Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])[C:3](O)=[O:4].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH3:1][CH:2]([C:3]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:4])[C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:11][C:10]1=2)=[O:7]
Reactant: Nc1ccccc1
Reactant: CC(C(=O)O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C(=O)Nc1ccccc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid (20 mg, 0.059 mmol) and aniline (6 mg, 0.059 mmol) were placed in a disposable polypropylene tube and dissolved in DMF (2 ml). TPTU (2-(2-pyridon-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 19 mg, 0.065 mmol) was added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=414.2 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.[Cl:41][C:42]1[S:43][C:44]([CH2:47]Cl)=[CH:45][CH:46]=1.FC1C=CC(CBr)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:47][C:44]4[S:43][C:42]([Cl:41])=[CH:46][CH:45]=4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=C1Nc2ccccc2C12COc1ccc(Br)cc12
Agent: Fc1ccc(CBr)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ccc(Cl)s2)c2ccccc2C12COc1ccc(Br)cc12

Procedure:
Following the procedure described in EXAMPLE 10, and making non-critical variations using 5-bromospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-chloro-5-(chloromethyl)thiophene to replace 4-fluorobenzyl bromide, the title compound was obtained (95%) as a white solid: mp 140-142° C.; 1H NMR (300 MHz, CDCl3) δ 7.33-7.26 (m, 2H), 7.16-7.02 (m, 2H), 6.94 (d, 1H), 6.97-6.75 (m, 4H), 5.07-4.91 (m, 3H), 4.68 (d, 1H); MS (ES+) m/z 446.7 (M+1), 448.7 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: C1CCNC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCCC2)ccc1N
Reaction time: 2 h

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (167 mg, 1 mmol) in dichloromethane (20 mL) at 0° C. was added pyrrolidine (71 mg, 1 mmol), hydroxybenzotriazole monohydrate (270 mg, 2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (384 mg, 2 mmol) and triethylamine (0.5 mL, 3 mmol). After stirring for 2 hours, the mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated and the residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 5/1 petroleum ether/ethyl acetate to give the title compound. MS: 220 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][CH:6]=1.[CH2:13]=O.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[CH3:13][C:6]1[NH:5][C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:3][C:2]=1[CH2:1][N:25]1[CH2:26][CH2:27][CH:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1
Reactant: Cc1c[nH]c(-c2ccccc2)n1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: C=O
Solvent: CC(=O)O
Product: Cc1[nH]c(-c2ccccc2)nc1CN1CCC(Cc2ccccc2)CC1
Temperature: 100 °C

Procedure:
To a solution of 1 g of 1 methyl-2-phenylimidazole in 10 mL acetic acid were added 0.4 mL of 37% aqueous formaldehyde and 1.2 mL of 4-benzylpiperidine. The reaction mixture was heated at 100° C. for 10 hours and the acetic acid then removed by evaporated under reduced pressure. The residue was dissolved in water and made alkaline with 5% sodium hydroxide and extracted with 2×100 mL of dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and concentrated to small volume under reduced pressure to give 1 methyl-2-phenyl-4-[(4-benzylpiperidin-1-yl)methyl]-imidazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>CN(C=O)C>[ClH:22].[Cl:22][C:13]1[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:10][CH:11]=2)[N:16]=[CH:15][N:14]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccncc3)ccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: Clc1ncnc2cc(OCc3ccncc3)ccc12
Temperature: 60 °C
Yield: 98 %

