Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH3:21])[N:9]=[C:10]2[C:19]=1[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:12]=[C:11]2[NH2:20].FC(F)(F)C(O)=O>[Pt](=O)=O>[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH3:21])[N:9]=[C:10]2[C:19]=1[C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=1[N:12]=[C:11]2[NH2:20]
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: O=[Pt]=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Yield: 79.3 %

Procedure:
A mixture of 1-(4-chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine hydrochloride (2.8 g, prepared as described in Examples 454-488), platinum (IV) oxide (2.1 g), and trifluoroacetic acid (43 mL) was placed under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr shaker for 2 days. The reaction mixture was filtered through a layer of CELITE filter agent and the filter cake was rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL), made basic (pH 14) by the addition of 50% sodium hydroxide and then extracted with dichloromethane. The extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (40+M cartridge eluting with chloroform/CMA in a gradient from 100:0 to 80:20) to provide 2.0 g of 1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:13]=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].C(OC(=O)C)(=O)C.Cl[C:23](Cl)([F:28])[C:24]([O:26][CH3:27])=[O:25]>[Zn].[Cu]Cl.O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([CH:13]=[C:23]([F:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:11][CH2:12]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: CCOc1ccc(C2(C=O)CC2)cc1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(C2(C=C(F)C(=O)OC)CC2)cc1
Yield: 62.7 %

Procedure:
The method of Example 1 was repeated using zinc powder (4.1 g), copper (I) chloride (0.63 g), molecular sieve 4A (4.2 g), tetrahydrofuran (72 ml), 1-(4-ethoxyphenyl)-1-formylcyclopropane (4.7 g), acetic anhydride (2.6 ml) and methyl dichloro-fluoroacetate (3.3 g) to yield the title compound (3.4 g, 52%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 56.7 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-propionylquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (46 mg, 0.091 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (37 mg, 0.137 mmol) to afford the desired product (32 mg, 60%) as an yellow solid: ESI MS m/z 619, [C33H35ClFN5O4+H]+
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6](=O)[CH2:7][CH3:8])[CH2:2]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(OCC)(=O)C>[CH3:8][C:7]1[N:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:6]=1[CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CCC(=O)C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C2CCOC2)nc2ccc([N+](=O)[O-])cn12

Procedure:
Operations similar to Production Example 1-(1) were conducted using 1-tetrahydro-3-furanyl-1-propanone in place of 3-methyl-2-butanone, and successively those of Production Example 1-(2) were conducted using 2-amino-5-nitropyridine. The resulting solid was suspended in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to provide the title compound as yellow crystals.
Reaction SMILES: BrC1[C:10]2C(Cl)=NC=[N:6][C:5]=2[N:4](C(C)C)C=1.ClC1C=C(C=C(C)N=1)C(Cl)=O.[NH2:26][C:27]1[C:28]2[C:35]([C:36]([C:38]3[CH:43]=[CH:42][CH:41]=C(N)N=3)=[O:37])=[CH:34][N:33]([CH:45]([CH3:47])[CH3:46])[C:29]=2[N:30]=[CH:31][N:32]=1>>[NH2:26][C:27]1[C:28]2[C:35]([C:36]([C:38]3[CH:43]=[C:42]([CH3:41])[N:4]=[C:5]([NH2:6])[CH:10]=3)=[O:37])=[CH:34][N:33]([CH:45]([CH3:46])[CH3:47])[C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Reactant: CC(C)n1cc(C(=O)c2cccc(N)n2)c2c(N)ncnc21
Agent: Cc1cc(C(=O)Cl)cc(Cl)n1
Product: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1

Procedure:
The title compound was prepared from 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (15.8 g, 50.7 mmol) and 2-Chloro-6-methyl-isonicotinoyl chloride (9.6 g, 50.7 mmol) by procedures analogous to those described for the preparation (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(6-amino-pyridin-2-yl)-methanone. MS: 311.2 (MH+); HPLC Rf: 3.23 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1.Cl.[F:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH2:27].O>CN(C=O)C>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][CH2:26][C:25]([F:24])([CH3:29])[CH3:28])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: CC(C)(F)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(F)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 100.1 %

Procedure:
Triethylamine (17.3 g, 171 mmol) was added to a suspension of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (52.2 mmol) in DMF (50 mL), and then a solution of 2-fluoro-2-methylpropan-1-amine hydrochloride (5.46 g, 42.8 mmol) in DMF (25 mL) was added dropwise over a period of ten minutes. The reaction mixture was stirred at room temperature for 14.5 hours, and water (500 mL) was added. The resulting mixture was stirred for one hour. A solid was present and was isolated by filtration, washed with water, and dried overnight in a vacuum oven at 65° C. to provide 14.7 g of 7-bromo-N-(2-fluoro-2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a reddish-brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:33])[CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:32])[C:10]2[CH:34]=[CH:35][CH:36]=[CH:37][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:19](=[O:33])[CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[C:27]([O:31][CH3:38])[CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:32])[C:10]2[CH:34]=[CH:35][CH:36]=[CH:37][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2cccc(O)c2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cccc2c1C(=O)N(CC(=O)N1c3ccccc3N(Cc3ccccc3)C(=O)[C@H]3CCC[C@H]31)C2=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 96.7 %

Procedure:
To a suspension of (3aR*,10aS*)-9-benzyl-4-((3-hydroxyphthalimido)acetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (343 mg, 0.69 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (115 mg, 0.83 mmol) and methyl iodide (0.10 mL, 1.6 mmol). The mixture was stirred for 4.5 hours at room temperature, to which was added water. The resulting solid was separated by filtration, and the filtrate was subjected to extraction with chloroform. In this organic layer was dissolved the solid previously separated by filtration. The solution was dried over magnesium sulfate, which was subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was recrystallized from chloroform-diethylether to give 340 mg (yield 96%) of the titled compound, m.p. 247°-248° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.N1C=CC=CC=1.[CH3:17][N:18]=[C:19]=[O:20].CN(C=O)C>CO>[CH3:17][NH:18][C:19](=[O:20])[NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1
Reactant: Nc1nc2cnccc2s1
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: CO
Solvent: c1ccncc1
Product: CNC(=O)Nc1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
A mixture of 2-aminothiazolo[4,5-c]pyridine (151 mg, 1 mmole), pyridine (1.8 ml), CH3NCO (1.2 ml) and 3 ml DMF was stirred at room temperature for 2 days. To the reaction mixture was added CH3OH, and the mixture was evaporated in vacuo. The residue was treated with CH3OH and ether to give 165 mg (79%) of crystalline solid. Mp. 178°~187° C. (dec.).
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].O>C1(C)C(C)=CC=CC=1>[C:1]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:18]([OH:20])=[O:19])[NH2:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCC(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 81.9 %

Procedure:
Lysine octanoate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 26.9 g of Nε-octanoyl lysine (yield 81.9%). This is designated Derivative B.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].I(C1C=CC=CC=1C(O)=O)(=O)=O>C1COCC1.CS(C)=O>[CH3:8][CH:6]([CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:28])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][CH2:14]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][C:22](=[O:27])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:11][CH2:10]1)[CH3:1])[CH3:7]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 89.5 %

Procedure:
A solution of dihydrocholesterol (1.94 g; 5 mmol) in THF (8 ml) was added to a solution of o-iodoxybenzoic acid I (2.10 g, 7.5 mmol) in DMSO (14 ml). After 2 hr precipitation of a white solid was observed. After 5 hr the reaction solution was poured into Na2CO3 (5%, 40 ml) and extracted with diethyl ether/n-hexane (50:50; 3×30 ml). The combined organic layers were washed with water (2×15 ml), dried over sodium sulfate and brought to dryness under vacuum. The residue was crystallised from ethanol to give 1.73 g (89%) of 5α-cholestan-3-one mp 129°-130° C. (lit. 128°-130° C.: Beilsteins Handbuch der organischen Chemie, III E., 7, 1330b).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16](Cl)=[O:17])[O:9][CH2:8][CH2:7]1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])[O:9][CH2:8][CH2:7]1
Reactant: O=C(Cl)C1CCCCC12OCCO2
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(C1CCCCC12OCCO2)N1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
Pyrrolidine (0.21 mL, 2.5 mmol) was added at 0° C. to a 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene (1 mL, 1 mmol). The mixture was stirred at 20° C. for 1 h, then diluted with ethyl acetate (40 mL), and washed successively with water (10 mL), saturated aquous sodium carbonate solution (10 mL), 1 N hydrochloric acid, and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (97 mg, 41%) as a white solid. MS ISP (m/e): 240.3 (100) [(M+H)+].
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:35]#[N:36])[N:19]=3)=[CH:13][C:12]=2[F:37])[CH:7]=[CH:6][N:5]=1)(=O)N.[ClH:38].[NH2:39]C1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC(F)=CC=3F)=O)=CC=2F)C=CN=1>>[ClH:38].[ClH:38].[NH2:39][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=4[F:34])=[O:25])=[CH:22][N:21]=[C:20]([C:35]#[N:36])[N:19]=3)=[CH:13][C:12]=2[F:37])[CH:7]=[CH:6][N:5]=1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reactant: N#Cc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Agent: Cl
Product: N#Cc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(N)c3)c(F)c2)n1
Yield: 53 %

Procedure:
4-(4-(2-Carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-2-cyano-N-(2,4-difluorophenyl)pyrimidine-5-carboxamide (171 mg, 0.33 mmol) was converted to the title compound (90 mg, 53%) in a manner similar to the preparation of 2-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (Step E of Example 3). 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 10.83 (s, 1H), 9.11 (s, 1H), 7.99 (m, 2H), 7.83 (br s, 2H), 7.68-7.40 (m, 4H), 7.20 (m, 1H), 6.75 (dd, 1H, J=7.3, 2.4 Hz), 6.20 (d, 1H, J=2.4 Hz); MS(ESI+) m/z 478 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[Cl:20][C:17]([F:19])([F:18])[S:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:33]3[CH:32]=[N:31][CH:30]=[C:29]([F:28])[CH:34]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 185 using (R)-5-bromo-N-(4-((chlorodifluoromethyl)thio)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 217.1) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white foam. HPLC (Condition 4) tR=5.69 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=495.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.77 (m, 1H) 1.79-1.89 (m, 1H) 2.87 (d, J=11.34 Hz, 1H) 3.20 (m, J=11.10, 4.50 Hz, 2H) 3.33-3.44 (m, 1H) 4.19 (br. s, 1H) 4.86 (d, J=3.13 Hz, 1H) 7.66 (d, J=8.60 Hz, 2H) 7.82 (d, J=9.78 Hz, 1H) 7.91 (d, J=8.60 Hz, 2H) 8.06 (d, J=1.00 Hz, 1H) 8.50 (s, 1H) 8.58 (d, J=2.35 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 10.27 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:11](#[N:13])[CH3:12].O1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:16]([C:17]1[CH:18]=[C:15]([CH2:12][CH2:11][NH2:13])[CH:16]=[CH:17][CH:18]=1)=[CH2:15]
Reactant: CC#N
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: C=Cc1cccc(CCN)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of aluminium chloride (1.44 g, 10.8 mmol) in tetrahydrofuran (25 ml) was added carefully to lithium aluminium hydride (1.23 g, 32.4 mmol) in tetrahydrofuran (25 ml), and the mixture stirred at room temperature for 10 mins. A solution of the intermediate acetonitrile in tetrahydrofuran (50 ml) was then added and the reaction stirred at room temperature for 3 hrs. The reaction was quenched by the addition of hydrochloric acid, then basified using aqueous NaOH solution. The mixture was extracted with ethyl acetate, the combined organic extracts dried over MgSO4 and evaporated under reduced pressure. The crude product was redissolved in ethyl acetate, extracted into citric acid, and these aqueous extracts rebasified using aqueous NaHCO3 solution. This was then re-extracted with ethyl acetate, and the combined extracts evaporated under reduced pressure to provide the title compound as a yellow oil, (1.79 g, 47%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:34])[NH:10][C@@H:11]([CH2:27][C:28]2[N:29]=[CH:30][N:31]([CH3:33])[CH:32]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:34])[CH2:27][C:28]3[N:29]=[CH:30][N:31]([CH3:33])[CH:32]=3)[S:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cn(C)cn1)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1cnc(C[C@H](NC(=O)[C@H]2O[C@@H]2C(=O)O)C(=O)Nc2nc(-c3ccc(F)cc3)cs2)c1
Yield: 33.2 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 21 (93 mg, 0.19 mmol); LiOH (4.5 mg, 0.19 mmol); THF/MeOH/H2O (1.5 mL: 0.5 mL: 0.5 mL); yielded 36 as a white solid (29 mg, 33.1%). 1H NMR (400 MHz, DMSO-d6): 12.50 (bs, 1H), 8.82-8.80 (d, 1H): 7.93-7.91 (m, 2H); 7.76 (s, 1H); 7.63 (s, 1H); 7.46-7.24 (t, 2H); 6.99 (s, 1H); 4.79-4.74 (m, 1H); 3.67-3.66 (d, 1H); 3.62 (s, 3H); 3.49-3.48 (d, 1H); 3.12-2.90 (m, 2H). 13C NMR (400 MHz, DMSO-d6): 169.72, 168.60, 165.56, 162.97, 160.54, 157.78, 147.88, 137.17, 130.84, 127.71, 127.63, 118.35, 115.68, 115.47, 108.08, 53.07, 52.98, 51.56, 33.11, 29.60. ESI-HRMS (m/z): [M+H+] calcd. for C20H18FNO5S: 460.1085, observed: 460.1090. Rt=18.1 min, purity=95.3%.
Reaction SMILES: [CH3:1][C:2]([O:4][CH:5]1[CH:9]([O:10][C:11]([CH3:13])=[O:12])[CH:8]2[CH:14]([O:19][C:20]([CH3:22])=[O:21])[CH:15]=[CH:16][C:17](=[O:18])[N:7]2[CH2:6]1)=[O:3].[H][H]>C(O)C>[CH3:22][C:20]([O:19][C@H:14]1[C@@H:8]2[C@H:9]([O:10][C:11]([CH3:13])=[O:12])[C@H:5]([O:4][C:2]([CH3:1])=[O:3])[CH2:6][N:7]2[CH:17]([OH:18])[CH2:16][CH2:15]1)=[O:21]
Reactant: [H][H]
Reactant: CC(=O)OC1C=CC(=O)N2CC(OC(C)=O)C(OC(C)=O)C12
Solvent: CCO
Product: CC(=O)O[C@H]1[C@H]2[C@H](OC(C)=O)CCC(O)N2C[C@H]1OC(C)=O
Reaction time: 8 h

Procedure:
(1S,2R,8R,8aR)-1,2,8-triacetoxy-1,2,3,5,8,8a-hexahydro-5-oxyindolizine, 13, 22 g (0.070 mole), was hydrogenated at atmospheric pressure of hydrogen in 400 mL ethanol containing 3 g 10% Pd on carbon. The reaction was allowed to proceed overnight. The catalyst was filtered, and the filtrate was evaporated to dryness. The crystalline residue was taken up in ether and hexane and filtered to afford (1S,2R,8R,8aR)-1,2,8-triacetoxy-octahydro-5-oxyindolizine, 14, 21.4 g (0.068 mole; 97%) as a white crystalline solid of m.p. 146°-147° C. (lit. 143-145; A. C. Richardson et. al., Carb. Res., 136:225(1985)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][N:9]2[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)=[CH:4][CH:3]=1.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28].CN(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.F[B-](F)(F)F>[CH3:31][O:30][C:26](=[O:29])/[CH:27]=[CH:28]/[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][N:9]2[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=23)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: CN1CCN(CCc2cnn3ccccc23)C(c2ccc(Br)cc2)C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc(C2CN(C)CCN2CCc2cnn3ccccc23)cc1
Temperature: 135 °C
Yield: 97.1 %

Procedure:
A mixture of 3-{2-[2-(4-bromo-phenyl)-4-methyl-piperazin-1-yl]-ethyl}-pyrazolo[1,5-a]pyridine (1.0 g, 2.49 mmol), methyl acrylate (0.458 mL, 4.98 mmol), N-methyldicyclohexylamine (584 mg, 2.99 mmol), tri-(tert-butyl)phosphine-tetrafluoroborate (28.9 mg, 0.0997 mmol) and Pd2(dba)3 (22.8 mg, 0.02 mmol) in 1,4-dioxane (10 mL) was flushed with nitrogen and heated at 100° C. for 1 h and at 135° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, filtered through Celite pad, and concentrated in vacuo. Purification via flash silica gel column chromatography (heptane/ethyl acetate) gave (E)-3-{4-[4-methyl-1-(2-pyrazolo[1,5-a]pyridin-3-yl-ethyl)-piperazin-2-yl]-phenyl}-acrylic acid methyl ester (0.978 g, 97% yield). LCMS (m/z): 405.30 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>C(#N)C>[CH2:26]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[CH3:1])[CH2:13][CH2:14]1)[CH:25]=[CH2:24]
Reactant: Cc1c(C2CCNCC2)cccc1S(C)(=O)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(c2cccc(S(C)(=O)=O)c2C)CC1

Procedure:
Preparation according to Example 1: 4-[2-methyl-3-(methylsulfonyl)phenyl]piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 293 (M+, 16), 292 (16), 278 (26), 266 (bp), 129 (19).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([Cl:8])=[C:5](Cl)[Cl:6].[CH3:10][NH:11][NH2:12].C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1>[Cl:8][C:4]1[C:3]([OH:2])=[N:12][N:11]([CH3:10])[C:5]=1[Cl:6]
Reactant: COC(=O)C(Cl)=C(Cl)Cl
Reactant: CNN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1nc(O)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.3 %

Procedure:
A mixture of 74 gms (0.391 mol) methyl-2,3,3-trichloroacrylate, 18 gms (21 ml) methyl hydrazine and 54 gms (0.391 mol) potassium carbonate in 500 ml toluene was stirred at room temperature for one day, and then heated to reflux for one day. An additional 5 gms methyl hydrazine was then added and the reaction mixture was stirred an additional day at reflux. The reaction mixture was then acidified with dilute hydrochloric acid. At this point, there was a large amount of solid which did not dissolve in either phase. The solids were removed by filtration, resuspended in water and the suspension was filtered again. The solids were air-dried overnight, yielding 60.9 gms of product, melting point 212°-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Br:20][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:17])[C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(Cl)cc2)c(Br)c2ccccc21
Reaction time: 3.5 h

Procedure:
Under an argon atmosphere in a round bottom flask 2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indole (5.0 g, 18.40 mmol) was dissolved in 46 ml of tetrahydrofuran. To this solution was added N-bromosuccinimide (3.28 g, 18.4 mmol of a freshly recrystallized lot), dissolved in 46 ml of tetrahydrofuran. The resulting mixture was stirred over an ice bath for about 3.5 hours, after which time the reaction mixture was poured into about 500 ml of water in which 5.0 grams of sodium sulfate had been dissolved.