Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1.Cl[C:34]1[N:39]=[CH:38][C:37]([CH2:40][CH2:41][CH3:42])=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:31][C:2]([F:32])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]([C:34]1[N:39]=[CH:38][C:37]([CH2:40][CH2:41][CH3:42])=[CH:36][N:35]=1)[CH2:7][CH2:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCc1cnc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2C(F)(F)F)nc1

Procedure:
Condensation of methyl 2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (250 mg; 0.54 mmol) with 2-chloro-5-propyl-pyrimidine (85 mg; 0.54 mmol) as per general procedure E (1.25 eq. K2CO3, dioxane, 220C, 15 hr) was accompanied by partial ester hydrolysis and afforded the title compound in low yield. For ease of purification, the carboxylic acid was converted to its methyl ester derivative (using a standard trimethylsilyldiazomethane/MeOH protocol), chromatographed and subjected to the base-mediated hydrolysis procedure H to afford the title compound in 17% yield (29 mg).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:44])[C@@H:19]([CH:20]=[CH:21][C:22](=[O:24])[OH:23])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26].[C:45]([CH:47](O)[C:48](Cl)([Cl:50])[Cl:49])#[N:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:44])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:23])[O:24][C:47]([C:45]#[N:46])=[C:48]([Cl:50])[Cl:49])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C=CC(=O)O
Reactant: N#CC(O)C(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC(C#N)=C(Cl)Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
140 mg of 4-dimethylaminopyridine and then 1.76 g of dicyclohexylcarbodiimide were added at 0° C. to a mixture of 3.36 g (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate, 1.7 g of chloral cyanohydrin and 16 ml of methylene chloride and the mixture was stirred at 20° C. for 21/2 hours and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 1.65 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-(2,2-dichloro-1-cyanovinyloxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+40° (c=0.3% in chloroform).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[OH-].[Na+].Br[CH:31]([OH:33])[CH3:32]>C(O)(C)C.CCOC(C)=O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:32][CH2:31][OH:33])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1O
Reactant: CC(O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 15 h
Yield: 105.4 %

Procedure:
To a solution of Intermediate 11 (1.5 g, 4.08 mmol) in isopropanol (20 mL) is added 3M aq. NaOH (5 mL) followed by bromoethanol (2.90 mL, 40.8 mmol). The reaction mixture is stirred at rt for 15 h, and is then diluted with EtOAc. The org. solution is washed with 1M aq. NaOH followed by brine, dried over Na2SO4, filtered and concentrated. The crude compound is purified by CC (eluting with Heptane/EA 4:1) to give the title compound as a yellow oil (1.77 g); LC-MS: tR=1.16 min; [M+H]+=412.09. 1H NMR (CDCl3) δ1.26 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 2.78 (q, J=7.5 Hz, 2H), 2.16 (t, J=5.5 Hz, 1H), 3.76 (q, J=7.0 Hz, 4H), 4.01 (m, 4H), 7.23 (s, 1H), 7.90 (d, J=5.8 Hz, 2H).
Reaction SMILES: F[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>CCO.O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[NH:13][CH3:12]
Reactant: CN
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Solvent: CCO
Solvent: O
Product: CNc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
2-Fluoro-3-chloronitrobenzene (3.0 g, 17 mmol) was dissolved in EtOH (6 mL) and Methylamine 40% in Water (6 mL) was added dropwise at 0° C. and mixture was warmed up to RT overnight. Mixture went to a dark orange precipitate within 10 min. The solid was isolated by filtration, rinsed with water (2*10 mL) and dried in a desiccators under vacuum to afford 3 g of 2-chloro-N-methyl-6-nitrobenzenamine (Yield: 90%) as an orange crystalline solid.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:5]=1[O-:13])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]2[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)C#CCC.O>CN(C)C=O>[CH2:8]([C:9]1[C:4]([C:5](=[O:13])[CH3:6])=[C:16]2[C:17]3[CH2:23][CH2:22][O:21][C:18]=3[CH:19]=[CH:20][N:15]2[N:14]=1)[CH3:7]
Reactant: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Reactant: N[n+]1ccc2c(c1)CCO2
Agent: CCC#CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn2ccc3c(c2c1C(C)=O)CCO3
Temperature: 40 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
A mixture of 5-amino-2,3-dihydrofuro[3,2-c]pyridin-5-ium 2,4-dinitrobenzenolate (2.00 g, 6.24 mmol), potassium carbonate (1.21 g, 8.75 mmol) and 3-hexyn-2-one (0.750 mL, 6.87 mmol) in dimethylformamide (30 mL) was stirred at 40° C. for 16 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→40/60) to give the title compound (314 mg, yield 22%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1([S:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([NH2:74])[CH:69]=2)(=[O:61])=[O:60])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C=O)C>[N:53]1([S:59]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([NH:74][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:69]=2)(=[O:61])=[O:60])[CH2:54][CH2:55][O:56][CH2:57][CH2:58]1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 51.8 %

Procedure:
DIEA (0.009 mL, 0.052 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.013 g, 0.047 mmol) and HATU (0.020 g, 0.052 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-(Morpholine-4-sulfonyl)-biphenyl-3-ylamine (0.015 g, 0.047 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected were collected and the solvent removed under vacuum to give 0.014 g of product in 50% yield: LCMS (ESI) m/z 591 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[O:10][CH3:11].[Cl:12]CCOCCCl>C(O)(=O)C.O>[CH3:11][O:10][C:3]1[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[C:7]([Cl:12])[C:2]=1[CH3:1]
Reactant: COc1cccc(C)c1OC
Reactant: ClCCOCCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cl)c(C)c1OC
Yield: 67980.1 %

Procedure:
To a mixture of 25 g (0.16 mmol) of 1-methyl-2,3-dimethoxybenzene in 25 mL of acetic acid, was slowly added 26.4 g (0.33 mmol) of 1-chloromethylmethylether. The resultant reaction mixture was reacted overnight at 30° C. and then diluted with cold water, resulting in the formation of a precipitate. This precipitate was purified by recrystallization from hot hexanes and then reduced to dryness under reduced pressure to provide 20.3 g of a white solid (m.p. 69-70° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 48.8 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.9 mmol) was reacted with benzenesulfonyl chloride (0.24 mL, 1.9 mmol) to provide 0.38 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as brown granules, m.p. 215.4–216.0° C. Analysis: Calculated for C21H23N5O2S: % C, 61.59; % H, 5.66; % N, 17.10. Found: % C, 61.24; % H, 5.65; % N, 16.95.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([S:15]([NH:18][C:19]2[S:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])[CH:9]=1.C(N(CC)CC)C>O1CCCC1>[CH:12]1[C:13]([NH:14][C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:7])=[CH:8][CH:9]=[C:10]([S:15]([NH:18][C:19]2[S:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:16])[CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 67 %

Procedure:
an Indo-Sulfathiazole Analog: Compound 27j was synthesized by the method outlined in FIG. 1. Briefly, Compound 27j was synthesized by first complexing succinic anhydride with sulfathiazole by reacting these compounds at room temperature for 6 hours in tetrahydrofuran (THF) in the presence of triethylamine (TEA) to produce succinylsulfathiazole as a white solid (67% yield). The succinylsulfathiazole was then reacted for 2 hours at room temperature with O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) in dichloromethane in the presence of TEA to produce the corresponding succinimidyl ester, which was reacted with 1-(4-aminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide in dichloromethane in the presence of TEA at room temperature for 16 hours to produce Compound 27j as a yellow gummy mass (45% yield). Compound 27j was characterized by NMR, two-dimensional NMR, and mass spectroscopy.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]1[CH2:10][C:11]([OH:13])=[O:12].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21]>CN(C=O)C>[O:21]=[C:16]1[CH2:17][CH2:18][C:19](=[O:20])[N:15]1[O:12][C:11](=[O:13])[CH2:10][N:4]1[CH:3]([CH3:2])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:9]
Reactant: O=C1CCC(=O)N1O
Reactant: CC1CCCC(C)N1CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CC1CCCC(C)N1CC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.60 g (60 mMol) (2,6-Dimethyl-piperidin-1-yl)-acetic acid hydrochloride (5), in 100 ml DMF, was added to 7.02 g (60 mMol) N-hydroxysuccinimide and 12.58 g (60 mMol) N,N-dicyclohexylcarbodiimide. The reaction mixture was stirred for 16 h at RT. The residue was filtered and the filtrate was evaporated in vacuo to dryness. After dissolving the residue in 300 ml CH2Cl2, the solution was washed with NaHCO3, dried over sodium sulphate and the solvent was evaporated. The compound was then recrystallised from diisopropylether (activated charcoal).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=O)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[CH2:32]([N:34](CC)[CH2:35]C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:20](=[O:22])[N:34]([CH3:35])[CH3:32])=[CH:17][CH:18]=2)=[CH:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
The hydrogenated compound 31 (4.0 g, 9.3 mmol) was dissolved in CH2Cl2 (60 mL) and stirred at room temperature under an atmosphere of argon. Triethylamine (1.56 mL, 11.0 mmol) and BOP reagent (4.53 g, 10.0 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 23.3 mL, 47.0 mmol) was added and the resulting solution was stirred at room temp for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (200 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×100 mL) and brine (1×100 mL). Drying and concentration of the organic layer gave the desired amide 32 (3.7 g, 87%). 1H NMR (400 MHz, DMSO-d6): 7.34 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 6.93 (overlapped d, J=8.8 Hz, 2H), 6.92 (overlapped d, J=8.0 Hz, 2H), 5.50 (d, J=8.0 Hz, 1H), 3.59 (s, 3H), 2.90 (s, 3H), 2.80-2.84 (m. 5H), 2.63 (t, J=7.6 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]#[N:11].C(O)C[OH:18].[OH-].[K+]>O>[CH:7]1[CH:8]=[CH:9][N:5]2[CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:11][C:10](=[O:18])[C:6]=12
Reactant: N#Cc1cccn1Cc1ccccc1N
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1Nc2ccccc2Cn2cccc21