Procedure:
A mixture of 7-(4-pyridylmethoxy)-3,4-dihydroquinazolin-4-one (320 mg, 1.26 mmol), DMF (1 drop) and thionyl chloride (10 ml) was heated at 60° C. for 1 hour. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-chloro-7-(4-pyridylmethoxy)quinazoline hydrochloride (435 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1.C[O-].[Na+].[C:27](OCC)(=[O:29])C.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:29][CH3:27])[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1
Reactant: Cc1c(Cc2cnn3c(Cl)cc(Cl)nc23)cccc1C(F)(F)F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc2c(Cc3cccc(C(F)(F)F)c3C)cnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidine (247 mg, 0.69 mmol) in methanol (2 ml) stirred under nitrogen at room temp was added a 25% sodium methoxide solution in methanol (163 mg, 0.75 mmol) dropwise. The reaction mixture was stirred at 25° C. for 30 minutes. Reaction mixture was diluted ethyl acetate (30 mL) and 5% HCl (10 mL). Two layers were separated. Organic layer was dried and concentrated. The titled product was obtained and used in next step. (193 mg, 79%); LC/MS: MS (ES+) m/e 356 (MH+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[N:42]1([CH2:47][CH2:48][CH2:49][NH2:50])[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:50][CH2:49][CH2:48][CH2:47][N:42]5[CH:46]=[CH:45][N:44]=[CH:43]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCn1ccnc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCn2ccnc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.12 mL (0.66 mmole) of ethyldiisopropyl amine and 0.029 mL (0.25 mmole) of 3-imidazol-1-yl-propylamine in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.086 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-imidazol-1-yl-propyl)-3-methoxy-benzamide (I-61) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]OCCOCCOCCOCC#C)([O-:3])=[O:2].[N:41]([CH2:44][CH2:45][CH2:46][CH2:47][C@H:48]([NH:56][C:57](=[O:76])[NH:58][C@@H:59]([CH2:67][CH2:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[N+:42]=[N-:43].O=[C:78]1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.C(O)(C)(C)C.S([O-])([O-])(=O)=O.[Cu+2]>[C:52]([O:51][C:49](=[O:50])[C@@H:48]([NH:56][C:57](=[O:76])[NH:58][C@@H:59]([CH2:67][CH2:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[C:60]([O:62][C:63]([CH3:64])([CH3:65])[CH3:66])=[O:61])[CH2:47][CH2:46][CH2:45][CH2:44][N:41]1[CH:78]=[C:27]([CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:43]=[N:42]1)([CH3:55])([CH3:54])[CH3:53]
Reactant: C#CCOCCOCCOCCOCCOCCOCCOCCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN=[N+]=[N-])C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCn1cc(COCCOCCOCCOCCNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])nn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 265.3 %

Procedure:
To a mixture of 10 (76 mg, 0.145 mmol, 1.0 equiv) and 14 (74.4 mg, 0.145 mmol, 1.0 equiv.) in water (1 mL) and tert-butanol (1 mL) in a 5 ml μwave reaction tube was added sodium ascorbate (7 mg, 0.036 mmol, 0.25 equiv.) and aqueous solution of 0.1 M copper (II) sulfate (0.0725 ml, 0.00725 mmol, 0.05 equiv.). The tube was capped, and subjected to microwave radiation for 10 minutes at 110° C. The reaction was then concentrated and redissolved in trifluoroacetic acid (2 mL) and dichloromethane (1 mL) in a 5 ml microwave reaction tube. The tube was capped and subjected to microwave radiation for 2 m at 70° C. The resulting reaction mixture was concentrated under reduced pressure, chromatographed using HPLC, and concentrated to yield 3 (87 mg, 58% yield) as a yellow oil. IR (thin film/NaCl) 3359 (w), 2925 (s), 1737 (s), 1622 (m), 1170 (s) cm−1; 1HNMR (100 MHz, MeOD) δ 9.07 (d, J=2.7 Hz, 1H), 8.33 (dd, J=2.7, 9.6 Hz, 1H), 8.03 (s, 1H), 7.27 (d, J=9.6 Hz, 1H), 4.66 (s, 2H), 4.45 (t, J=7 Hz, 2H), 4.35-4.28 (m, 2H), 3.83 (t, J=7 Hz, 2H), 3.73-3.61 (m, 32H), 2.44-2.36 (m, 2H), 2.17-2.08 (m, 1H), 1.99-1.82 (m, 4H), 1.71-1.64 (m, 1H), 1.46-1.38 (m, 2H); 13CNMR (125 MHz, MeOD) δ 176.4, 176.1, 175.7, 160.0, 149.9, 145.9, 137.0, 131.5, 131.0, 125.2, 124.7, 116.1, 71.6, 71.6, 71.5, 71.5, 70.9, 69.9, 64.8, 53.7, 53.5, 51.2, 44.1, 32.8, 31.1, 30.6, 28.8, 23.4 ppm; HRMS (ES+) calc'd for C37H58N8O19 (M+H) m/z 919.389098. Found 919.38801. NAALADase Inhibition Experiments
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].CN(C=O)C.[Cl:11][C:12]1[C:13]([CH3:19])=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:4][C:3]([CH3:5])=[CH2:2])[C:13]=1[CH3:19]
Reactant: Cc1c(O)cccc1Cl
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)COc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
3-bromo-2-methylpropene (8.5 mL, 84.2 mmol) was added to a mixture of DMF (200 mL) containing 3-chloro-2-methylphenol (10.0 g, 70.1 mmol) and potassium carbonate (19.4 g, 140 mmol), and the mixture was stirred at room temperature for 15 hours. The reaction solution was distributed using ethyl acetate and water, and the organic layer was washed with water and saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10:1) to give 13.7 g of the title compound as an amorphous solid (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21]3(OCCC[O:24]3)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1nccs1)C(CC1CCC2(C1)OCCCO2)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Yield: 72.3 %

