Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)Cc1ccccc1)OCC
Agent: Cl
Product: NCC(Cc1ccccc1)CP(O)O
Temperature: 25 °C

Procedure:
A solution of 3.5 g of ethyl 3-amino-2-benzylpropyl(diethoxymethyl)phosphinate in 35 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 3 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-benzylpropylphosphonous acid, m.p. 205°-212° C., 31P=+26.1 ppm (D2O).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH3:29][CH2:30][O:31][C:32]([CH:34](P(OCC)(OCC)=O)[CH3:35])=[O:33].[Li]CCCC>C1COCC1>[CH2:30]([O:31][C:32](=[O:33])[C:34]([CH3:35])=[CH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:4]2[C:5]3[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=3)[CH:11]=[C:2]([CH3:1])[C:3]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:22][CH:21]=1)[CH3:29]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Yield: 77.5 %

Procedure:
As described above, 4-(6-Methoxy-3-methyl-2-phenyl-naphthalen-1-yloxy)-benzaldehyde (8) (0.21 g, 0.570 mmol), triethyl 2-phosphonopropionate (0.183 mL, 0.855 mmol), 1.6 M nBuLi (0.57 mL, 0.912 mmol) in dry THF (8 mL) afforded 0.2 g (78%) of the title compound (219) as oil. 1H NMR (400 MHz, d-CDCl3): δ 1.31 (t, J=7.1 Hz, 3H), 2.04 (s, 3H), 2.24 (s, 3H), 3.93 (s, 3H), 4.20-4.25 (m, 2H), 6.59 (d, J=8.8 Hz, 2H), 7.03-7.06 (m, 1H), 7.11-7.16 (m, 5H), 7.21-7.25 (m, 3H), 7.55 (d, J=9.7 Hz, 2H), 7.75 (d, J=9.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.00 g, 6.30 mmol), potassium carbonate (2.62 g, 18.90 mmol), tetrakis(triphenylphosphine)palladium (0.73 g, 0.63 mmol) and trimethyl boroxine (0.88 mL, 6.30 mmol) in 1,4-dioxane (2 mL) and water (8 mL) was heated to 110° C. (oil bath temperature) for 6 h and then stirred for 16 h at rt. The mixture was then filtered through a celite pad, washing through with THF. The filtrate was adsorbed onto silica gel in vacuo and purified via flash column chromatography eluting with ethyl acetate/hexanes (3:7) to give the title compound as a yellow solid. δH (CDCl3): 2.86 (3H, s), 7.34 (1H, dd), 8.26 (1H, dd), 8.71 (1H, dd).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1.[I-].[Na+]>CN(C)C=O.O>[CH:36]1([CH2:35][N:15]2[C:16]([CH3:27])=[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14]2)[CH2:38][CH2:37]1
Reactant: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CC3CC3)c2C)cc1

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole (0.081 g) in N,N-dimethylformamide (1 mL) were added cesium carbonate (0.40 g), bromomethylcyclopropane (0.099 mL) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 7 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-8/1) to give 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-methylthiophenyl)methyl]-1H-pyrazole (0.041 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:78])[C@H:10]([CH2:74][CH:75]([CH3:77])[CH3:76])[NH:11][C:12](=[O:73])[C@H:13]([C:69]([CH3:72])([CH3:71])[CH3:70])[NH:14][C:15](=[O:68])[C@H:16]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[CH3:67])[NH:17][C:18](=[O:59])[C@H:19]([CH2:50][CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[NH:20][C:21](=[O:49])[C@H:22]([CH2:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[NH:23]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:78])[C@H:10]([CH2:74][CH:75]([CH3:76])[CH3:77])[NH:11][C:12](=[O:73])[C@H:13]([C:69]([CH3:72])([CH3:71])[CH3:70])[NH:14][C:15](=[O:68])[C@H:16]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[CH3:67])[NH:17][C:18](=[O:59])[C@H:19]([CH2:50][CH2:51][C:52](=[O:58])[O:53][C:54]([CH3:55])([CH3:56])[CH3:57])[NH:20][C:21](=[O:49])[C@H:22]([CH2:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[NH2:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C

Procedure:
A solution of 10.088 g (9.4 mmol) of N-[N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly 20% ethyl acetate in hexane and then 10% methanol in dichloromethane for the elution. Evaporation gave N-[N-[N-[N-[O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl-2-methyl-L-phenylalanyl]-3-methyl-L-valyl-L-leucine benzyl ester in the form of an oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23](OC(C)=O)=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:23](=[O:24])[CH3:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(c1ccc(F)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(4-Fluoro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.8 g; 9.51 mmol; 1 eq.) was dissolved in DCM (30 mL) and Ac2O (2.2 mL; 23.77 mmol; 2.5 eq.) was added. DMAP (1.51 g; 12.36 mmol; 1.3 eq.) was introduced and the reaction was stirred overnight (approx. 18 hours) at room temperature. The solution was diluted with DCM (150 mL) and washed with 1N HCl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under high vacuum to provide the product as an oil. The crude product was used without further purification. LC/MS M/Z 337.3, Retention time=2.95 minutes; 10-99% CH3CN/H2O gradient with 0.05% TFA). H NMR (400 MHz, CDCl3) δ7.16-7.05 (m, 4H), 4.77 (tt, J=12.2 Hz, 3.8 Hz, 1H), 4.13 (d, J=7.1 Hz, 2H), 2.81 (t, J=12.4 Hz, 2H), 1.82-1.73 (m, 2H), 1.77 (s, 3H), 1.41 (s, 9H), 1.26-1.16 (m, 2H).
Reaction SMILES: C([S:4][CH:5]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=1)[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[SH:4][CH:5]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=1)[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCCCc1ccc(OCC(CC#CCCCC(=O)OC)SC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCc1ccc(OCC(S)CC#CCCCC(=O)O)cc1