Procedure:
A mixture of 10 g. of 1-(o-aminobenzyl)-2-pyrrolecarbonitrile [M. Artico et al., I1 Farmaco Ed. Sci., 24 (11), 980 (1969)], 60 ml. of ethylene glycol and 8 g. of 85% potassium hydroxide is heated in an oil bath at 180° C. for 2 hours, cooled and then diluted with 100 ml. of water. The crystals which form are collected by filtration and recrystallized from 95% ethanol, giving pure 5,10-dihydro-11H-pyrrolo[2,1-c][1,4]-benzodiazepin-11-one. The aqueous mother liquor, when treated with acetic acid to pH 4-5, gives 1-o-aminobenzyl-2-pyrrolecarboxylic acid.
Reaction SMILES: C(O[C:9](=O)[NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:35])[CH:20]([C:22](=[O:34])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[CH3:21])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])C1C=CC=CC=1.[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1C=O.C([BH3-])#N.[Na+]>CO.[Pd]>[CH3:37][C:38]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:39]=1[CH2:9][NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:35])[CH:20]([CH3:21])[C:22]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=1)=[O:34])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)C(C)C(=O)Nc1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)C(C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 0.08 mmol) in MeOH (2 mL) was charged with 5% Pd/C, Degussa style (8 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (2 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.009 mL, 0.06 mmol) and sodium cyanoborohydride (5 mg, 0.08 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=494.4.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:26]=[C:27]=[O:28]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:27]([NH:26][CH:4]([CH2:5][CH3:6])[CH3:3])=[O:28])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: Fc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)c(C(F)(F)F)c1
Agent: Cl
Product: CCC(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(F)cc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]azetidine hydrochloride (125) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.C[O:30][CH:31]1[CH:35]=[CH:34][CH:33](OC)O1.Cl>C(#N)C.CCOC(C)=O>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([N:1]3[CH2:33][CH:34]=[CH:35][C:31]3=[O:30])[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:25])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N)sc2c1-c1ccc(Cl)cc1
Reactant: COC1C=CC(OC)O1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CC=CC3=O)sc2c1-c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
To a solution of (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (40 mg, 0.1 mmol) in acetonitrile (1 mL) was added 2,5-dimethoxy-2,5-dihydrofuran (26 μL, 0.2 mmol), followed by hydrochloric acid (0.2 N, 0.8 mL, 0.16 mmol). The mixture was stirred for 24 hours, and was diluted with EtOAc and quenched with saturated sodium bicarbonate solution. The organic layer was separated, and was washed with water and brine, dried with sodium sulfate and filtered. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl)benzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C25H25ClN2O4S: 485.1 (M+H+); Found: 485.2 (M+H+).
Reaction SMILES: C[C:2]1[C:3]([CH2:11][CH2:12][CH2:13][CH:14]([C:20]#[N:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([CH:8]=[CH:9][CH:10]=1)C([O-])=O.OCCCC1C=CC([C:30]([O:32][CH3:33])=[O:31])=CC=1.C(CC(OCC)=O)#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12][CH2:11][C:3]1[CH:2]=[CH:10][C:9]([C:30]([O:32][CH3:33])=[O:31])=[CH:8][CH:4]=1)#[N:21]
Reactant: CCOC(=O)C(C#N)CCCc1c(C)cccc1C(=O)[O-]
Reactant: COC(=O)c1ccc(CCCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(=O)CC#N
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CCCc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
Preparation of methyl-(4-cyano-4-ethoxycarbonylbutyl)benzoate ##STR21## To a 250 mL flame dried round bottom flask were charged 10.0 g (51.5 mmol) of methyl 4-(-hydroxypropyl)benzoate and 5.48 mL (51.5 mmol) of ethyl cyanoacetate dissolved in 40 mL of anhydrous tetrahydrofuran (THF). To this solution was then added dropwise to a solution of 20.2 g (77 mmol) of triphenylphosphine and 12.1 mL (77 mmol) of diethyl azodicarboxylate dissolved in 60 mL of anhydrous THF. After the addition, the reaction was stirred at ambient temperature for 1.5 hours. The volatiles were removed in vacuo and the crude oil was dissolved in 300 mL of EtOAc, washed with brine, dried over Na2SO4, and removed in vacuo. This crude oil was then purified on silica gel using a Waters Prep LC 2000 eluting with a gradient of 1:1 MeCl2 /Hex to 100% MeCl2 to give 6.0 g (40%) of methyl 4-(4-cyano-4-ethoxycarbonylbutyl)benzoate as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[N:22]=[C:21]2[C:17](=[N:18][CH:19]=[N:20]2)[C:16](=[O:23])[N:15]=1)[CH2:2][CH3:3].[OH-].[Na+].C(O)(=O)C>O.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([C:14]2[N:22]=[C:21]3[C:17](=[N:18][CH:19]=[N:20]3)[C:16](=[O:23])[N:15]=2)[CH:7]=1
Reactant: CCCOc1ccc([N+](=O)[O-])cc1C1=NC(=O)C2=NC=NC2=N1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCOc1ccc(N)cc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
A solution of the crude product of Example 42 (1.5 g) in water (50 ml) containing 2 Normal sodium hydroxide (2.3 ml) and 10% palladium on charcoal (0.15 g) was shaken under hydrogen (50 psi) until the uptake was complete. Neutralisation of the filtered solution with acetic acid gave a fine precipitate of 2-(5-amino-2-propoxyphenyl)-purin-6-one. This mixture was warmed with 2 Normal hydrochloric acid (2.5 ml) and the solution was treated with acetic anhydride (0.55 ml) and sodium acetate trihydrate (0.8 g). The mixture was warmed for 10 minutes then cooled and filtered to give a crude product (1.02 g) which was recrystallised from aqueous dimethylformamide twice to give the title compound, 0.49 g, m.p. 320-323° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[C:4]([N+:10]([O-])=O)[C:3]=1[NH2:13].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:22](OC)(OC)OC.CN(C=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[N:13]=[CH:22][NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1Cl
Reactant: COC(OC)OC
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Clc1cc2[nH]cnc2c(Cl)c1Cl
Temperature: 100 °C
Yield: 43 %