Procedure:
A solution of crude 2-(3,4-dichloro-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-N-thiazol-2-yl-propionamide (768.5 mg, 1.74 mmol) in tetrahydrofuran (8.7 mL) and a 5% aqueous hydrochloric acid solution (3.9 mL) was stirred at 25° C. for 64 h. The resulting reaction solution was concentrated in vacuo to remove tetrahydrofuran and then diluted with ethyl acetate (100 mL). The organic layer was washed with a 1% aqueous hydrochloric acid solution (50 mL), water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (481.9 mg, 47% over 2 steps) as a white solid: mp 146–148° C.; (ES)+-HRMS m/e calcd for C17H16Cl2N2O2S (M+H)+ 383.0383 found 383.0385.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[CH3:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[NH:17])=[NH:14])=[CH:9][CH:8]=1.[CH3:31][C:32]([CH3:34])=[O:33].N1CCCCC1>CO>[C:7]([OH:6])(=[O:33])[CH3:30].[CH3:31][C:32]1([CH3:34])[N:14]=[C:13]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:30][CH:29]=2)[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:17]1
Reactant: CC(C)=O
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CO
Product: CC(=O)O
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(OC)cc2)N1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
55 ml of 5N aqueous sodium hydroxide was added to 40 g (92.1 mmol) of N1-(4-methoxybenzyl)-N5-decylbiguanide dihydrochloride in 400 ml of methanol, and the mixture was stirred at 60° C. for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The extract was washed with water, and the solvent was distilled off under reduced pressure to give a residue, to which were added 450 ml of acetone, 150 ml of methanol and 6.4 ml (46.6 mmol) of piperidine. The mixture was refluxed for 15 hours, and the solvent was distilled off under reduced pressure. The residue was washed with water while stirring, dissolved in ethyl acetate, and washed with water. After removal of the solvent by evaporation under reduced pressure, the residue was dried under reduced pressure to obtain 37 g of a colorless solid (1). Then, 2.3 g (5.9 mmol) of the solid was dissolved in 100 ml of methanol, and 169 g (19.7 mmol) of methanesulfonic acid was added thereto. The solvent was distilled off under reduced pressure, and the residue was dissolved in 70% aqueous acetonitrile. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)). Crystallization took place upon addition of ether to obtain 1.9 g of colorless crystals (2) having a melting point of 56 to 58° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:31]([O:32][CH3:33])=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:34])[CH:24]=1>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:31]([O:32][CH3:33])=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:34])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)c(F)cc1N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (158 mg, 0.5 mmol), 4-amino-2-fluoro-5-methoxy benzoic acid (obtained above), i-PrOH (5 mL) and conc. HCl (10 drops) were heated to 100° C. overnight. The reaction mixture was then cooled to room temperature. The reaction mixture contains desired product plus lots of de-carboxylation byproduct, which were separated by RP-HPLC to give the product as a white solid (12 mg). [M+H] calc'd for C21H22F3N5O4, 466. found 466.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[O:17][CH2:18][C:19]([OH:21])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC(S(NCCC2C=C(C=CC=2)OCCCC(O)=O)(=O)=O)=CC=1.C(C1NC=CN=1)(C1NC=CN=1)=O.C1C([N+]([O-])=O)=CC=C(O)C=1.[CH2:73]([NH2:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>>[CH2:73]([NH:80][C:19](=[O:21])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[C:14]([CH2:13][CH2:12][NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:15]=1)[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NCCc2cccc(OCC(=O)O)c2)cc1
Agent: O=C(O)CCCOc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=[N+]([O-])c1ccc(O)cc1
Product: Cc1ccc(S(=O)(=O)NCCc2cccc(OCC(=O)NCc3ccccc3)c2)cc1
Temperature: 40 °C

