Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:15])[CH2:8][C:9]2=[O:14])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].Cl>CCOCC>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:15])[CH:8]([N+:16]([O-:18])=[O:17])[C:9]2=[O:14])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)Oc1cccc2c1C(=O)CC2=O
Agent: Cl
Solvent: CCOCC
Product: CC(C)Oc1cccc2c1C(=O)C([N+](=O)[O-])C2=O

Procedure:
4-Isopropyloxy indane-1,3-dione (0.16 g; 0.003 mole) suspended in dry ether (5 ml) was treated dropwise and with stirring with fuming nitric acid (1.0 ml) at 10°C. The resulting dark solution was treated with 5N hydrochloric acid and evaporated to a yellow crystalline product; m.p. (water, hydrochloric acid) 80°-81°C. (Found: C, 57.94; H, 4.43; N, 5.46; C12H11NO5 requires: C, 57.83; H, 4.45; N, 5.62%).
Reaction SMILES: [Li][C:2]#[C:3][CH:4]([CH3:6])[CH3:5].[C:7](OCC)(=[O:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1>[CH3:5][CH:4]([CH3:6])[C:3]#[C:2][C:7](=[O:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)OC(C)(C)C
Reactant: [Li]C#CC(C)C
Solvent: C1CCOC1
Product: CC(C)C#CC(=O)C(=O)OC(C)(C)C

Procedure:
reacting 1-lithio-3-methylbut-1-yne with a 150% to 165% excess of the stoichiometric amount of ethyl t-butyl oxalate in THF containing an amount of a suitable hydrocarbon solvent sufficient to solubilize said 1-lithio-3-methylbut-1-yne, the reaction being carried out under anhydrous conditions in an inert atmosphere at a temperature of from 0° to 10° to form t-butyl 5-methyl-2-oxohex-3-ynoate;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.C(OCC)(=O)C.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:20]=[CH:19][C:18]([CH:22]=[CH2:23])=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ncc(Br)cn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1cnc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)nc1
Temperature: 90 °C
Yield: 35.7 %

Procedure:
(S,S)-5-(5-Bromo-pyrimidin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (177 mg, 0.5 mmol), tributyl vinyl tin (634 mg, 2 mmol) and Cl2Pd(dppf)CH2Cl2 (60 mg) was mixed in DMF (3 mL). The mixture was heated at 90° C. over 3 days. The cooled down reaction was participate between ethyl acetate (50 mL) and H2O (10 mL). The organic layer washed with H2O (10 mL), brine (10 mL), dried (MgSO4) and filtered. The conc. filtrate was purified on silica gel column eluting with 33% to 50% ethyl acetate/hexanes to yield the title compound as a white solid (54 mg). MS (303, MH).
Reaction SMILES: [CH:1]([CH:3]1[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:17][NH2:18]>C1C=CC=CC=1>[CH3:17][N:18]=[CH:1][CH:3]1[C:8]2[N:9]([CH3:16])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CN
Reactant: Cn1c2c(c3ccccc31)SCCC2C=O
Solvent: c1ccccc1
Product: CN=CC1CCSc2c1n(C)c1ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-formyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (1.2 g) in benzene (12 ml) is added 10% solution (3.2 g) of methylamine in benzene. The mixture is stirred at room temperature for 2.5 hours and then evaporated to give 4-methyliminomethyl-5-methyl-2,3,4,5-tetrahydrothiopyrano[3,2-b]indole as an oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][N:6]=[C:7]([C:10]1[C:11](=[O:29])[CH2:12][CH:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])[CH2:14][C:15]=1[OH:16])[CH2:8][CH3:9])[CH3:4].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[C:30]([O:29][C:11]1[CH2:12][CH:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])[CH2:14][C:15](=[O:16])[C:10]=1[C:7](=[N:6][O:5][CH2:3][CH3:4])[CH2:8][CH3:9])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(OC)cc(OC)cc2OC)CC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC(c2c(OC)cc(OC)cc2OC)CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
Aqueous 1% sodium hydroxide solution (6.1 ml) was added to a solution of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethoxyphenyl)cyclohex-2-en-1-one (0.52 g; 1.40 mmole) in acetone (25 ml). The mixture was stirred at room temperature for a period of 5 minutes and then benzoyl chloride (0.21 g) was added dropwise. The mixture was stirred for a further period of 15 minutes and then the solvent was removed by evaporation under reduced pressure. The product was purified by chromatography over silica gel (eluant dichloromethane) to give 3-benzoyloxy-2-[1-(ethoxyimino)propyl]-5-(2,4,6-trimethoxyphenyl)cyclohex-2-en-1-one (0.50 g; 73.9%) as a pale yellow solid, mp 139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[O:8][CH2:9][C:10]2[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(OCC)(=O)C.C(=O)([O-])O.[Na+].O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[O:8][CH2:9][C:10]2[CH:16]=[C:15]([NH:17][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccccc1CNC1=Nc2ccc(N)cc2CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)C3CC3)cc2CO1
