Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2].[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2C=C(S([O-])(=O)=O)C=C[C:29]=2C)=[CH:24][CH:23]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([C:3]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)([CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#CC(Cc1cccnc1)c1ccc(Cl)cc1
Reactant: COc1ccc(-c2cc(S(=O)(=O)[O-])ccc2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CCC(C#N)(Cc2cccnc2)c2ccc(Cl)cc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
1-Cyano-1-(4-chlorophenyl)-2-(3-pyridyl)ethane (4.0 gms, 0.0165 m) was placed in a 100 ml three neck flask, under a nitrogen atmosphere, equipped with a magnetic stirrer, thermometer, gas inlet tube and a cooling bath. To the flask was added 50 ml DMF-toluene (1:2), and the resulting solution was cooled to 5° C. Sodium hydride (0.4 gm, 0.018m of 60% NaH) was added and the mixture was stirred for 30 minutes. Then 4-methoxyphenyl-p-toluene-sulfonate (5.0 gm, 0.0165 m) was added and the mixture was stirred for 1 hour at 5° C., followed by stirring at room temperature for another 2 hours. The reaction mixture was quenched with water (10 ml), then placed in a separatory funnel using methylene chloride (200 ml) as a rinse. The organic layer of methylene chloride was washed with water (5×100 ml) and brine (100 ml), then dried. Solvent removal followed by column chromatographic purification afforded 3.6 gms of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](OC)=O)[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]#[N:20]>CN(C=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH:7]3[CH2:11][NH:20][CH2:19][CH2:18][N:8]3[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: Clc1ccc2c(c1)N1CCNCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 165.8 %

Procedure:
To a stirred solution of methyl 6-chloroindole-2-carboxylate (9.8 g, 46.7 mmol) (D. Knittel, Synthesis, 1985, 2, 186-188) in DMF (80 mL) under Ar at ambient temperature was added sodium hydride (60%; 2.80 g, 70 mmol) portionwise over 10 min. After 30 min, chloroacetonitrile (5.9 mL, 93.2 mmol) was added dropwise and the resultant mixture was heated at 75° C. (bath temp.) for 45 min, then allowed to cool. The reaction mixture was poured onto ice (500 mL) and the solid product was filtered, washed with ice-cold water (100 mL), and triturated with refluxing ethanol (150 mL). After allowing to cool to ambient temperature, then cooling in ice, the solid product was filtered-off and washed with ice-cold ethanol (50 mL) to afford the title compound (9.49 g, 82%) as a light grey solid: mp 177-8° C.; IR νmax (Nujol)/cm−1; 3094, 2955, 2925, 2854, 1713, 1613, 1568, 1527, 1519, 1448, 1421, 1398, 1378, 1336, 1306, 1260, 1150, 1108, 1060, 943, 908, 834, 802, 761, 737, 682, 618, 597, 518 and 478; NMR δH (400 MHz, DMSO-d6) 3.95 (3H, s), 5.56 (2H, s), 7.22 (1H, dd, J 8.5, 2 Hz), 7.34 (1H, d, J 1 Hz), 7.43 (1H, br s) and 7.62 (1H, d, J 8.5 Hz).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.Cl.[Br:10][C:11]1[CH:12]=[C:13]([NH:17]N)[CH:14]=[CH:15][CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]2[N:17]=[CH:7][C:4]3([CH2:5][CH2:6][S:1][CH2:2][CH2:3]3)[C:14]2=[CH:15][CH:16]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[N:17]=[CH:7][C:4]3([CH2:5][CH2:6][S:1][CH2:2][CH2:3]3)[C:12]=12
Reactant: O=CC1CCSCC1
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c(c1)N=CC21CCSCC1
