Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][CH:9]1[CH2:23][C:22]2[C:11](=[CH:12][C:13]3[N+:18]([O-:19])=[N:17][C:16](N)=[N:15][C:14]=3[CH:21]=2)[CH2:10]1.[I:24]CI>C1COCC1.[Cu]I>[I:24][C:16]1[N:17]=[N+:18]([O-:19])[C:13]2[CH:12]=[C:11]3[C:22]([CH2:23][CH:9]([CH3:8])[CH2:10]3)=[CH:21][C:14]=2[N:15]=1
Reactant: ICI
Reactant: CC1Cc2cc3nc(N)n[n+]([O-])c3cc2C1
Agent: [Cu]I
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: CC1Cc2cc3nc(I)n[n+]([O-])c3cc2C1
Yield: 66.7 %

Procedure:
tert-Butyl nitrite (2.5 mL, 18.6 mmol) was added a stirred mixture of amine 94 (1.30 g, 6.0 mmol), diiodomethane (4.8 mL, 60 mmol) and CuI (1.2 g, 6.3 mmol) in THF (50 mL) and the mixture stirred at reflux temperature for 3 h. The solution was cooled and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (20-50%) of EtOAc/pet. ether, to give chloride 100 (1.31 g, 67%) as a pale yellow solid: mp (EtOAc/pet. ether) 140-142° C.; 1H NMR δ 8.15 (s, 1H, H-9), 7.70 (s, 1H, H-5), 3.20-3.30 (m, 2H, CH2), 2.65-2.79 (m, 3H, H-7, CH2), 1.20 (d, J=6.4 Hz, 3H, CH3); 13C NMR δ 155.5, 149.9, 147.6, 133.4, 122.5, 121.7, 114.6, 41.3, 41.0, 35.0, 20.2. Anal. calcd for C11H10IN3O: C, 40.4; H, 3.1; N, 12.9. Found: C, 40.6; H, 3.0; N, 12.7%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][OH:14])[C@H:9]([O:11][CH3:12])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C>CS(C)=O.C(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=[O:14])[C@H:9]([O:11][CH3:12])[CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: CO[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CO[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice cold solution of ((1R,2R)-1-hydroxymethyl-2-methoxy-propyl)-carbamic acid t-butyl ester (5 g, 22 mmol) in DMSO (20 mL) and DCM (250 mL) was added DIEA (12 mL, 69 mmol), followed by dropwise addition of a solution of Py.SO3 (11 g, 69 mmol) in DMSO (50 mL, +20 mL to rinse the funnel). The reaction mixture was stirred at rt for 5 h. After removal of the DCM, the residue was diluted with Et2O (400 mL) and washed with H2O (2×100 mL) and brine (150 mL). The aqueous layer was back extracted with Et2O (100 mL). The combined Et2O layer was washed with saturated NaHCO3 (150 mL) and dried (Na2SO4). The solvent was removed to give the titled compound. MS (MH+ 218).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].O>[CH2:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:9]1[O:11][CH2:10]1
Reactant: ClCC1CO1
Reactant: CCCCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCOCC1CO1
Temperature: 115 °C
Yield: 113.2 %

Procedure:
n-Pentanol (88 g) and 6.82 g of zinc chloride were heated to 100° C. while stirring, followed by the dropwise addition of 138.8 g of epichlorohydrin over 1 hour. The reaction mixture was heated to 115° C. and reacted for 5 hours. After completion of the reaction, the reaction mixture was cooled to 50° C. While maintaining the temperature at 50° C., 92 g of a 48% aqueous solution of sodium hydroxide was added dropwise over 1 hour. After stirring for 3 hours, 150 mL of water was added to the reaction mixture to cause separation. The water layer thus formed was then removed and the residue was washed twice with 100 mL of water, whereby 163 g of crude pentyl glycidyl ether was obtained.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>O1CCCC1>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2ccccn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C#Cc1ccc(-c2ccccn2)cc1
Yield: 89.6 %

Procedure:
A solution of (2) (2.26 g, 8.97 mmol) and tetrabutylammonium fluoride (1 M in tetrahydrofuran, 36 mL, 36 mmol) in tetrahydrofuran was stirred at room temperature under argon for 3 hours. Dichloromethane (100 mL) and water (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous magnesium sulfate, filtered and the solvent completely removed. The residue was purified by passing through a silica plug using dichloromethane as eluent to give (3) (1.44 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].C(OC([N:21]1[CH:26]([C:27]2[CH:32]=CC=C[CH:28]=2)[CH2:25][C:24]2[NH:33][N:34]=[CH:35][C:23]=2[CH2:22]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:21]2[CH:26]([CH:27]([CH3:32])[CH3:28])[CH2:25][C:24]3[NH:33][N:34]=[CH:35][C:23]=3[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2CC1c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C1Cc2[nH]ncc2CN1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Benzyl 2-isopropyl-4-oxopiperidine-1-carboxylate, prepared as described for compound 67 in Example 3 using isopropylmagnesium chloride, was formylated and treated with hydrazine hydrate as described for compound 50 in Example 1 to give benzyl 6-isopropyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate. This compound was then deprotected and treated with 4-chlorophenylsulfonyl chloride followed by NaOH as described for compound 52 in Example 1. The enantiomers were separated using HPLC Method [2].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[C:8]2[C:3]=1[C:4](=[O:16])[CH2:5][CH2:6][S:7]2.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[C:8]2[C:3]=1[C:4](=[O:16])[C:5](=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:6][S:7]2
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc(Cl)c2c1SCCC2=O
Product: COC(=O)c1ccc(Cl)c2c1SCC(=CN(C)C)C2=O
Yield: 97 %

Procedure:
30 g (0.078 mol) of methyl 5-chloro-4-oxothiochromane-8-carboxylate in 300 ml of N,N-dimethylformamide dimethyl acetal were refluxed for 6 hours. Volatile components were then distilled off, the residue was taken up in methylene chloride and the organic phase was washed with water. Drying and removal of the solvent gave 35.3 g (97%) of methyl 5-chloro-3-(N,N-dimethylaminomethylidene)-4-oxothiochromane-8-carboxylate.
Reaction SMILES: Cl[CH2:2][Si:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[O:4]C(C)C.[Na].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([Si:3]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([OH:4])[CH2:2][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:9][CH:10]=1
Reactant: CC(C)O[Si](CCl)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: O[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 30.9 %

Procedure:
A mixture of 10.0 g (30.6 mmol) of chloromethyl[bis(4-fluorophenyl)](2-propoxy)silane and 3.1 g (30.6 mmol) of 1,2,4-triazole sodium salt in dimethylformamide was stirred at 80°-90° under nitrogen for 2 hours. Workup as in Example 37 gave a waxy solid that was washed with 1:1 ether-hexanes to leave 3.0 g (30%) of the title compound. Recrystallization from chlorobutane gave a purer sample: m.p. 130°-131°; nmr (CDCl3) 4.1 (2H, s), 5.8 (1H, broad s), 7.1 (4H, t), 7.7 (4H, d of d), 7.8 (1H, s), 8.0 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[C:5]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[O:6].C1C(=O)N([Br:24])C(=O)C1>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([CH2:16][Br:24])[CH:13]=[CH:12][C:4]=1[C:5]([NH:7][S:8]([CH3:11])(=[O:9])=[O:10])=[O:6]
Reactant: COc1cc(C)ccc1C(=O)NS(C)(=O)=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1C(=O)NS(C)(=O)=O
Yield: 56.5 %

Procedure:
2-Methoxy-4-methyl-N-(methylsulfonyl)benzamide (Preparation 24, 500 mg, 2.06 mmol), N-bromosuccimide (402 mg, 2.36 mmol), azobisisobutyronitrile (10 mg, 0.06 mmol) and carbon tetrachloride (20 mL) were combined and stirred at reflux under nitrogen, whilst being irradiated with light from a lamp for 1 hour. After cooling, the mixture was evaporated, the residue suspended in water (30 mL) and extracted with EtOAc (1×30 mL). The organic layer was separated, washed with saturated brine (2×20 mL), dried over sodium sulfate, filtered and evaporated to give a solid, which was triturated with diethyl ether:hexane (1:4) to yield the title compound as a white solid (375 mg, 57%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:43])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:44])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:43])[NH:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)cc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc(C(=O)NCc3ccc(F)cc3)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 65 %

Procedure:
A solution of (2S)-ethyl 2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-((4-fluorobenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (12 mg, 0.020 mmol) and 1M NaOH (0.079 mL, 0.079 mmol) in MeOH (1 mL) was heated at 60° C. for 16 h. Then, the reaction mixture was cooled and purified by prep HPLC to afford (2S)-2-(tert-butoxy)-2-(7-(8-fluoro-5-methylchroman-6-yl)-2-((4-fluorobenzyl)carbamoyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (8 mg, 0.013 mmol, 66.4% yield) as white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ: 7.31 (dd, J=8.5, 5.5 Hz, 2H), 7.26 (t, J=6.4 Hz, 1H), 7.21 (s, 1H), 7.05-6.99 (m, 2H), 6.87 (d, J=10.7 Hz, 1H), 5.02 (s, 1H), 4.60 (d, J=6.4 Hz, 2H), 4.35-4.32 (m, 2H), 2.77 (s, 3H), 2.76-2.71 (m, 2H), 2.20-2.14 (m, 2H), 1.85 (s, 3H), 1.19 (s, 9H). LCMS (M+H)=579.4.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32](C)[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(OC(Cl)C)=O.[I-].[Na+]>ClCCCl>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Agent: CC(Cl)OC(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(N2CCNCC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Yield: 63.6 %

Procedure:
Into a 50 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 50 mg (0.115 mmol, 1.0 equiv.) of 6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Example 31) and 10 mL of 1, 2 dichloroethane. To this solution is then added via syringe 49 mg, 37 μL (0.345 mmol, 3.0 equiv.) of 1-chloroethyl chloroformate. A precipitate forms, indicating formation of an intermediate. The reaction is heated to reflux for 3 days, whereupon an analysis of an aliquot by LC/MS indicates only a trace of product has formed. At this time 52 mg (0.345 mmol, 3.0 equiv.) of sodium iodide are added to the refluxing reaction. LC/MS analyses then progressively show formation of demethylated product over 5 additional days. The reaction is then cooled, concentrated on a rotary evaporator, then dried over K2CO3 as a suspension in methylene chloride containing methanol, removal of solids by filtration, followed by flash chromatography of the solution, using a gradient of 5 to 20% methanol in methylene chloride, gives 34 mg (64%) of the pure product as a reddish solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]4[CH:28]=[CH:29][CH:30]=[C:19]34)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[O:31][CH3:32])([CH3:4])[CH3:3].[H-].[Na+].[CH3:35]I>C1COCC1.CN(C=O)C>[CH3:32][O:31][C:6]1[CH:7]=[C:8]([C:11]([N:13]2[CH2:14][CH2:15][C:16]3([O:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]4[CH:28]=[CH:29][CH:30]=[C:19]34)[CH2:17][CH2:18]2)=[O:12])[CH:9]=[CH:10][C:5]=1[C:2]([O:1][CH3:35])([CH3:3])[CH3:4]
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1C(C)(C)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)ccc1C(C)(C)OC
Reaction time: 0.03 h
Yield: 35 %

Procedure:
(4-(2-Hydroxypropan-2-yl)-3-methoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (crude material from step 1) was dissolved in a mixture of THF (3 mL) and DMF (3 mL). NaH (28 mg, 0.69 mmol) was added and the reaction mixture was allowed to stir for 2 minutes. MeI (54 μL, 0.86 mmol) was then added and the reaction mixture was allowed to stir for 1 h. The reaction mixture was evaporated to dryness and the residue was suspended in 25 mL of dichloromethane. The suspension was washed two times with a 1M solution of hydrochloric acid, followed by two washes with a saturated aqueous solution of sodium bicarbonate, followed by two washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified by column chromatography utilizing a gradient of 0-35% ethyl acetate in hexanes give (3-methoxy-4-(2-methoxypropan-2-yl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (94 mg, 35% over 2 steps). ESI-MS m/z calc. 446.2, found 447.5 (M+1)+; Retention time: 7.60 minutes (15 min run). 1H NMR (400 MHz, DMSO) δ 7.68-7.65 (m, 1H), 7.50-7.49 (m, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.17-6.98 (m, 5H), 6.29-6.28 (m, 1H), 6.18-6.17 (m, 1H), 4.49-4.34 (m, 1H), 3.83 (s, 3H), 3.80-3.41 (m, 3H), 3.13 (s, 3H), 2.11-1.81 (m, 4H) and 1.50 (s, 6H).
Reaction SMILES: F[P:2](F)([C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].C([SiH](CC)CC)C.FC=C>>[F:9][C:3]([P:2]([C:10]([F:15])([F:16])[C:11]([F:12])([F:13])[F:14])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: FC(F)(F)C(F)(F)P(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: C=CF
Agent: CC[SiH](CC)CC
Product: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Yield: 82.8 %

Procedure:
56.0 g (131.4 mmol) of difluorotris(pentafluoroethyl)phosphorane and 38.0 g (326.8 mmol) of triethylsilane were refluxed with vigorous stirring for 12 hours in an FEP (fluoroethylene polymer) flask at a bath temperature of 110° C. The reaction mixture was subsequently distilled under atmospheric pressure under an inert-gas atmosphere, and 48.0 g of the fraction having a boiling range of 81–85° C. were collected. This fraction was subsequently cooled to −20° C., and the lower phase (desired product) was separated off. 42.2 g of virtually pure tris(pentafluoroethyl)phosphine were obtained, corresponding to a yield of 82.8%, based on the difluorotris(pentafluoroethyl)phosphorane employed.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br>>[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH:21][CH:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)CBr
Reactant: NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Product: COC(=O)CNC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 20.1 %

Procedure:
The title compound (24 mg, 21%) was prepared from the compound from Example 12 (120 mg, 0.35 mmol) and 2-bromoacetic acid methyl ester (53 mg, 0.35 mmol) by the procedure described in step 1 of Example 1: MS (ESI) m/z 341 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.51-1.61 (m, 4H), 1.95 (br, 2H), 2.61 (m, 11H), 2.75 (dd, J=2.4, 12 Hz, 2H), 3.56 (m, 2H), 3.75 (s, 3H), 6.90-6.96 (m, 6H), 7.03 (m, 1H), 7.28 (m, 2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:18])[F:17])[CH2:10][C:11]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:13])=[CH:5][C:4]=1[C:19]([F:20])([F:21])[F:22])#[N:2]
Reactant: Nc1ccccc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CC(=O)Nc2ccccc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and aniline: MS (APCI) m/z 402 (M+1).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[CH3:21][C:22]1[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]#[N:31])[CH:25]=[CH:24][N:23]=1>>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]2[CH:10]=[C:28]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=3)[CH:29]=[C:30]([NH2:31])[N:12]2[N:13]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: Cc1cc(/C=C/C#N)ccn1
Product: Cc1cc(-c2cc(N)n3nc(-c4ccco4)nc3c2)ccn1

Procedure:
The title compound, mp. 100-101° C. and MS (EI) m/e (%): 291 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and (E)-3-(2-methyl-pyridin-4-yl)-acrylonitrile.
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH:5](C(OC)=O)[C:6]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[F:16])=[O:7])[CH2:3][CH2:2]1>C(#N)C.O.Cl>[CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[F:16])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)C(C(=O)c1sc(C)c(OC)c1F)C(=O)C1CC1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: COc1c(C)sc(C(=O)CC(=O)C2CC2)c1F
Yield: 65.4 %

Procedure:
A solution of 3-cyclopropyl-1-(4-fluoro-3-methoxy-2-methylthiophenyl)-2-methoxycarbonyl-propane-1,3-dione (0.15 g) in a mixture of acetonitrile/water (95:5) containing 3 drops of hydrochloric acid (2M) was heated at reflux for 44 hours, cooled, dried (magnesium sulphate) and evaporated to give the title compound (0.08 g), NMR 0.9 (m, 2H), 1.1 (m, 2H), 1.65 (m, 1H), 2.37 (s, 3H), 3.96 (s, 3H), 4.15 (s, 1H), 5.9 (s, 1H), 6.95-7.15 (m, 2H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]([N:29]1[CH2:33][C@@H:32]([S:34][CH3:35])[CH2:31][C@H:30]1[CH2:36][O:37][Si](C(C)(C)C)(C)C)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]([N:29]1[CH2:33][C@@H:32]([S:34][CH3:35])[CH2:31][C@H:30]1[CH2:36][OH:37])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS[C@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
85.5 ml (85.5 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran were added to a solution of 30.74 g (77.7 mmol) of (2S,4S)-1-benzyloxycarbonyl-2-(t-butyldimethylsilyloxy)methyl-4-methylthiopyrrolidine [obtained as described in Preparative Example in 12(iii)′ above] in 155 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature overnight. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 21.87 g (yield: quantitative) of the title compound as a yellow oil.
Reaction SMILES: C([NH:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])(OC(C)(C)C)=O.O1CCOCC1>Cl>[NH2:8][C:9]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[S:11][C:10]=1[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19]
Reactant: C=CCOC(=O)c1sc(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC(=O)c1sc(C(C)(C)C)cc1N
Reaction time: 120 h
Yield: 89.7 %

Procedure:
Allyl 3-(N-carbo-tert-butoxyamino)-5-tert-butylthiophene-2-carboxylate (0.14 g, 0.41 mmol) was dissolved in solution of HCl in dioxane (4N, 11.0 mL, 4.1 mmol, 10 equiv). The resulting solution was stirred at room temp. for 5 d, diluted with CHCl, (5 mL), washed with a 1N HCl solution (5 mL) and a saturated NaCl solution (5 mL), dried Na2SO4), and concentrated under reduced pressure. The residue was filtered through a plug of SiO2 with the aid of a 10% EtOAc/CH2Cl2 solution to give allyl 3-amino-5-tert-butylthiophene-2-carboxylate as a yellow oil (0.088 g, 95%): 1H NMR (CDCl3) δ1.32 (s, 9H), 4.72 (ddd, J=4.1, 1.5, 1.5 Hz, 2H), 5.21 (ddd, J=10.3, 2.9, 1.5 Hz, 1H), 5.36 (ddd, J=17.3, 3.1, 1.5, 1H), 5.42 (br s, 2H), 5.92-6.03 (m, 1H), 6.34 (s, 1H). This material was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1B(O)O)(=[O:20])[CH3:19].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 41.1 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 218a (130 mg, 0.44 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclo-penta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (175 mg, 0.44 mmol), PdCl2(dppf) (36 mg, 0.044 mmol), K3PO4 (343 mg, 1.32 mmol), sodium acetate (108 mg, 1.32 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 218b as a red solid (103 mg, 42%). MS-ESI: [M+H]+ 570.2