Temperature: 23 °C
Reaction time: 0.33 h
Yield: 60.1 %

Procedure:
To a vigorously stirred solution of N2-(2-methoxy-benzyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 4) (128 mg, 0.45 mmol; HPLC 0.41 min) in ethyl acetate (2 ml) and sat. sodium hydrogen carbonate-sol. (1.2 ml) at 23° C. was dropwise added cyclopropanecarbonyl chloride (50 ul, 0.54 mmol) and the mixture was stirred at 23° C. for 20 min. Diluted with ethyl acetate and water, separated phases, washed organic layer with brine and dried over sodium sulfate. Removal of the solvent in vacuum left an off-white solid which was purified by silica gel column chromatography with heptane/ethyl acetate 1:1 to 0:1 followed by trituration with diethyl ether to give the title compound as a white solid (95 mg, 55%, HPLC 0.998 min 100%), MS (ISP) m/e=352.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].C(#N)C>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 80.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H- indazole (3.5 g, 16 mmol), K2CO3 (2.2 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol) and acetonitrile (90 ml) was refluxed for 16 hours. The reaction was poured into water and the resulting white solid, which precipitated from solution, was collected to afford 5.5 g of the desired product. The compound was recrystallized from dimethylformamide (twice) to afford 3.0 g (44%) of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-methoxyphenyl]ethanone as a white solid, m.p.=202°-204° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[CH:26]1([O:31][C:32](=[O:39])[C@@H:33]([NH2:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:38][C@H:33]([C:32]([O:31][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: CC(C)C[C@H](NC1CCCN(C(=O)OC(C)(C)C)C1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To a solution of 3-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.458 g, 2.3 mmol) in dichloroethane (18 mL) was added the tosic acid salt of (S)-2-amino-4-methyl-pentanoic acid cyclopentyl ester (0.496 g, 2.53 mmol) and sodium triacetoxyborohydride (0.975 g, 4.6 mmol). The solution was stirred at room temperature for 18 hours. An aqueous solution of sodium hydrogen carbonate (20 mL) was added and the mixture stirred for 20 minutes. The desired product was extracted into ethyl acetate (3 times 15 mL). The organic layers were combined, dried (MgSO4) and concentrated to give the desired product (0.840 g, 95% yield) which was used without further purification. LC/MS: m/z 383 [M+H]+
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:23]=[CH:24][C:25]=1[F:26]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(F)c(Cl)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(F)c(Cl)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [CH:1]([Si:4]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:17]3[CH:18]=[C:19]([O:22][C@H:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C@@H:26]([NH2:33])[CH2:25][CH2:24]4)[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:9][CH2:8]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:43][C:44](=O)[NH:45][C:46]1[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=[C:49]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:50]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:51]([C:49]1[CH:50]=[C:46]([NH:45][C:44]([NH:33][C@@H:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]([O:22][C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([N:10]5[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:34]([CH3:36])[CH3:35])[CH:37]([CH3:39])[CH3:38])[CH2:8][CH2:9]5)=[N:14][N:15]=4)[CH:18]=3)[CH2:24][CH2:25]2)=[O:43])[N:47]([C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[N:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A solution of Intermediate 54c (171 mg, 0.311 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 132 mg, 0.327 mmol) in 1,4-dioxane (3 mL) and DIPEA (87 μL, 0.50 mmol) was stirred at 90° C. for 3 h, and then at 100° C. for 2.5 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM, to give the title compound as a pale brown solid (215 mg, 86%). LCMS (Method 3): Rt 5.70 min, m/z 805.4 [MH+].