Product: Brc1cccc2c1C1(C=N2)CCSCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred ice cooled solution of tetrahydro-2H-thiopyran-4-carbaldehyde (2.1 g, 16.1 mmol) in DCM (30 mL) was added 3-bromophenylhydrazine hydrochloride (1.0 eq., 3.6 g) in one portion. The resulting mixture was stirred at 0° C. for 10 min before TFA (3.0 eq., 5.52 g) was added dropwise via syringe. The resulting mixture was stirred at 0° C. for 10 min and then at rt for 4 h. After this time the mixture was poured into ice and NH3H2O (28%) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was dissolved in benzene and evaporated in vacuo to give 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran] and 4-bromo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran] in a ratio of 1 to 1.3. Mass Spectrum (ESI) m/e=282.0 [(M+1) (79Br)] and 284.0 [(M+1) (81Br)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].S(=O)(=O)(O)O.[CH:22]([OH:25])(C)C>CC(C)=O.C(OCC)C.CO.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([C:14]([O:25][CH3:22])=[O:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CC(C)O
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
A solution of (5R)-(−)-3-[3-fluoro-4-iodophenyl]-5-hydroxymethyl-2-oxazolidinone (Step 1, 7.61 g, 22.58 mmol) in acetone (150 mL) at —10° C. is treated with a mixture of CrO3 (6.21 g, 62.1 mmol) in sulfuric acid (6M, 16.9 mL, 101 mmol) dropwise over 15 minutes. The resulting mixture is allowed to slowly warm to ambient temperature with vigorous stirring (slight exotherm to 35° C.) and is stirred for an additional 16 h. The mixture is then treated with isopropanol (35 mL), diluted with saline (150 mL) and diethyl ether (150 mL), stirred until all solids are dissolved, and the layers are separated. The aqueous phase is extracted with diethyl ether (100 mL), and the combined organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude carboxylic acid intermediate which is taken up in methanol (225 mL) and treated with concentrated sulfuric acid (8 drops). The resulting homogeneous mixture is stirred at ambient temperature for 20 h and is then concentrated under reduced pressure to give the crude methyl ester product which is chromatographed on two Flash 40M 90 g silica gel (32-63 μm) cartridges, eluting with a gradient of ethyl acetate/heptane (20/80-40/60). Pooling and concentration of those fractions with an Rf=0.36 by TLC (ethyl acetate/hexane, 50/50) gives the title compound, mp 106-109° C.; MS (ESI+) for C11H9FINO4 m/z 366 (M+H)+; [α]25D=−30 (c 0.93, DMSO).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26].ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (15.0 mg, 0.0359 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (13.6 mg, 0.0430 mmol) (Peak I), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1.8 mg, 0.0022 mmol) and potassium phosphate (22.8 mg, 0.108 mmol) in 1,4-dioxane (0.48 mL) and water (0.24 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=482.1.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH3:14].CON(C)[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:12]2[C:7]([Cl:6])=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[Cl:13])=[O:26])=[CH:20][CH:21]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(C(=O)c2ccc(Cl)cc2)c1Cl
Reaction time: 1 h
Yield: 55.1 %

Procedure:
n-BuLi (1.6M, 76 ml) was added dropwise to a solution of 2,4-dichlorotoluene (16.7 ml, 121 mmol) in dry THF (125 ml) at -78° C. under a nitrogen atmosphere. After 1 h a solution of N-methoxy-N-methyl-4-chlorobenzamide (24.26 g, 1 eq.) in dry THF (50 ml) was added slowly to the reaction mixture and the stirring was continued for an additional 1 h. The reaction was then quenched with 1M NH4Cl, and allowed to room temperature. The solvent was removed in vacuo and the resulting mixture was diluted with ether. The organic layer was separated, washed with 1M NH4Cl, water, and brine, and dried over MgSO4. The solvent was removed in vacuo to give an oil, which upon crystallization from hexanes gave 3-(4-chlorobenzoyl)-2,4-dichlorotoluene (19.98 g) as white crystals, mp 132.0°-135.8° C.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[CH:12][C:11]2[C:14]([CH3:18])([CH3:17])[CH2:15][NH:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][C:21](Cl)=[O:22].C(O)(=O)C.C(O)(=O)C.[F:32][CH2:33][CH:34]1[CH2:39][NH:38][CH2:37][CH2:36][NH:35]1>>[CH2:1]([C:8]1[N:13]=[CH:12][C:11]2[C:14]([CH3:18])([CH3:17])[CH2:15][N:16]([C:21](=[O:22])[CH2:20][N:38]3[CH2:37][CH2:36][NH:35][CH:34]([CH2:33][F:32])[CH2:39]3)[C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CNc2cc(Cc3ccccc3)ncc21
Reactant: FCC1CNCCN1
Solvent: CC(=O)O
Product: CC1(C)CN(C(=O)CN2CCNC(CF)C2)c2cc(Cc3ccccc3)ncc21

Procedure:
Prepared in an analogous method to that described in Prep 203 using 6-benzyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine, chloroacetyl chloride and 2-fluoromethyl-piperazine, diacetate salt. The product was purified by preparative HPLC (basic method) to provide the title compound (0.05 g). 1H NMR (Me-d3-OD): 8.24 (1H, s), 7.93 (1H, s), 7.36-7.14 (5H, m), 4.53-4.39 (1H, m), 4.39-4.26 (1H, m), 4.10 (2H, s), 4.05-3.66 (3H, m), 3.52-3.37 (2H, m), 3.25-2.76 (5H, m), 2.31 (1H, d), 2.25-2.08 (1H, m), 1.42 (6H, s). MS: [M+H]+=397.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)([C:14]([OH:16])=O)[CH:11]=[CH:10]1)=O)(C)(C)C.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:38]=[C:37]2[C:32]([CH2:33][CH2:34][NH:35][CH2:36]2)=[CH:31][CH:30]=1.[O:41]1[CH2:46][CH2:45]C(=O)[CH2:43][CH2:42]1>>[O:41]1[CH2:46][CH2:45][CH:6]([NH:8][C@@H:9]2[CH2:10][C@H:11]3[O:19][CH2:18][CH2:17][C@@:12]3([C:14]([N:35]3[CH2:34][CH2:33][C:32]4[C:37](=[CH:38][C:29]([C:28]([F:27])([F:39])[F:40])=[CH:30][CH:31]=4)[CH2:36]3)=[O:16])[CH2:13]2)[CH2:43][CH2:42]1
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO[Si](C)(C)C(C)(C)C)(C(=O)O)C1
Product: O=C(N1CCc2ccc(C(F)(F)F)cc2C1)[C@@]12CCO[C@@H]1C[C@@H](NC1CCOCC1)C2

Procedure:
The title compound was prepared from reaction of the product of Step B of Example 1 and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline following the procedure described in Example 1, Step C, following Steps D through G, and then using tetrahydro-4H-pyran-4-one following the procedure described in Example 1, Step H.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([F:35])=[CH:29][C:28]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.CS(OCCCC1CCCC1)(=O)=O>>[CH:25]1([CH2:20][CH2:19][CH2:18][N:39]2[CH2:40][CH2:41][N:36]([C:28]3[CH:29]=[C:30]([F:35])[C:31]([O:33][CH3:34])=[CH:32][C:27]=3[F:26])[CH2:37][CH2:38]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrCCc1ccccc1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: COc1ccc(N2CCNCC2)cc1
Agent: CS(=O)(=O)OCCCC1CCCC1
Agent: Cl
Product: COc1cc(F)c(N2CCN(CCCC3CCCC3)CC2)cc1F

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (342 mg) and 3-cyclopentylpropyl methylsulfonate (309 mg), respectively, to provide crude 1-(3-cyclopentylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (486 mg).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]=[N+]=[N-])=[CH:8][C:7]=1[NH:16][C:17](=[O:35])[CH2:18][CH:19]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:5])([CH3:4])[CH3:3]>CC(C)=O.[Zn]>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][C:7]=1[NH:16][C:17](=[O:35])[CH2:18][CH:19]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:3])([CH3:4])[CH3:5]