Procedure:
A mixture of 0.73 g of methyl 8-(acetylthio)-9-(4-pentylphenoxy)-5-nonynoate, the product of Example 12a, 1.25 g of potassium carbonate, 0.6 ml of H2O and 32 ml of MeOH was stirred at RT for 12 hr. MeOH was removed and the residue was acidified with 3N HCL and extracted with Et2O to obtain the crude product. The crude product was purified by silical gel chromatography (CH2Cl2 -MeOH) and then recrystallized in petroleum ether-Et2O to obtain the title compound, mp 70.0-70.5.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23].O[CH2:26][C@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[C:38]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]([F:53])([F:52])[F:51])[NH:39][C:40]3=[O:43])=[CH:35][CH:34]=2)[CH2:28]1.COCCOCCOCCOCCOCCOCCO>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([O:24][CH2:26][C@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[C:38]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:50]([F:52])([F:51])[F:53])[NH:39][C:40]3=[O:43])=[CH:35][CH:34]=2)[CH2:28]1)=[O:23].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: COCCOCCOCCOCCOCCOCCO
Agent: COCCOCCOCCOCCOCCOCCOCC(=O)O
Product: COCCOCCOCCOCCOCCOCCOCC(=O)OC[C@@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1

Procedure:
The title compound was synthesized by a condensation method similar to that of Step A of Example 3-1 using {2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}acetic acid instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14. However, {2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}acetic acid was synthesized by a method similar to that of Step A of Example 4-39 using hexaethylene glycol monomethyl ether instead of pentaethylene glycol monobenzyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH2:21])=[NH:20])[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C.[OH-].[Na+]>C(#N)C.CN(C1C=CN=CC=1)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:21][S:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[NH:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N=C(N)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N=C(NS(=O)(=O)c1ccc(F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Part B: To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.50 gram, 1.68 mmol) and 4-fluorophenylsulfonyl chloride (0.34 gram, 1.75 mmol) in acetonitrile (10 ml) was added N,N-dimethyl-4-aminopyridine (0.020 gram, 0.175 mmol) and triethylamine (1 ml). The resulting solution was stirred at room temperature for 30 minutes. After addition of a 2 N sodium hydroxide solution and extraction with ethylacetate (400 ml), the ethylacetate layer was concentrated in vacuo. The resulting crude residue was further purified by means of flash chromatography (petroleum ether/diethyl ether=1/1 (v/v), followed by ethylacetate). Subsequent concentration in vacuo afforded solid 3-(4-chlorophenyl)-4,5-dihydro-N-((4-fluorophenyl)sulfonyl)-4-phenyl-1H-pyrazole-1-carboxamidine (0.55 gram, 72% yield). Melting point: 214-215° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=[O:7])C.CO.O.O[Li].O>C1COCC1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][C:4]([OH:22])=[O:3])[CH2:13][CH2:12]1
Reactant: CCOC(=O)CC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a stirred solution of malonic acid monoethyl ester (1.2 g, 0.0089 mole) in DMF (10 mL) was added DIPEA (2.5 g, 0.02 mole), HOBt (1.3 g, 0.0097 mole) and EDCI.HCl (1.9 g, 0.0097 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (2 g, 0.0081 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 1.1 g (42%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 326.11 (M+1)+, 90.2%. To a stirred solution of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (1.1 g, 0.0034 mole) in a mixture of THF (20 mL), methanol (4 mL) and H2O (4 mL) was added LiOH.H2O (0.286 g, 0.0068 mole) at ambient temperature. The resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.75 g (75%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[C:26]([CH3:28])[CH:27]=1.O>CN(C=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([S:29][C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=2[C:6]#[N:7])[CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2cccc([N+](=O)[O-])c2C#N)c1
Temperature: 0 °C
Yield: 73011.2 %

Procedure:
A mixture of 2,6-dinitrobenzonitrile (1.4 g 7.2 mmol) and K2CO3 (1.1 g, 7.9 mmol) in 10 ml of DMF was chilled to 0° C. A solution of 3,5-dimethylthiophenol (1.1 g 0.0079 mmol) in 10 ml of DMF, was added dropwise over 30 min with stirring under nitrogen. After stirring an additional 30 min, the reaction mixture was poured into 150 ml of water and stirred for 1 hr. The solid was collected by vacuum filtration. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 1.64 g (80%) of 2-[(3,5-dimethylphenyl)thio]-6-nitrobenzonitrile: mp 155°-156° C.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>C(#N)C>[OH:24][C:22]([CH2:21][N:20]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:23]
Reactant: NCC(=O)O
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CC#N
Product: Cc1ccc(CN2C(=O)c3ccccc3C2=O)n1CC(=O)O