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:12])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[CH:20][C:21](=[O:23])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CS(O)(=O)=O.O>C(#N)C.C(OCC)(=O)C>[O:23]=[C:21]([CH3:22])[CH2:20][CH:13]([C:11]1[O:10][C:9](=[O:12])[NH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)C=Cc1ccccc1
Reactant: O=c1[nH]c(-c2ccccc2)co1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)CC(c1ccccc1)c1oc(=O)[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
4-Phenyl-2-oxo-4-oxazoline (1.61 g) and benzalacetone (1.46 g) were dissolved in acetonitrile (20 mL), and methanesulfonic acid (0.96 mL) was added. The obtained mixture was stirred at room temperature for 1 h and water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. The organic layer was separated, washed twice with water (50 mL), and concentrated under reduced pressure to give an oily substance. The obtained oily substance was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (1:1). The solvent was evaporated and isopropyl ether (50 mL) was added to the obtained oily substance to allow crystallization and the mixture was stirred at room temperature for 1 h. The crystals were collected by filtration and washed with isopropyl ether (20 mL) to give the title compound (2.65 g; yield 86.3%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C@H:4]1[C:16]1[S:17][CH:18]=[CH:19][N:20]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[C:16]1[S:17][CH:18]=[CH:19][N:20]=1
Reactant: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1nccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1CCNC[C@H]1c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
Stir tert-butyl trans-4-methoxy-3-thiazol-2-yl-piperidine-1-carboxylate (4.8 g, 16.1 mmol) in dichloromethane (80.4 mL) and add trifluoroacetic acid (7.30 mL, 96.51 mmol). Stir the mixture at ambient temperature overnight. Remove the solvent under reduced pressure, and purify the residue via SCX (50 g cartridge) eluting with 2N NH3/MeOH. Concentrate the appropriate fractions under reduced pressure to give the title compound (3.2 g, 85.3%) as a waxy solid. MS (m/z): 199 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:45])[C@@H:7]([NH:13][C:14](=[O:44])[CH2:15][CH2:16][C:17](=[O:43])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])(C)(C)C.[B-](F)(F)(F)F.CN(C(O[N:59]1[C:64](=[O:65])[CH2:63][CH2:62][C:60]1=[O:61])=[N+](C)C)C>>[O:61]=[C:60]1[CH2:62][CH2:63][C:64](=[O:65])[N:59]1[O:5][C:6](=[O:45])[C@@H:7]([NH:13][C:14](=[O:44])[CH2:15][CH2:16][C:17](=[O:43])[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:8][CH2:9][C:10]([O:12][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:11]
Reactant: CC(C)(C)OC(=O)CCCCCCC(=O)NCCOCCOCCNC(=O)CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)CCCCCCC(=O)NCCOCCOCCNC(=O)CCC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O

Procedure:
(S)-2-[3-(2-{2-[2-(7-tert-Butoxycarbonylheptanoylamino)ethoxy]ethoxy}-ethylcarbamoyl)propionylamino]pentanedioic acid 1-tert-butyl ester (0.6 g, 0.93 mmol) was activated with TSTU using the procedure described above.