Procedure:
A mixture of 2,3,4-trichloro-6-nitro-phenylamine (0.250 g, 1.04 mmol), sodium dithionite (0.907 g, 5.21 mmol), trimethyl orthoformate (4 ml), DMF (4 mL), and acetic acid (0.5 mL) was heated in a sealed tube for 15 h at 100° C. The reaction mixture was cooled to 23° C. and partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was collected and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated to yield the titled compound (0.098 g, 43%). MS (ESI/CI): mass calcd. for C7H3Cl3N2, 219.9; m/z found, 221.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.16 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [F:1][CH2:2][C:3](=[CH2:14])[CH2:4][N:5]([CH2:11][CH:12]=O)[C:6](=[O:10])[O:7][CH2:8][CH3:9].O.[NH:16]([CH2:18]C(O)=O)[CH3:17]>C1(C)C=CC=CC=1>[F:1][CH2:2][C:3]12[CH2:4][N:5]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[CH2:11][CH:12]1[N:16]([CH3:18])[CH2:17][CH2:14]2
Reactant: CNCC(=O)O
Reactant: C=C(CF)CN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2N(C)CCC2(CF)C1

Procedure:
9.1 g (43 mmol) of ethyl N-(2-fluoromethylallyl) -N-(2-oxoethyl)-carbamate are heated under reflux overnight in a water separator with 3.9 g (43 mmol) of powdered sarcosine in 170 ml of toluene. The mixture is concentrated and the residue is distilled.