Procedure:
To a 40° C. warm mixture of 10.0 g (28.6 mmol) 3-[2-(4-methylphenylsulphonylamino)-ethyl]-phenoxyacetic acid and 100 ml abs. THF one adds 4.64 g (28.6 mmol) carbonyl-bisimidazole and allows to react for 10 min. 0.4 g (28.6 mmol) p-nitrophenol are then added thereto. After 10 min. one adds thereto 3.1 g (28.6 mmol) benzylamine and stirs fortwo hrs. at 60° C. Subsequently, THF is distilled off, the residue mixed with ice and dil. HCl and shaken out with methylene chloride. One extracts the organic phase twice with NaHCO3 solution and once with water. After drying with MgSO4, it is evaporated and recrystallised (ethanol). Yield 10.2 g (81% of theory); m.p. 118°-120° C.
Reaction SMILES: Cl[C:2]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=O.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=C)=[CH:20][CH:19]=1.C(N(C)C)C1C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:2][C:4]2[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)C=Cc1ccc(C(=O)Cl)cc1
Reactant: C=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CCOC(=O)C=Cc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 10.2 %

Procedure:
4.77 g (20 mmols) of ethyl 4-chloroformylcinnamate, 4.04 g (20 mmols) of 4-bromostyrene, 2.72 g (20 mmols) of N-benzyldimethylamine and 0.0448 g (0.2 mmol) of palladium acetate are added under argon to 50 ml of p-xylene, and the reaction mixture is stirred at 130° C. for 1.5 hours. The product which has been precipitated is filtered off at room temperature and is then recrystallised from methanol. 0.73 g (10% of theory) of ethyl 4-bromostilbene-4'-acrylate is obtained in the form of yellow crystals; melting point 166.9° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2].[Cl:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:15][CH2:16][C:17]([CH3:22])([CH3:21])[C:18]([NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])=[O:19]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCl)C(=O)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a solution of 2-nitro-4-(trifluoromethyl)benzenamine (3.00 g, 14.9 mmol, 1.0 equiv) in CH2Cl2 (90 mL) at 25° C., was added 3-chloro-2,2-dimethylpropanoyl chloride (3.9 mL, 29.8 mmol, 2.0 equiv) followed by triethylamine (4.2 mL, 29.8 mmol, 2.0 equiv). The solution was heated to 40° C. After 48 h, the solution was washed with water (50 mL), and brine (50 mL). After concentration in vacuo, the residue was purified by silica gel chromatography (1:10 hexanes:EtOAc to 1:5 hexanes:EtOAc) to afford 3-chloro-2,2-dimethyl-N-(2-nitro-4-(trifluoromethyl)phenyl)propanamide. MS—No (MH+) observed.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[NH:29][C:28]([C:38]3[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=3[O:48][CH2:49][CH3:50])=[N:27]2)=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH:30]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[N:29]([C:7]([C:6]3[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=3)=[O:8])[C:28]([C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=[CH:40][C:39]=3[O:48][CH2:49][CH3:50])=[N:27]2)=[CH:24][CH:25]=1
Reactant: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
4-Chloromethylbenzoyl chloride (140 mg, 0.74 mmol) was added to a cooled solution of triethylamine (0.20 mL, 1.44 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-1H-imidazole (300 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with methylene chloride and washed with water and brine, and dried over anhydrous sodium sulfate. The solvents were removed under reduced pressure and flash chromatography of the residue over silica gel using 10-25% ethyl acetate in hexanes gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl)-methanone (330 mg, 84%).