Reaction SMILES: O=C1C2C=C3C=CC=CC3=CC=2C(=O)N1CC[C@@H](N[C@H](C(N[C@H](C1C=CC=CC=1)C)=O)CC(C)C)C(O)=O.CC([O:43][C:44](=[O:79])[C@H:45]([NH:63][C@H:64]([C:69]([NH:71][CH:72]1[CH2:76][CH2:75][S:74](=[O:78])(=[O:77])[CH2:73]1)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])[CH2:46][CH2:47][N:48]1[C:56](=[O:57])[C:55]2[CH:54]=[C:53]3[CH:58]=[CH:59][CH:60]=[CH:61][C:52]3=[CH:51][C:50]=2[C:49]1=[O:62])(C)C>>[O:62]=[C:49]1[C:50]2[CH:51]=[C:52]3[CH:61]=[CH:60][CH:59]=[CH:58][C:53]3=[CH:54][C:55]=2[C:56](=[O:57])[N:48]1[CH2:47][CH2:46][C@@H:45]([NH:63][C@H:64]([C:69]([NH:71][CH:72]1[CH2:76][CH2:75][S:74](=[O:78])(=[O:77])[CH2:73]1)=[O:70])[CH2:65][CH:66]([CH3:68])[CH3:67])[C:44]([OH:79])=[O:43]
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NC1CCS(=O)(=O)C1
Agent: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)O)C(=O)N[C@@H](C)c1ccccc1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)O)C(=O)NC1CCS(=O)(=O)C1

Procedure:
Prepared as described for Example 1, Part (b) by hydrolysis of the product of Part (a) above to give the title compound as a white solid; 8 mg.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:16])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][CH:12]([OH:15])[CH2:13][OH:14])[C:6]=2[N:7]=1.FC(F)(F)C(O)=O.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(O)C.C(Cl)Cl.CO>[F:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[C:26]=1[N:32]1[CH2:37][CH2:36][N:35]([C:2]2[NH:3][C:4](=[O:16])[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][CH:12]([OH:15])[CH2:13][OH:14])[C:6]=3[N:7]=2)[CH2:34][CH2:33]1
Reactant: O=c1[nH]c(Cl)nc2c1ccn2CC(O)CO
Reactant: Fc1cccc(F)c1N1CCNCC1
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(N2CCN(c3c(F)cccc3F)CC2)nc2c1ccn2CC(O)CO
Temperature: 100 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
A mixture of 2-chloro-7-(2,3-dihydroxy-propyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (16 mg, 65.7 μmol) in ethanol (460 μL) was treated with 1-(2,6-difluorophenyl)piperazine trifluoroacetic acid salt (40.9 mg, 131 μmol) and N,N-diisopropylethylamine (36.6 μL, 210 μmol). The reaction was heated to 100° C., where it stirred overnight. At this time, the reaction was allowed to cool to room temperature. The reaction was then diluted with methylene chloride and methanol and concentrated in vacuo onto Celite®. Flash chromatography (4 g silica gel column, 1-4% methanol/methylene chloride) afforded 2-[4-(2,6-difluoro-phenyl)-piperazin-1-yl]-7-(2,3-dihydroxy-propyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a purple solid (15.3 mg, 57.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (br. s., 4H) 3.23-3.31 (m, 2H) 3.54-3.70 (m, 4H) 3.71-3.93 (m, 2H) 4.09 (dd, J=13.68, 4.39 Hz, 1H) 4.67 (t, J=5.77 Hz, 1H) 4.94 (d, J=5.27 Hz, 1H) 6.24 (d, J=3.51 Hz, 1H) 6.80 (d, J=3.51 Hz, 1H) 6.95-7.24 (m, 3H) 10.85 (br. s., 1H). LC-MS calcd. for C19H22F2N5O3 [(M+H)+] 406, obsd. 406.0.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([N+:13]([O-:15])=[O:14])[C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]>C(OCC)C.Cl>[F:10][C:9]1[C:4]([CH:3]=[O:2])=[C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:6]([N+:13]([O-:15])=[O:14])=[C:7]([O:11][CH3:12])[CH:8]=1
Reactant: COc1cc(F)c(C(OC)OC)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Product: COc1cc(F)c(C=O)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A mixture of (2-dimethoxymethyl-3-fluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (4.2 g, 8.7 mmol) in diethyl ether (70 mL) and 4M HCl (50 mL) was stirred at room temperature for 8 hours. The mixture was extracted with ethyl acetate, the organic extract washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow solid (3.1 g, 82%). LCMS (Method B) RT=4.00 no molecular ion.
