is then filtered and the solvent is distilled off in vacuo. The residue is purified by extraction by shaking with ether and aqueous 2 normal sodium carbonate solution. 99 g of 2-(3'-nitrobenzamido)propane-2-phosphonic acid diethyl ester of melting point 95°-96° C are obtained. This product is reduced with hydrogen as indicated in Example 2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[C:16]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)=[O:24])([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: OCc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)OCc2ccc(O)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.24 g (0.01 mol) of 4-hydroxybenzenemethanol, 1 ml (0.01 mol) of pyridine and 50 ml of THF are introduced into a round-bottomed flask. While cooling in an icebath, a solution of 2.2 g (0.01 mol) of 3-tert-butyl-4-methoxybenzoyl chloride in 50 ml of THF is introduced dropwise and the mixture is stirred at room temperature for 24 h. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and ethyl ether (97:3).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=2)=[CH:5][C:4]=1[CH3:15]>C(O)(=O)C>[CH3:15][C:4]1[CH:5]=[C:6]([C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=2)[CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(-c2ccn(C)n2)cc1C
Solvent: CC(=O)O
Product: Cc1cc(-c2ccn(C)n2)ccc1O
Yield: 90.8 %

Procedure:
A mixture of 3-(4-methoxy-3-methyl-phenyl)-1-methyl-1H-pyrazole 2.9 g, 47% hydrobromic acid 21 ml and acetic acid 21 ml was stirred with heating under reflux for twenty hours. The solvent was distilled off and to the resulting residues was added ethyl acetate 100 ml, and the resulting mixture was stirred at room temperature for one hour. The precipitates were filtered and were washed with hexane, and were concentrated under reduced pressure to give 2-methyl-4-(1-methyl-1H-pyrazol-3-yl)-phenol 2.45 g.