Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 110 °C
Yield: 87.4 %

Procedure:
A mixture of 2-bromo-5-nitro pyridine (300 mg, 1.48 mmol) and pyrrolidine (313 mg, 4.41 mmol) in toluene (5 mL) was heated at 110° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature, poured onto ice-water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford 5-nitro-2-pyrrolidin-1-yl-pyridine (250 mg, 88%) as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([O:15][CH3:16])=[O:14])[N:10]=2)[CH2:3]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([O:15][CH3:16])=[O:14])[N:10]=2)[CH2:5]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)NCc1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCc1csc(N2CC(OS(C)(=O)=O)C2)n1
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of 3-hydroxy-1-[4-(methoxycarbonylamino-methyl)-1,3-thiazol-2-yl]azetidine (426 mg, 1.75 mmol) (obtained as described in Reference Example 63(2)) in methylene chloride (20 ml) were added methanesulfonyl chloride (0.16 ml, 2.10 mmol) and triethylamine (0.29 ml, 2.10 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-[4-(methoxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (448 mg, yield 80%) as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=[O:21])[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:17]1[CH:15]([CH2:14][N:13]2[C@@H:8]3[CH2:7][C:6]4[CH:1]=[CH:2][C:3]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:4]5[O:19][C@H:18]6[C:20]([CH2:22][CH2:23][C@:9]3([OH:24])[C@:10]6([C:5]=45)[CH2:11][CH2:12]2)=[O:21])[CH2:16]1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 60 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of naltrexone (2.5 g, 7.3 mmol) and benzylbromide (1.5 g, 8.8 mmol) in DMF (25 mL) was added potassium carbonate (2.8 g, 20 mmol). The mixture was stirred for 12 hrs at 60° C., then cooled and diluted with water. The resulting oily product was extracted with EtOAc. The extract was washed with water dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (hexane-EtOAc, 3;2) to afford 3-benzylnaltrexone (4) (2.3 g, 74%). 1H NMR (CDCl3) δ 0.15(2H, m, H-20β, H-21β), 0.56(2H, m, H-20α, H-21α), 0.87(1H, m, H-19), 1.58(1H, dd, J=12.3 Hz, 2.4 Hz, H-15), 1.64(1H, dt, J=13.5 Hz, 2.4 Hz, H-8), 1.89(1H, d, J= 13.5 Hz, H-8), 2.13(1H, dt, J=12.3 Hz, 2.4 Hz, H-15), 2.30(1H, dt, J=12.3 Hz, 2.4 Hz, H-16), 2.40(3H, m, H-7, H-18), 2.55(1H, dd, J=18.3 Hz, 6.0 Hz, H-10), 2.69(1H, dd, J=12.3 Hz, 2.4Hz, H-16), 3.03(2H, m, H-7, H-10), 3.18(1H, d, J=6.0 Hz, H-9), 4.70(1H, s, H-5), 5.20(1H, d, J=12.0 Hz, Bz CH), 5.29(1H, d, J=12.0 Hz, Bz CH), 6.56(1H, d, J=7.2 Hz, H-1), 6.71(1H, d, J=7.2 Hz, H-2), 7.25-7.60(5H, m, Bz aromatic H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][C:5]([Cl:16])=[O:6]
Reactant: CCCCC(CC(=O)O)C(F)(F)F
Reactant: O=S(Cl)Cl
Product: CCCCC(CC(=O)Cl)C(F)(F)F
Yield: 83.1 %

Procedure:
2.0 g (10 mmol) of 3-trifluoromethylheptanoic acid and 6 ml (about 80 mmol) of thionyl chloride were reacted for 2 hours under heat-refluxing, followed by distillation to obtain 1.8 g of 3-trifluoromethylheptanoic acid chloride (b.p.: 72.2°-75.0° C./25 mmHg). The acid chloride was dissolved in 10 ml of diethyl ether and added dropwise to a preliminarily ice-cooled ether solution of diazomethane, followed by stirring overnight at room temperature. After distilling off the solvent, the remainder was suspended in 15 ml of dioxane and then added to an aqueous solution at 70° C. of 1.1 g of silver oxide and 2.7 g of sodium thiosulfate (penta-hydrate), followed by stirring for 70 min. After the reaction, potassium hydroxide aqueous solution was added thereto and the mixture was filtered. 5N-nitric acid was added to the filtrate to provide an acidity as judged by Congo Red, followed by extraction with diethyl ether. The resultant ether layer was dried with anhydrous sodium sulfate, followed by distilling-off of the solvent and distillation of the product to obtain 0.42 g of objective 4-trifluoromethyloctanoic acid (b.p.: 130°-135° C./26 mmHg).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=[O:18])[CH:12]=1>CO.[Pd]>[NH2:8][C:7]1[C:2]([OH:1])=[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=[O:18])[CH:12]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2cccc([N+](=O)[O-])c2O)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Yield: 94.1 %

Procedure:
A solution of 2′-hydroxy-3′-nitrobiphenyl-3-carboxylic acid (800 g, 3.2 mol) in methanol (5 L) was hydrogenated over 5 Pd/C (160 g) at room temperature for 8 hours. The reaction mixture was filtered, concentrated and slurried in THF (2.5 L) to give 3′-amino-2′-hydroxybiphenyl-3-carboxylic acid (690 g, 50.5%) as a brown solid. PXRD analysis provided the diffractogram as shown in FIG. 32.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13]([N:17]1[C:25]2[N:24]=[C:23]([Cl:26])[NH:22][C:21]=2[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30]/[C:31](=[N:34]/[H])/[NH:32]O)[C:18]1=[O:36])[CH2:14][CH2:15][CH3:16]>CN(C=O)C>[CH2:13]([N:17]1[C:25]2[N:24]=[C:23]([Cl:26])[NH:22][C:21]=2[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30][C:31]2[N:32]=[C:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=3)[O:12][N:34]=2)[C:18]1=[O:36])[CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: [H]/N=C(/CCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCc2noc(Cc3ccc(O)c(F)c3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C

Procedure:
A mixture of (3-fluoro-4-hydroxyphenyl)acetic acid (27 mg, 0.16 mmol) in DMF (1.5 ml) was treated with CDl (26 mg, 0.16 mmol) and left to react for 45 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (60 mg, 0.18 mmol) was added and the mixture heated in the microwave at 140° C. for 15 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by MDAP. The title compound was obtained as a white solid (10 mg, 12%).
Reaction SMILES: Cl.C([N:9]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15]2)[CH2:10]1)C1C=CC=CC=1.Cl.O1CCOCC1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:10]1[C@H:11]2[C@H:16]([CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH2:12]2)[CH2:17][NH:9]1
Reactant: [H][H]
Reactant: c1ccc(CN2C[C@H]3Cc4ccccc4C[C@H]3C2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: c1ccc2c(c1)C[C@H]1CNC[C@H]1C2
Reaction time: 48 h
Yield: 64.9 %

Procedure:
To a solution of cis-2-benzyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole hydrochloride (210 mg, 0.80 mmol) in 10 mL of ethanol was added palladium hydroxide (210 mg, 20 wt % on carbon) and 4 N hydrochloric acid solution in dioxane (1 mL, 4 mmol). The mixture was placed on a Parr apparatus, the vessel was pressurized to 50 psi with hydrogen, and the mixture was shaken for 2 days. TLC of the mixture showed very little reaction, so the same amounts of palladium hydroxide and hydrochloric acid were added again. The vessel was pressurized to 50 psi with hydrogen, and the mixture was shaken for an additional 3 days. TLC of the mixture showed that the reaction was still incomplete, and so the same amounts of palladium hydroxide and hydrochloric acid were added, the vessel was pressurized to 50 psi with hydrogen, and the mixture was shaken for an additional 6 days. The mixture was filtered through celite, and the cake was rinsed with methanol. The filtrate was stripped, the residue was taken up in 20 mL of 1 N sodium hydroxide, and the aqueous was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and stripped to yield 90 mg of an amber oil, which was purified by flash chromatography, eluting with ethyl acetate followed by 20% methanol/chloroform. Obtained 35 mg of a colorless oil. Yield=25%. NMR (300 MHz, CDCl3) δ 7.17-7.09 (m, 4H), 3.17-3.16 (m, 2H), 2.79 (bd, 2H, J=9 Hz), 2.58-2.43 (m, 6H), 2.36 (s, 1H).
Reaction SMILES: C(O)=O.[CH2:4]([NH:11][CH2:12][CH2:13]O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Cl:26])=[O:18]>C(Cl)Cl>[CH2:4]([N:11]1[CH2:12][CH2:13][O:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[Cl:26])[CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(CBr)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: O=CO
Product: Fc1ccc(C2CN(Cc3ccccc3)CCO2)c(Cl)c1
Reaction time: 20 h
Yield: 99.7 %

Procedure:
Combine formic acid (98-100%; 0.30 mL, 8 mmol) and 2-benzylaminoethanol (1.21 g, 8 mmol) and cool the resulting mixture with an ice bath. Add 2-bromo-1-(2-chloro-4-fluoro-phenyl)ethanone (1.0 g, 4 mmol); heat the mixture to reflux; and stir at that temperature for 20 h. Dilute the mixture with DCM and wash with saturated aqueous Na2CO3 solution. Dry organic phases over MgSO4; filter; collect the filtrate; and concentrate under reduced pressure. Purify via flash column chromatography eluting with a gradient of 0-20% methyl tertiary-butyl ether in hexanes. Combine the product fractions and remove the solvents under reduced pressure to give the title compound as a yellow oil (1.22 g, 43%). MS (m/z): 306 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([CH2:42]O)[CH2:38][CH2:37]3)[N:30]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:58]1(=[O:68])[NH:62][C:61](=[O:63])[C:60]2=[CH:64][CH:65]=[CH:66][CH:67]=[C:59]12>C1(C)C=CC=CC=1.O>[N:20]1([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C@H:36]3[CH2:37][CH2:38][C@H:39]([CH2:42][N:62]4[C:58](=[O:68])[C:59]5[C:60](=[CH:64][CH:65]=[CH:66][CH:67]=5)[C:61]4=[O:63])[CH2:40][CH2:41]3)[N:30]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (972 mg, 1.2 eq) was added to a solution of trans-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanol (1 g, 1 equivalent; prepared in a similar manner as described in Example 4) in toluene (100 mL), it was then followed by the dropwise addition of DIAD (0.73 mL, 1.2 eq). The reaction mixture was stirred at RT for 10 minutes and then phthalimide (545 mg, 1.2 eq) was added. The mixture was stirred overnight at RT, water was then added and the resulting mixture was extracted 3 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude residue was triturated with MeOH to give 976 mg (70% yield) of trans-2-[4-(4-benzo-triazol-1-yl-pyrimidin-2-ylamino)-cyclohexylmethyl]-isoindole-1,3-dione; MS=454.40 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12.[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CN1CCCC1=O>[C:16]1([C@H:22]([NH:24][C:2]2[N:7]=[N:6][C:5]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)=[C:4]3[S:13][CH:14]=[CH:15][C:3]=23)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Clc1nnc(-c2cccs2)c2sccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(-c2cccs2)c2sccc12)c1ccccc1
Temperature: 150 °C
Reaction time: 10 h
Yield: 65.2 %

Procedure:
0.31 g of 4-chloro-7-(2-thienyl)thieno[2,3-d]pyridazine and 0.48 g of (R)-1-phenylethylamine was dissolved in 2 ml of N-methylpyrrolidone, and the solution was stirred at 150° C. for 10 hours. After cooling the solution, an aqueous 5% KOH solution was added thereto, and the solution was extracted with chloroform and dried. The solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 0.27 g of (R)-4-(1-phenylethylamino)-7-(2-thienyl)-thieno[2,3-d]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18]O)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:29])CC)C>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH2:18][F:29])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)CO)c1F
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)CF)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a solution of ethyl 6-chloro-2-fluoro-3-((3-hydroxy-2,2-dimethylpropanamido)methyl)benzoate (Intermediate-59, step 1, 200 mg, 0.60 mmol) in THF (2 mL) was added diethylaminosulfur trifluoride (146 mg, 0.90 mmol) and the reaction mixture was stirred at rt for 12 h. Then the reaction mixture was quenched with water and was extracted with CHCl3. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 0.104 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.32 (t, 1H), 7.44-7.36 (m, 2H), 4.47-4.29 (m, 6H), 1.33-1.29 (t, J=6.9 Hz, 3H), 1.14 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1Cl)#[N:2].[CH3:13][NH:14][NH2:15].O>CS(C)=O>[CH3:13][N:14]1[C:4]2[C:5]3[C:6]([S:11][C:3]=2[C:1]([NH2:2])=[N:15]1)=[N:7][CH:8]=[CH:9][CH:10]=3
Reactant: CNN
Reactant: N#Cc1sc2ncccc2c1Cl
Solvent: CS(C)=O
Solvent: O
Product: Cn1nc(N)c2sc3ncccc3c21
Yield: 81.6 %

Procedure:
15 Grams (0.066 mole) of 2-cyano-3-chlorothieno (2,3-b)pyridine and 17.5 ml (0.33 mole) of methylhydrazine were dissolved in 110 ml of dimethylsulfoxide and heated to 75° for 15 hr under nitrogen. The reaction was cooled and poured into water. The solid was filtered and dried to give 11 g of 1-methyl-1H-pyrazolo(3',4':4,5)thieno(2,3-b)pyridine-3-amine. m.p. 194°-196° C. NMR(CDCl3) δ4.0(s,3); 5.2(s,2); 7.4(dd,1); 8.4(m,2).
Reaction SMILES: [Se:1]1(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Na].[CH3:12]I>O>[CH3:12][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[Se:1](=[O:10])[CH2:2]1
Reactant: O=[Se]1C=Nc2ccccc21
Reactant: CI
Agent: [Na]
Solvent: O
Product: CN1C[Se](=O)c2ccccc21
Reaction time: 12 h

Procedure:
0.01 mol of benzoselenazolinone is introduced into a ground-necked round-bottomed flask containing 0.35 gram (0.015 gram-atom) of sodium dissolved in 50 l cm3 of absolute alcohol. 3.1 cm3 (0.05 mol) of methyl iodide are added dropwise and with stirring. After 12 hours, the solvent is evaporated off. The solid obtained is taken up with 30 to 40 cm3 of water and then extracted with chloroform. The chloroform phase is dried over calcium chloride and the solvent is then evaporated off under reduced pressure. The product is recrystallized in cyclohexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH:18]([CH3:20])[CH3:19])=[C:15]([C:21](O)=[O:22])[C:14]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N:30]1([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:35][CH2:36][CH2:37][NH:38][C:21]([C:15]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:13]([CH:12]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:17][C:16]=2[CH:18]([CH3:20])[CH3:19])=[O:22])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)O
Reactant: NCCCN1CCCC1
Product: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCCN1CCCC1
Yield: 89 %

Procedure:
5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (127 mg, 0.28 mmol) was condensed with 3-pyrrolidin-1-yl-propylamine (43 mg, 0.336 mmol) to give 140 mg (66%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:15]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[O:14][C@:8]([O:12][CH3:13])([C:9]([OH:11])=[O:10])[CH2:7][C@@H:6]1[OH:22])(=[O:3])[CH3:2].C(O[C:27](=[O:29])[CH3:28])(=O)C>N1C=CC=CC=1>[C:1]([NH:4][C@H:5]1[C@H:15]([C@@H:16]([C@@H:18]([CH2:20][O:21][C:15](=[O:14])[CH3:5])[O:19][C:9](=[O:10])[CH3:8])[O:17][C:1](=[O:3])[CH3:2])[O:14][C@:8]([O:12][CH3:13])([C:9]([OH:11])=[O:10])[CH2:7][C@@H:6]1[O:22][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@@]1(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Solvent: c1ccncc1
Product: CO[C@@]1(C(=O)O)C[C@H](OC(C)=O)[C@@H](NC(C)=O)[C@H]([C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)=O)O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96 %

Procedure:
After a mixture of methyl 5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonulopyranosidonic acid [Chem. Ber., 99, 611 (1966)] (150 mg; 0.464 mmol), acetic anhydride (2.3 ml) and pyridine (2.3 ml) was stirred at room temperature for 7 h, the reaction solution was evaporated to dryness in vacuo. The residue was dissolved in chloroform, and treated with Amberist-15 (H type) to obtain the title compound (218 mg, 96%) as white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)(C(F)(F)F)=O>>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 75.8 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (Intermediate 3) (0.35 g, 1.14 mmol, 1 eq), 4-amino-3-methoxybenzoic acid (0.57 g, 3.42 mmol, 3 eq) and TFA (0.42 mL, 5.7 mmol, 5 eq) were heated to reflux in TFE (10 mL) for 36 hours. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (0.38 g, 76%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: C1CCOC1
Product: CN1CCC(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of (S)-(−)-N-Boc-3-aminopyrrolidine (500 mg, 2.68 mmol) and 1-methyl-4-piperidone (0.34 mL, 2.95 mmol) in THF (10 mL) MP-(OAc)3BH resin (Argonaut; 2.55 mmol/g; 2.63 g, 6.71 mmol) was added and the reaction mixture was agitated at room temperature for 18 hours. Then, 1-methyl-4-piperidone (0.28 mL, 2.42 mmol) was added and the reaction mixture was agitated for 24 hours more. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 12% MeOH in CH2Cl2 as eluent to afford (S)-3-(1-methyl-piperidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (750 mg, 99%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:12])[CH2:10]O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:10][C:9]([CH3:12])=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CC(=Cc1ccc(F)cc1)CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=Cc1ccc(F)cc1)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 53.6 g (0.32 mole) of 3-(4-fluorophenyl)-2-methyl-2-propen-1-ol in 100 ml methylene chloride was added dropwise a solution of 57.1 g (0.48 mole) of thionyl chloride in 100 ml methylene chloride. The reaction mixture was stirred at room temperature for 2 hours, then concentrated by rotary evaporation. The product was checked by NMR, then used crude in the reaction with ammonia.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[Cl:34])[C:20](=O)[CH3:21])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=1[Cl:34])=[C:20]([CH3:21])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.85 g), 2-(2-chloro-4-methanesulfonylbenzyl)-3-oxobutyric acid ethyl ester (2.1 g) and polyphosphoric acid (10 g) was heated at 130° C. for 2 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel to afford title compound, 0.35 g.