Reaction SMILES: Cl.Cl[CH:3]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>O>[N:12]1([CH:3]2[C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:5][CH2:4]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: ClC1CCc2cccnc21
Reactant: C1CCNC1
Agent: Cl
Solvent: O
Product: c1cnc2c(c1)CCC2N1CCCC1
Temperature: 25 °C

Procedure:
5 g of 7-chloro-6,7-dihydro-5H-1-pyrindine hydrochloride were dissolved in 10 ml of water and 8.8 ml of pyrrolidine were added, followed by stirring for two-and-a-half hours at ambient temperature. Extraction was done with methylene chloride and the extracts were washed with water, dried and concentrated to dryness under reduced pressure. The residue was taken up in ethyl acetate, treated with active charcoal, filtered and taken to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of ethyl acetate and triethylamine (95-5) to obtain 4.71 g of the expected product.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH2:17][P:18]([O:21]CC)([CH3:20])=[O:19])[C:14](=[O:24])[O:13]C1)=O)C1C=CC=CC=1.[ClH:25]>>[ClH:25].[NH2:11][C@H:15]([C:14]([OH:24])=[O:13])[CH2:16][CH2:17][P:18]([CH3:20])(=[O:19])[OH:21]
Reactant: CCOP(C)(=O)CC[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Agent: Cl
Product: CP(=O)(O)CC[C@H](N)C(=O)O
Yield: 82.1 %

Procedure:
0.50 g (1.4 mmol) of (4S)-3-benzyloxycarbonyl-4-{2-[ethoxy (methyl)phosphinyl]ethyl}-1,3-oxazolidin-5-one (from Example 12) are, as described in DE-A-3,817,956, hydrolyzed by heating in 6 N hydrochloric acid. 0.25 g (82.1% of theory) of L-homoalanin-4-yl(methyl)phosphinic acid hydrochloride are obtained as a white solid having a melting point of Mp 202° C. (decomposition).
Reaction SMILES: CN.[CH2:3]([N:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[CH3:19])C1=S)C=C>C(O)C.ClCCl>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([CH3:19])=[C:12]([NH:8][CH2:9][CH2:10][CH2:11][NH:6][CH3:3])[CH:17]=1
Reactant: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Agent: CN
Solvent: CCO
Solvent: ClCCl
Product: CNCCCNc1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
To an 8.03 M solution of methylamine in ethanol (27 mL) was added the hydrobromide salt of Example 8, Step B (7.5 g). The reaction was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and 1N sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 98:2 to 90:10 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.9 g, 84.1%) as a pale orange oil, which was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10][CH:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([OH:4])[CH3:3].I[CH2:17][CH2:18][CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:20]([C:11]([CH2:10][C:7]1[CH:6]=[C:5]([C:2]([CH3:1])([OH:4])[CH3:3])[O:9][N:8]=1)([C:12]#[N:13])[C:14]#[N:15])[CH2:19][CH:18]=[CH2:17]
Reactant: CC(C)(O)c1cc(CC(C#N)C#N)no1
Reactant: C=CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(C#N)(C#N)Cc1cc(C(C)(C)O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
0.41 g of {[5-(1-methyl-1-hydroxyethyl)isoxazol-3-yl]methyl}malononitrile and 0.63 g of 4-iodo-1-butene were dissolved in 6 ml of N,N-dimethylformamide, and 0.55 g of potassium carbonate was then added under ice-cooling. The mixture was stirred at room temperature overnight. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.43 g of (3-butenyl){[5-(1-methyl-1-hydroxyethyl)isoxazol-3-yl]methyl}malononitrile represented by the following formula: