Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:8][CH2:9][CH:10]([CH3:14])[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30].CN1CCOCC1>O1CCCC1.CC(N(C)C)=O>[C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:8][CH2:9][CH:10]([CH3:14])[C:11]([N:27]2[CH2:34][CH2:33][CH2:32][C@H:28]2[C:29]([OH:31])=[O:30])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Triphenylmethylthio-2-methylpropanoic acid (1.8 g.) and N,N'-carbonyldiimidazole (0.8 g.) are dissolved in tetrahydrofuran (10 ml.) with stirring at room temperature. After 20 minutes, the solution is added to a mixture of L-proline (0.6 g.) and N-methylmorpholine (1 g.) in dimethylacetamide (20 ml.). The resulting mixture is stirred overnight at room temperature, concentrated to dryness and the residue dissolved in a mixture of ethyl acetate and 10% aqueous potassium bisulfate. The organic layer is separated and dried and concentrated to dryness in vacuo to obtain 1-[3-(triphenylmethylthio)-2-methylpropanoyl]-L-proline. Rf : = 0.4 (Silica gel, Benzene/acetic acid 3:1), Rf 1.0 (Silica gel, Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4](Cl)[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[K+]>C(O)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][CH2:10][CH2:11][CH3:12])[CH:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: C1CCNCC1
Reactant: CCCNc1cc(Cl)nc(N)[n+]1[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCNc1cc(N2CCCCC2)nc(N)[n+]1[O-]
Reaction time: 1 h
Yield: 38.3 %

Procedure:
2 g of 2-amino-4-propylamino-6-chloropyrimidine 3-oxide, prepared according to the first two stages of the process of Example 1, are suspended in 20 ml of ethanol. 1.75 g of piperidine are added. The reaction mixture is refluxed for 19 hours. After it has returned to room temperature, 660 mg of potassium hydroxide are added as a solution in 10 ml of ethanol. After 1 hour's stirring the mixture is filtered on paper. The filtrates are evaporated to dryness. The residue is recrystallized from 25 ml of acetone. 950 mg of 2-amino-4-propylamino-6-piperidinopyrimidine 3-oxide are obtained.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:13]([NH2:14])=[C:12]([CH3:15])[CH:11]=[CH:10][N:9]=1.[NH4+].[OH-]>>[CH3:15][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:7]=[C:1]([CH2:2][CH2:3][CH3:4])[NH:14][C:13]=12
Reactant: Cc1ccnc(N)c1N
Reactant: CCCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCc1nc2nccc(C)c2[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
A mixture of butyric acid (6.57 mL, 71.9 mmol), 2,3-diamino-4-picoline (8.05 g, 65.4 mmol) (Lappin, G. R., Slezak, F. B. J. Am. Chem. Soc. (1950) 72, 7806-7) and polyphosphoric acid (50 g) was heated to 100° C. with stirring for 3 hours. The reaction was monitored by tlc of NH4OH neutralized aliquots. Basification (NH4OH), extraction (CH2Cl2, 4×50 mL), drying (K2CO3), purification (by filtering through 100 g SiO2, EtOAc elution), and concentration gave 10.0 g (95%) of the title compound as an amorphous tan solid which was judged pure by 1H NMR and tlc: mp 110°-112° C. (without recrystallization); 1H NMR (300 MHz, CDCl3) δ8.13 (d, 1H, J=5 Hz), 7.01 (d, 1H, J=5 Hz), 3.01 (t, 2H, J=7.8 Hz), 2.67 (s, 3H), 2.07-1.93 (m, 2H), 1.06 (t, 3H, J=7.5 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:13][C:8]=2[CH2:7][N:6]([CH:19]([CH3:21])[CH3:20])[S:5]1(=[O:23])=[O:22].[F:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([C:34]3[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=3)=[CH:30][NH:31]2)=[CH:27][CH:26]=1.[I-].[Na+].C(=O)(O)[O-].[Na+]>O>[CH2:17]([S:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:4]([CH2:3][CH2:2][N:37]3[CH2:38][CH:39]=[C:34]([C:29]4[C:28]5[C:32](=[CH:33][C:25]([F:24])=[CH:26][CH:27]=5)[NH:31][CH:30]=4)[CH2:35][CH2:36]3)[S:5](=[O:23])(=[O:22])[N:6]([CH:19]([CH3:21])[CH3:20])[CH2:7][C:8]=2[CH:13]=1)(=[O:16])=[O:15])[CH3:18]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCCl
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCS(=O)(=O)c1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
1-(2-Chloroethyl)-3,4-dihydro-6-(ethylsulfonyl)-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide (1.03 g, 0.0027 mol), 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.706 g, 0.0033 mol), sodium iodide (0.408 g, 0.0027 mol) and sodium bicarbonate (1.586 g, 0.015 mol) were suspended in water (75 ml). The reaction mixture was heated at reflux overnight. The product mixture was then cooled to room temperature. The product was extracted into ethyl acetate (3×50 ml). The organic extracts were combined, washed with water (150 ml), dried (MgSO4) and concentrated in vacuo to afford 3,4-dihydro-6-ethylsulfonyl-1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. δ(1H NMR, DMSO, ppm): 1.10 (9H, m), 2.50 (2H, m), 2.80 (4H, m), 3.25 (4H, m), 4.10 (3H, m), 4.90 (2H, s), 6.10 (1H, s), 6.90 (1H, dt), 7.20 (1H, dd), 7.35 (1H, d), 7.40 (1H, d), 7.80 (3H, m), 11.20 (1H, s).
Reaction SMILES: CON(C)[C:4]([C:6]1([CH3:14])[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8][CH2:7]1)=[O:5].[CH3:16][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:13][C:9]1([CH3:12])[O:8][CH2:7][C:6]([C:4](=[O:5])[CH3:16])([CH3:14])[CH2:11][O:10]1
Reactant: CON(C)C(=O)C1(C)COC(C)(C)OC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C1(C)COC(C)(C)OC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a mixture of N-methoxy-N,2,2,5-tetramethyl-1,3-dioxane5-carboxylic acid amid (1.07 g, 4.92 mmol) and THF (10 mL) was gradually added 3 mol/L methylmagnesium bromide in THF (2.46 mL, 7.4 mmol) at 0° C. under nitrogen atmosphere, and the resulting mixture was stirred at 0° C. for 4 hours. After the reaction was completed, saturated ammonium chloride aqueous solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give 1-(2,2,5-trimethyl-1,3-dioxane5-yl)ethanone (0.76 g, yield: 90%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH:7]=O.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+]>C(O)C.O>[CH3:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7][NH:16][S:13]([NH2:17])(=[O:15])=[O:14]
Reactant: Cc1oc2ccccc2c1C=O
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1oc2ccccc2c1CNS(N)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylbenzofuran-3-carbaldehyde (0.51 g, 3.18 mmol) was dissolved in anhydrous ethanol (25 mL). Sulfamide (1.5 g, 16 mmol) was added and the mixture was heated to reflux for 4 days. The mixture was cooled to room temperature. Sodium borohydride (0.132 g, 3.50 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction was diluted with water (100 mL) and extracted with DCM (3×75 mL). The extracts were concentrated and suspended in a minimal amount of DCM and filtered to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:25]#[N:26]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:21][C:22]3[C:29](=[CH:28][CH:27]=[C:24]([C:25]#[N:26])[CH:23]=3)[N:30]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ccc(C#N)cc3nc2-c2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (200 mg, 0.74 mmol, 1.00 equiv) in acetic acid (20 mL), 3,4-diaminobenzonitrile (118.2 mg, 0.89 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at reflux in an oil bath. The reaction was then quenched by the addition of water. The solids were collected by filtration and washed with MeOH. This resulted in 205 mg (71%) of 2,3-bis(4-methoxyphenyl)quinoxaline-6-carbonitrile as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[Cl:23][C:24]1[CH:29]=[C:28]([NH:30][NH2:31])[CH:27]=[CH:26][N:25]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:30]([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([Cl:23])[CH:29]=2)[N:31]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: NNc1ccnc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1-c1ccnc(Cl)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 445c) was reacted with (2-chloro-pyridin-4-yl)-hydrazine (CAS Reg. No. 700811-29-6) to give the title compound as brown solid. MS (ESI): m/z=439.4 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:34](=[O:41])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:18]2(=[O:33])=[O:32])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[CH2:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:18]2(=[O:32])=[O:33])[CH:11]=1)[C:34]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:41]
Reactant: CCCCCNC(=O)[C@H](Cc1cccc(CN2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCNC(=O)[C@@H](N)Cc1cccc(CN2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of the title F compound, ((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamic acid t-butyl ester (77 mg, 0.127 mmol) in CH2Cl2 (1 mL) is added TFA (1 mL). After 30 min, the solvent is removed under stream of nitrogen. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The organic solution is washed with brine, dried over anhydrous MgSO4 and concentrated to yield (S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-N-pentyl-propionamide as a clear oil: [M+1]+=503.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].CC(O)=O.C[N:33](C)C=O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:20]=[C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[N:33]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccco1
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc(F)c(F)c2)cc(-c2ccco2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,4-difluorophenyl)-5-(furan-2-yl)-1-(2-hydroxyphenyl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (0.80 g), and AcOH (1.0 mL) in dimethylformamide (20 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-[4-(3,4-difluoro-phenyl)-6-furan-2-yl-pyridin-2-yl]-phenol; mp 147-148° C.; 1H NMR (DMSO-d6) d 6.78 (m, 1H), 6.98 (m, 2H), 7.37 (m, 1H), 7.43 (m, 1H), 7.67 (m, 1H), 8.00 (m, 2H), 8.15 (d, J=1.3 Hz, 1H), 8.31 (m, 2H), 8.39 (d, J=1.3 Hz, 1H), 14.26, (s, 1H); IR (KBr) 1605 cm−1; MS [M+H]+ m/z=350. Anal. calcd for C21H13F2NO2: C, 72.20; H, 3.75; N, 4.01; Found: C, 71.94; H, 3.62; N, 3.74.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([C:13]2[CH:14]=[N:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:19][C:16]1[N:15]=[CH:14][C:13]([CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)nc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)C1
Reaction time: 18 h
Yield: 77.8 %

Procedure:
3-(6-Amino-pyridin-3-yl)-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (538 mg, 2.06 mmol, Eq: 1.00) was dissolved in methanol (20 ml). The solution was put under argon and then treated with palladium on activated carbon (43.8 mg, 20.6 μmol, Eq: 0.01). The suspension was purged with hydrogen and stirred under hydrogen for 18 h. The reaction mixture was filtered through silica gel. The filtrate was concentrated and the residue was dissolved in methanol (12 ml). The solution was purged with argon for 10 min and then treated with palladium on activated carbon (Degussa) (43.8 mg, 20.6 μmol, Eq: 0.01). The suspension was purged with hydrogen and stirred under hydrogen for 18 h. The reaction mixture was filtered through a 45 μm frit. The filtrate was concentrated in vacuo to give tert-butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (422 mg, 78%). LC/MS-ESI observed [M+H]+ 264.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]2([C:12]3[N:16]4[CH2:17][CH2:18][N:19](C(OCC5C=CC=CC=5)=O)[CH2:20][CH2:21][C:15]4=[N:14][N:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1>CO.O1CCOCC1.[OH-].[Pd+2].[OH-]>[S:6]1[CH:2]=[CH:3][CH:4]=[C:5]1[C:7]1([C:12]2[N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]3=[N:14][N:13]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCc2nnc(C3(c4ccc(Cl)s4)CCCC3)n2CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: c1csc(C2(c3nnc4n3CCNCC4)CCCC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 53.3 %

Procedure:
Benzyl 3-[1-(5-chloro-2-thienyl)cyclopentyl]-5,6,8,9-tetrahydro-7H-[1,2,4]triazolo[4,3-d][1,4]diazepine-7-carboxylate (565 mg) was dissolved in a mixed solvent of methanol (10 ml) and 1,4-dioxane (5 ml). After palladium hydroxide (86 mg) was added thereto, the whole was stirred under a hydrogen atmosphere of 1 atm at room temperature for 48 hours to obtain 3-[1-(2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine (190 mg).
Reaction SMILES: [F:1][C:2]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([F:12])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]I.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:21]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][C:2]([P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([F:12])[F:1])=[N+:22]=[N-:23]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCI
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of diethyl 1,1-difluoro-3-(2-(2-iodoethoxy)ethoxy)propylphosphonate (1 eq) in DMF (0.5 M) was added sodium azide (3 eq). The reaction mixture was stirred at room temperature for 90 minutes. The mixture was diluted with ethyl acetate, and washed with water. The aqueous phases were back extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-50% EtOAc/Hex to give the product as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][C:7]1[CH:11]=[CH:10][NH:9][C:8]=1[CH2:12][OH:13].[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=1)[CH2:21][C:22]1[CH:26]=[CH:25][NH:24][C:23]=1[CH2:27][OH:28].[F:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1[NH:43][CH:44]([CH:48]([CH3:50])[CH3:49])[C:45](O)=[O:46]>>[F:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1[NH:43][CH:44]([CH:48]([CH3:50])[CH3:49])[C:45]([O:13][CH2:12][C:8]1[NH:9][CH:10]=[CH:11][C:7]=1[CH2:6][C:5]1[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:46].[F:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1[NH:43][CH:44]([CH:48]([CH3:50])[CH3:49])[C:45]([O:28][CH2:27][C:23]1[NH:24][CH:25]=[CH:26][C:22]=1[CH2:21][C:20]1[CH:29]=[CH:30][CH:31]=[C:18]([Cl:17])[CH:19]=1)=[O:46]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Reactant: COc1cccc(Cc2cc[nH]c2CO)c1
Reactant: OCc1[nH]ccc1Cc1cccc(Cl)c1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1[nH]ccc1Cc1cccc(Cl)c1
Product: COc1cccc(Cc2cc[nH]c2COC(=O)C(Nc2ccc(C(F)(F)F)cc2F)C(C)C)c1

Procedure:
Each of the alcohols, 3-(3-methoxybenzyl)-pyrrolylmethyl alcohol and 3-(3-chlorobenzyl)-pyrrolylmethyl alcohol, is reacted with 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid using the procedure of Example 3 to yield 3-(3-methoxybenzyl)-pyrrolylmethyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate and 3-(3-chlorobenzyl)pyrrolylmethyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:16]=[C:15]([C:17]([O-:19])=[O:18])[C:14]([CH3:20])=[CH:13][C:9]=1[C:10]([O-:12])=[O:11].CI>CN(C=O)C>[CH3:1][O:18][C:17]([C:15]1[C:14]([CH3:20])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:7])[CH:16]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)[O-])c(C)cc1C(=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 76 mg portion of potassium carbonate was added to a 20 ml DMF solution of 214 mg 2,5-dimethylterephthalate and stirred at room temperature for 30 minutes. 0.068 ml of methyl iodide was added to the reaction solution successively and stirred overnight at room temperature. Successively, work-up and purification were carried out in the standard method to obtain 90 mg of 4-methoxycarbonyl-2,5-dimethylbenzoic acid as colorless solid. EN: 207.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9](C(O)=O)[NH:8][C:7](=[O:14])[C:6]=12.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CN1CCCC1=O.N1C2C(=CC=CC=2)C=CC=1.[Cu-]=O>[CH3:1][C:2]1[N:3]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:14])[C:6]=12
Reactant: Cc1c2c(=O)[nH]c(C(=O)O)cc2c(-c2ccccc2Oc2ccccc2)n1COCC[Si](C)(C)C
Agent: O=[Cu-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CN1CCCC1=O
Solvent: c1ccc2ncccc2c1
Product: Cc1c2c(=O)[nH]ccc2c(-c2ccccc2Oc2ccccc2)n1COCC[Si](C)(C)C
Temperature: 190 °C

Procedure:
To a solution of Example 12a (0.037 g, 0.075 mmol) in a mixture of N-methyl-2-pyrrolidinone (0.3 mL) and quinoline (0.100 mL) were added 1,10-phenanthroline (0.027 g, 0.15 mmol) and copper(I) oxide (0.01 g, 0.075 mmol). The mixture sparged with nitrogen for 30 minutes and heated in a Biotage microwave reactor at 190° C. for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to afford a mixture of products containing the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21]O)=[CH:9][N:8]=1.C(N(CC)CC)C.CS([Cl:37])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][Cl:37])=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The above 1-(3-methoxybenzyl)-4-hydroxymethyl-6,7-dimethoxyisoquinoline (339 mg, 1.0 mmol) was dissolved in 5 ml of methylene chloride. Then at −30° C., triethylamine (160 ul, 1.10 eq) and methanesulfonyl chloride (85 ul, 1.10 eq) was added. The mixture was stirred at −30° C. for 30 minutes and then at room temperature overnight. The mixture was extracted with methylene chloride and water. After evaporation of solvents, a solid was obtained to give 1-(3-methoxybenzyl)-4-chloromethyl-6,7-dimethoxyisoquinoline (361 mg, 100%). ES-MS calculated for C20H20O3NCl (m/e) 357.39, observed 358.5 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]2[N:14]=[C:15]([CH2:30][CH2:31][CH2:32][CH3:33])[N:16]=[C:17]([NH:18]CC3C=CC(OC)=CC=3OC)[C:12]=2[NH:11][N:10]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:30]([C:15]1[N:16]=[C:17]([NH2:18])[C:12]2[NH:11][N:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[C:13]=2[N:14]=1)[CH2:31][CH2:32][CH3:33]
Reactant: C1CCNC1
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCCCBr)c2n1
Product: CCCCc1nc(N)c2[nH]nc(CCCCCCCN3CCCC3)c2n1

Procedure:
Prepared similarly to Example 7 from 3-(7-bromoheptyl)-5-butyl-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine and pyrrolidine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])=[C:6]([NH:8][CH:9]=O)[CH:7]=1>O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:11][N:12]([CH:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]3=[O:20])[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=CNc1cc(Cl)ccc1CNC1CCC(=O)NC1=O
Solvent: O
Product: O=C1CCC(N2C=Nc3cc(Cl)ccc3C2)C(=O)N1

Procedure:
A solution of 0.20 g of the product from stage 5 in 10 ml of distilled water was stirred for 72 hours at 20° C. The mixture was then filtered, the filtrate was concentrated by evaporation in vacuo, and the residue was dried. 0.13 g (68% of theory) of the title compound was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Yield: 21.1 %

Procedure:
To a mixture of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.50 g, 2.5 mmol) in acetonitrile (25 mL) was added sodium carbonate (0.34 g, 6.25 mmol) and iodoethane (0.39 g, 2.5 mmol) and the mixture was refluxed for 1 h. Water (50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.12 g). The amine was converted to the fumaric acid salt and lyophilized from water. MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).