Procedure:
5.2 g (0.02 mol) of 6-phthalimido-2,5-hexanedione and 1.6 g (0.02 mol) of glycine are stirred in 50 ml of acetonitrile at 80° C. for 1 hour. After the mixture has been concentrated, it is extracted under alkaline conditions with methylene chloride and the extract is acidified and extracted again. The resulting product is recrystallised from methanol.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:19][CH2:18]1)[CH3:4].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50](=[O:52])[CH3:51])=[CH:44][C:40]=1[C:41](O)=[O:42].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][N:28]([C:41]([C:40]3[CH:44]=[C:45]([CH:46]=[CH:47][C:39]=3[O:38][CH3:37])[O:48][CH2:49][C:50](=[O:52])[CH3:51])=[O:42])[CH2:27]2)[CH2:19][CH2:18]1)[CH3:4]
Reactant: COc1ccc(OCC(C)=O)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(OCC(C)=O)ccc4OC)C3)CC2)nc2ccccc21
Yield: 85.9 %

Procedure:
Stir a mixture of 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.33 g, 0.61 mmol, Preparation 12.1), 2-methoxy-5-(2-oxo-propoxy)-benzoic acid (0.14 g, 0.61 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.73 mmol), 1-hydroxybenzotriazole hydrate (0.099 g, 0.73 mmol), diisopropylethylamine (0.25 mL, 1.2 mmol) and dichloromethane (10 mL) overnight at room temperature. Dilute the reaction mixture with dichloromethane, wash with saturated brine, dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography on silica gel eluting sequentially with ethyl acetate, 3% methanol in dichloromethane and 5% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.35 g of the title compound, Rf=0.48 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30]C(=O)C)[CH2:4]1)[CH3:2].Cl>O1CCOCC1>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 95 °C
Yield: 55.9 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (6.0 g, 12.86 mmol, Example #8, Step L) in 1,4-dioxane (78 mL) was added aqueous HCl (6 N, 75 mL, 450 mmol). The reaction mixture was heated at about 95° C. for about 16 h. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 (100 mL). The aqueous portion was extracted with additional DCM (3×50 mL) and the combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-100% DCM/MeOH/NH4OH (950:45:5) in DCM to give (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (3.05 g, 56%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.85 min; MS m/z: 425 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.BrC1C([Cl:25])=C(O)C=CC=1>>[Br:1][C:2]1[C:3]([Cl:25])=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: Fc1c(Br)cccc1OCC1CCOCC1
Reactant: Oc1cccc(Br)c1Cl
Product: Clc1c(Br)cccc1OCC1CCOCC1

Procedure:
Prepared as described for 4-(3-bromo-2-fluoro-phenoxymethyl)tetrahydropyran SM25 using 3-bromo-2-chlorophenol
Reaction SMILES: [CH3:1][S:2][CH3:3].ClCl.[NH2:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Br:13].N1C=CC=CC=1>ClCCl>[Br:13][C:8]1[CH:9]=[N:10][N:11]([CH3:12])[C:7]=1[N:6]=[S:2]([CH3:3])[CH3:1]
Reactant: CSC
Reactant: Cn1ncc(Br)c1N
Agent: ClCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ncc(Br)c1N=S(C)C

Procedure:
A solution of 0.60 mL (8.2 mmol) of dimethyl sulfide in 30 mL of dichloromethane was cooled to -20° C. and 0.50 g (7.0 mmol) of chlorine was added through a sparge tube with cooling and stirring. Subsequently, 1.0 g (5.7 mmol) of 5-amino-4-bromo-l-methylpyrazole and then 1.0 g (12.7 mmol) of pyridine were added with cooling and stirring. A 2 mL aliquot of this mixture was removed and the light yellow solids present were collected by filtration and washed with deuteroacetonitrile.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[Cl:14].[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>O1CCOCC1>[Cl:18][C:19]1[CH:24]=[C:23]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[N:22]=[CH:21][N:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Potassium carbonate (2M solution, 200 ml, 400.0 mmol) was added in one portion to a stirred solution of 3,4-dichlorophenyl boronic acid (38.5 g, 201.4 mmol) and 4,6-dichloropyrimidine (50.0 g, 335.6 mmol) in dioxane (600 ml). The mixture was degassed with nitrogen for 5 minutes, after which time palladium tetrakis triphenylphosphine (7.78 g, 6.71 mmol) was added in one portion, the mixture was then heated to 90° C. and stirred at this temperature for 16 hours under a nitrogen atmosphere. After this time the reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in DCM (500 ml), washed sequentially with water (200 ml) then brine (200 ml) before being dried (MgSO4), filtered and concentrated to give the title compound (47.8 g, 91% yield) as a white solid which was used without further purification. Tr=2.32 min m/z (ES+) (M+H+) 258, 260.