Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:40]([CH:37]4[CH2:39][CH2:38]4)(=[O:42])=[O:41])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NS(=O)(=O)C2CC2)cc1

Procedure:
(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine (29a, 100 mg, 0.24 mmol) was dissolved in MeCN (3 mL), triethylamine (0.104 mL, 0.75 mmol) was added followed by addition of cyclopropane sulfonylchloride (0.025 mL, 0.25 mmol). The reaction was followed by LC/MS. After 1 hour approximately 50% conversion was detected, more reagents cyclopropane sulfonylchloride (0.025 mL, 0.25 mmol) and triethylamine (0.07 mL, 0.50 mmol) were added in an attempt to increase conversion without any success. The reaction was quenched by addition of saturated NH4Cl (aq) and concentrated. The residual material was purified by HPLC, collected fractions was freeze dried to give the title compound as a colourless solid. Chiral HPLC was made using an Chiralpak IB™, 150×0.46 mm column, 15% EtOH in iso-Hexane, 0.5 mL/min, UV=254 nm, one major peak at 32.39 min (99.7%) and one minor peak at 30.69 min (0.3%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a round-bottom flask were charged methyl 3-(5-methylpyridin-2-yl)-5-(pyrrolidine-1-carbonyl)benzoate (0.80 g, 2.47 mmol), methanol (40 mL), sodium hydroxide (0.20 g, 5.0 mmol) and water (10 mL). The mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure. The residue was treated with 1N HCl (10 mL), concentrated, and purified via preparative HPLC to afford the desired product. LC-MS: 311.5 [M+1]+; 1H NMR (400 MHz, DMSO-d6): 8.61 (t, J=1.7 Hz, 1H), 8.52 (t, J=0.8 Hz, 1H), 8.16 (t, J=1.8 Hz, 1H), 7.99 (t, J=1.5 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.72-7.69 (m, 1H), 3.50 (t, J=6.7 Hz, 2H), 3.41 (t, J=6.5 Hz, 2H), 2.35 (s, 3H), 1.91-1.81 (m, 4H).
Reaction SMILES: C([O:3][CH:4]=[C:5]([C:11]#[N:12])[C:6](OCC)=O)C.[CH3:13][S:14][C:15](=[NH:17])[NH2:16].C[O-].[Na+].[Na]>CO>[OH:3][C:4]1[C:5]([C:11]#[N:12])=[CH:6][N:16]=[C:15]([S:14][CH3:13])[N:17]=1
Reactant: CSC(=N)N
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CSc1ncc(C#N)c(O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
To a 5° C. solution of 119 g (703 mmol) of freshly distilled ethyl (ethoxymethylene)cyanoacetate in 800 mL of methanol is added 108 g (599 mmol) of 2-methyl-2-thiopseudourea. To this mixture is added a solution of sodium methoxide prepared by dissolving 35.6 g (1.55 mol) of sodium metal in 800 mL of methanol. The solution is warmed to room temperature and stirred for 6 hours. After standing overnight, the solvent is removed under reduced pressure, the residue is dissolved in 1.5 L of water at 50° C. with stirring, and the solution is filtered hot. The filtrate is acidified to pH 2 with concentrated HCl and kept at room temperature overnight. The precipitated product is collected and dried to give 48.3 g (48%) of the title compound, which is used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([CH3:12])[CH:4]=1.Br[C:14]1C=CC(C(O)C)=CC=1C>>[OH:1][CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]([CH3:12])[CH:4]=1)[CH3:14]
Reactant: Cc1cc(C(C)O)ccc1Br
Reactant: CC(=O)c1ccc(CO)cc1C
Product: CC(=O)c1ccc(C(C)O)cc1C
Yield: 49 %

Procedure:
1-[4-(1-Hydroxy-ethyl)-2-methyl-phenyl]-ethanone is prepared following preparation 1a employing 1-(4-bromo-3-methyl-phenyl)-ethanol instead of (4-iodo-3-methyl-phenyl)methanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]1=[O:24]>C(N(CC)CC)C>[CH3:17][N:18]1[C:22](=[O:23])[CH2:21][CH:20]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[C:19]1=[O:24]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Product: CN1C(=O)CC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 88 %

Procedure:
The procedure of Example 1 is repeated using 11.92 grams 2,6-di-tert-butyl-4-mercaptophenol, 5.55 grams N-methylmaleimide, and 0.5 grams triethylamine. The residue is recrystallized from toluene: heptane to give 15.47 grams (88% yield), m.p. 132°-132.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([C:47]([F:50])([F:49])[F:48])[CH:41]=1>C([O-])(O)=O.[Na+]>[CH3:38][O:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:12](=[O:14])[CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)=[C:42]([C:47]([F:48])([F:49])[F:50])[CH:41]=1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Reactant: COc1ccc(N)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CC(=O)Nc2ccc(OC)cc2C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 20.2 %

Procedure:
Prepared using General Procedure 6: To a stirring solution of 2-(4-(methoxycarbonyl)phenyl)acetic acid (300 mg, 1.54 mmol) were added HOBt (417 mg, 3.09 mmol), EDC (593 mg, 3.09 mmol) and DIEA (539 μL, 3.09 mmol). After 1.5 h, 4-methoxy-2-(trifluoromethyl)aniline (325 mg, 1.70 mmol) was added. After stirring for 14 h, the mixture was diluted with NaHCO3 and extracted with EA. The combined organic extracts were dried (Na2SO4), concentrated, and purified by chromatography (EA/hexanes) to provide 114 mg (31%) of methyl 4-(2-((4-methoxy-2-(trifluoromethyl)phenyl)amino)-2-oxoethyl)benzoate INT-54. LCMS-ESI (m/z) calculated for C18H16F3NO4: 367; found 368 [M+H]+, tR=3.27 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=8.3 Hz, 2H), 7.91 (d, J=8.4 Hz, 1H), 7.40 (t, J=14.6 Hz, 2H), 7.13 (s, 1H), 7.09-6.96 (m, 2H), 3.92 (d, J=10.8 Hz, 3H), 3.81 (m, 5H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]2[O:8][CH2:9][CH:10]([OH:11])[CH:6]2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:10]1[CH2:9][O:8][CH:7]2[CH:3]([O:2][CH3:1])[CH2:4][O:5][CH:6]12)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC1COC2C(O)COC12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COC2C(OS(C)(=O)=O)COC12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
To a solution of 6-methoxyhexahydrofuro[3,2-b]furan-3-ol (1.03 g, 6.43 mmol) in anhydrous DCM (30 mL) were added N,N-diethylethanamine (1.3 mL, 9.4 mmol) and methanesulfonyl chloride (0.58 mL, 7.5 mmol). The reaction was stirred at rt for 6 h. The reaction was quenched with NaHCO3 (sat, 50 mL), and then extracted with EtOAc (80 mL×3). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as colorless oil (1.1 g, 71.9%).
Reaction SMILES: [C:1]1(Cl)[C:7](=[O:8])[C:6](Cl)=[C:5](Cl)[C:3](=[O:4])[C:2]=1Cl.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>C(#N)C.CN(C)C=O>[C:13]1(=[O:23])[N:17]([C:1]2[C:7](=[O:8])[C:6]([N:17]3[C:13](=[O:23])[C:14]4=[CH:22][CH:21]=[CH:20][CH:19]=[C:15]4[C:16]3=[O:18])=[C:5]([N:17]3[C:13](=[O:23])[C:14]4=[CH:22][CH:21]=[CH:20][CH:19]=[C:15]4[C:16]3=[O:18])[C:3](=[O:4])[C:2]=2[N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: [K]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)=C(N2C(=O)c3ccccc3C2=O)C(=O)C(N2C(=O)c3ccccc3C2=O)=C1N1C(=O)c2ccccc2C1=O

Procedure:
A suspension of chloranil (10.00 g, 0.04 mole) and potassium phthalimide (30.00 g, 0.16 mole) in acetonitrile is refluxed overnight. The deep purple solution is allowed to cool and then filtered, yielding a tan solid. This solid is then boiled in approximately 200 ml of dimethylformamide for ten minutes. The hot DMF suspension is then filtered yielding a white thixotropic solid.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[CH2:34](C(CC)(CC)C([O-])([O-])[O-])[CH3:35]>ClCCCl.C1CCN2C(=NCCC2)CC1>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:26][CH:25]=[C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=3)[N:1]=[C:34]2[CH3:35])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2cc(Oc3ccccc3)ccc2N)ccc1OCCN1CCCC1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: COc1cc(-n2c(C)nc3ccc(Oc4ccccc4)cc3c2=O)ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A solution of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide [Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) was treated with triethylorthoacetate (2 ml) and the mixture heated to 80° C. for 2 hours. The mixture was cooled, 1 drop of DBU added and the mixture evaporated. The residue was subjected to flash chromatography on silica gel eluting with (methanol-dichloromethane-aqueous ammonia) to give the title compound;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[CH:11]=O>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:11][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Nc1ccc(Br)cc1N
Solvent: O
Solvent: CCO
Product: Brc1ccc2nccnc2c1

Procedure:
To a solution of 4-bromobenzene-1,2-diamine (4.0 g, 21 mmol) in 60 mL of EtOH was added 40% glyoxal aldehyde (4.1 ml, 32 mmol) solution in water. The resulting mixture was refluxed for 10 hours. The mixture was concentrated in vacuo and the residue was diluted in 100 mL of EtOAc. The organic solution was washed with 40 mL of satd. NaHCO3 and 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silca gel column chromatography (5% EtOAc/hex to EtOAC) to give light yellow solid 6-bromoquinoxaline. MS (ESI, pos. ion) m/z: 208.9 (M+1).
Reaction SMILES: O.[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([O:15][C:16]([NH:18][C:19](=[N:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])SC)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:26]([O:25][C:23]([NH:22][C:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[N:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([OH:2])=[CH:4][CH:5]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: NCc1ccc(O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=NCc1ccc(O)cc1)NC(=O)OC(C)(C)C

Procedure:
4-hydroxybenzylamine hydrate, prepared as above (5.33 g) and N,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (10.96 g) were combined in 150 mL THF, and stirred at reflux for 4 hr. The mixture was concentrated, and the crude product chromatographed on silica gel with 10% ethyl acetate in dichloromethane. Recrystallization from methanol-water provided the title compound as a white solid, mp 187°-189° C. (10 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1nccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine is dissolved in dimethyl formamide. Potassium carbonate and 2-chloro-4-trifluoromethyl-pyrimidine are added and the reaction mixture is stirred at about 80° C. overnight. It is obtained 2-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-4-trifluoromethyl-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([NH:1][C:38](=[O:40])[CH3:39])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:12])=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(N)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(-c2c(NC(C)=O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a stirred solution of N-{2-amino-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Description 85) (40 mg, 0.087 mmol) in DCM (3 mL) was added triethylamine (0.036 mL, 0.261 mmol) and acetyl chloride (7.42 ul, 0.104 mmol) and the mixture stirred at RT for ca. 1 h. NaHCO3 solution (25 mL) was then added and the mixture extracted with DCM (20 mL×3) and the combined organics dried and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-50% ethyl acetate in DCM and was then further purified by MDAP (acidic conditions), to give the title compound (5.8 mg). LCMS (A) m/z: 502 [M+1]+, Rt 1.05 min (acidic).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=[O:8])[CH:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:18]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CCC(O)C1c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)C1CCC(OCc2ccccc2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To a solution of 10.0 gm of methyl 3-(SR)-(hydroxy)-2-(RS)-(4-fluorophenyl)cyclopentane-1-(RS)-carboxylate prepared as in Example 32 (lower isomer) and 10.8 gm of benzyl bromide in 50 mL of DMF was added in portions over 30 min 2.0 gm of 60% NaH in mineral oil. The reaction was stirred for 2 h at room temperature and was then diluted with ether and quenched by slow addition to water containing 25 mL of 2N HCl. The mixture was extracted twice with ether and the organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. By T.l.c. and NMR the crude product consisted of a mixture of desired benzylated starting material and dimer derived from transesterification. The crude product was taken up in 100 mL of methanol and 45 mL of 5N NaOH was added. The mixture was stirred at room temperature for 40 h residue was diluted with waste. The residue was diluted with water and extracted twice with ether and the ether layers washed with dilute NaOH. The combined aqueous layers were acidified with HCl (c) and extracted twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give 14 gm of title compound contaminated with some 3-(SR)-(hydroxy)-2-(RS)-(4-fluorophenyl)cyclopentane-1-(RS)-carboxylic acid. This could be further purified by flash chromatography eluting with 20% ethyl acetate in hexanes followed by 1% HOAc/20% ethyl acetate in hexanes. T.l.c. (1% HOAc/20% ethyl acetate in hexanes) Rf =0.4.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:31][O:32]C1C=CC(N=C=O)=CC=1>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][C:25]([O:32][CH3:31])=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(N2CCN(CCN3CCC(c4noc5cc(F)ccc45)CC3)C2=O)cc1

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 4-methoxyphenyl isocyanate in Step 1 of the synthesis. The expected product melts at 154°-157° C.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][O:25][CH3:26])=[N:18][C:12]=2[O:11][C@@H:10]([CH2:27][O:28][CH3:29])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:36]>CO.[OH-].[OH-].[Pd+2]>[ClH:36].[CH3:29][O:28][CH2:27][C@H:10]1[CH2:9][NH:8][CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][O:25][CH3:26])=[N:18][C:12]=2[O:11]1
Reactant: COCC1CCCN1c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCC1CCCN1c1cnc2c(n1)O[C@@H](COC)CNC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of (6R)-8-benzyl-6-(methoxymethyl)-3-[2-(methoxymethyl)pyrrolidin-1-yl]-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (329 mg) in methanol (10 mL) was added 20% Pd(OH)2/C (40 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (227 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were washed with ethyl acetate to give the title compound (155 mg, 54%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.O.[CH2:11]([NH2:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:11]([NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)[CH:12]=[CH2:13]
Reactant: C=CCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCNc1nc(Cl)nc(Cl)n1

Procedure:
18.5 parts of cyanuric chloride were dissolved in 100 parts of acetone and added, while stirring, to a mixture of 300 parts of water and 400 parts of crushed ice. The suspension thus obtained was added to 5.7 parts of allylamine over a period of 30 minutes and subsequently to an aqueous solution of 5.3 parts of sodium carbonate. The white crystalline reaction product was suction-filtered, washed several times with iced water, and dried over phosphorus pentoxide.
Reaction SMILES: C[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:4].[CH3:15][NH2:16]>CN(C=O)C>[CH3:15][NH:16][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH3:2])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CCC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ccc(C(C)=O)cc1[N+](=O)[O-]

Procedure:
1-(4-Methylamino-3-nitro-phenyl)-ethanone (153 mg) was prepared by following General Procedure A starting from methyl 1-(4-fluoro-3-nitro-phenyl)-ethanone (183 mg) and methylamine (2 M in THF, 1.0 ml) in DMF (5 mL). The crude product was used in the next step without further purification.
Reaction SMILES: ClC1C(NC)=C(N)C=C(Cl)N=1.[Cl:12][C:13]1[C:18]2[N:19]([CH3:24])[C:20]([CH3:23])(O)[NH:21][C:17]=2[CH:16]=[C:15]([Cl:25])[N:14]=1.CO.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)=O>[Cl:12][C:13]1[C:18]2[N:19]([CH3:24])[C:20]([CH3:23])=[N:21][C:17]=2[CH:16]=[C:15]([Cl:25])[N:14]=1
Reactant: CN1c2c(cc(Cl)nc2Cl)NC1(C)O
Agent: CNc1c(N)cc(Cl)nc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2cc(Cl)nc(Cl)c2n1C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
2,6-dichloro-N3-methylpyridine-3,4-diamine 2.45 (0.15 g, 0.78 mmol) was dissolved in AcOH (5 mL) and heated in a sealed tube at 100° C. After 48 hr, LC/MS indicated full conversion to desired intermediate 4,6-dichloro-2,3-dimethyl-2,3-dihydro-1H-imidazo[4,5-c]pyridin-2-ol 2.46. Reaction mixture was evaporated under reduced pressure and re-dissolved with MeOH (3 mL), 4-methylbenzenesulfonic acid (220 mg, 1.2 mmol) was added and mixture heated at 120° C. in a microwave reactor. After 20 min, LC/MS indicated full conversion to desired product. Solvent was removed under reduced pressure, and solids were diluted and extracted with ethyl acetate and water. The organic layer was washed with water and brine. Organic phase was then dried over MgSO4, and evaporated under reduced pressure to obtain 4,6-dichloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridine 2.47 that was used for next step without further purification.
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14](=[CH2:20])[CH2:15][N+](C)(C)C)=[CH:9][CH2:8][CH2:7]2.[CH3:21][OH:22]>[Ag]=O.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([CH2:15][C:13]1([CH2:12][CH3:11])[C:21](=[O:22])[CH2:6][CH2:5][C:4]1=[O:3])=[CH2:20])=[CH:9][CH2:8][CH2:7]2
Reactant: CO
Reactant: C=C(C[N+](C)(C)C)C1=CCCc2cc(OC)ccc21
Agent: O=[Ag]
Agent: [I-]
Solvent: O
Product: C=C(CC1(CC)C(=O)CCC1=O)C1=CCCc2cc(OC)ccc21
Reaction time: 3 h

Procedure:
A solution of 13 parts of 2-(6-methoxy-3,4-dihydro-1-naphthyl)-2-propen-1-yltrimethyl ammonium iodide in 200 parts by volume of methanol and 1 part of water is cooled to 0.5° and 4.5 parts of silver oxide is added. The resulting mixture is stirred for about 3 hours and the solid which forms is removed by filtration. At that time 5 parts of 2-ethylcyclopentane-1,3-dione is added to the filtrate. The resulting solution is concentrated to a small volume and 400 parts by volume of xylene together with 2 parts by volume of hexamethylphosphoramide and 5 parts by volume of triethylamine are added. That reaction mixture is slowly distilled to remove water and methanol, in the amount of approximately 50 parts by volume and the resultant mixture is heated at the reflux temperature for about 20 hours. After cooling that mixture is washed with water, 5% hydrochloric acid, water 5% aqueous sodium bicarbonate and the water again. Drying of that solution over anhydrous sodium sulphate followed by removal of the solvent under reduced pressure and crystallization of the resulting residue from methanol affords pure 2-(6-methoxy3,4-dihydro-1-naphthyl)-3-(2-ethylcyclopentane-1,3-dione-2-yl)propene, melting at about 100°-125°. This compound exhibits an ultraviolet absorption maxima at about 273 millimicrons with a molecular extinction coefficient of approximately 11,100.