Reactant: CCCCCC(CC(=O)Nc1cc(CN=[N+]=[N-])ccc1C(C)(C)C)c1ccc(OC)cc1OC
Agent: Cl
Agent: [Zn]
Solvent: CC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reaction time: 1 h
Yield: 87.3 %

Procedure:
301 mg (4.60 mmol) of zinc dust and then 5 ml of 2 N aqueous hydrochloric acid were added to a solution of 430 mg (0.92 mmol) of N-(2-t-butyl-5-azidomethylphenyl)-3-(2,4-dimethoxyphenyl)octanamide [prepared as described in step (i) above] in 10 ml of acetone, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was filtered to remove zinc dust, and the filtrate was made alkaline by adding a saturated aqueous solution of sodium hydrogencarbonate. The mixture was then extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 354 mg (yield 86%) of the title compound as a foam-like substance.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:33]=[N:32][CH:31]=[C:30]([N:34]3[CH2:46][CH2:45][C:44]4[N:43]5[C:38]([CH2:39][CH2:40][CH2:41][CH2:42]5)=[CH:37][C:36]=4[C:35]3=[O:47])[C:27]=2[CH:28]=[O:29])=[CH:3]1.[BH4-].[Na+]>CO>[OH:29][CH2:28][C:27]1[C:26]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH:22]5[CH2:25][O:24][CH2:23]5)[CH2:20][CH2:21]4)=[CH:12][N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:33][N:32]=[CH:31][C:30]=1[N:34]1[CH2:46][CH2:45][C:44]2[N:43]3[C:38]([CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:37][C:36]=2[C:35]1=[O:47]
Reactant: Cn1cc(-c2cncc(N3CCc4c(cc5n4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2cncc(N3CCc4c(cc5n4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
A mixture of 112f (130 mg, 0.20 mmol) and NaBH4 (20 mg, 0.5 mmol) in MeOH (5 mL) was stirred at 0° C. for 0.5 h. The mixture was quenched with water and extracted with EtOAc (5 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 112 (48 mg, 34%). LCMS: [M+H]:637. 1H NMR (500 MHz, DMSO) δ 8.58 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.86 (d, J=2.4, 1H), 7.37-7.36 (m, 2H), 7.23-7.21 (m, 1H), 6.02 (s, 1H), 5.02 (s, 1H), 4.54 (t, J=6.5, 2H), 4.45 (t, J=5.5, 2H), 4.36-4.35 (m, 2H), 4.00-3.79 (m, 4H), 3.59 (s, 3H), 3.43-3.41 (m, 1H), 3.07-2.96 (m, 6H), 2.70 (t, J=6.0, 2H), 2.39-2.38 (m, 4H), 1.92-1.90 (m, 2H), 1.75-1.73 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[OH:12][NH3+:13].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[N:13][OH:12])[NH2:5]
Reactant: [NH3+]O
Reactant: N#Cc1cccc(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.0 g (35.2 mmol) of 2,3-difluorobenzonitrile were initially charged in 43 ml of ethanol, and a solution of 3.7 g (52.8 mmol) of hydroxylammonium chloride and 5.9 ml (4.3 g, 42.3 mmol) of triethylamine was added at RT. The reaction mixture was stirred at RT for 16 h, concentrated under reduced pressure, taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic extracts were dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 5.7 g (94% of theory)
Reaction SMILES: C=C1C[CH2:6][CH:5]([C:8]2[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:11]3[N:31]=[CH:32][CH:33]=[C:10]3[N:9]=2)[CH2:4]C1.C[N+]1([O-])CC[O:38][CH2:37]C1.[CH3:42][C:43]([CH3:45])=[O:44].O.CC#N>O=[Os](=O)(=O)=O>[CH3:21][Si:19]([CH3:20])([CH3:22])[CH2:18][CH2:17][O:16][CH2:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:12]1[N:11]2[N:31]=[CH:32][CH:33]=[C:10]2[N:9]=[C:8]([CH:5]2[CH2:6][CH2:45][C:43]([CH2:37][OH:38])([OH:44])[CH2:42][CH2:4]2)[CH:13]=1
Reactant: C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(O)(CO)CC2)nc2ccnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of 5-(4-methylenecyclohexyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (4.89 g, 10.0 mmol) in Acetone/H2O/MeCN (60/20/20) was added NMO (4.15 mL, 20 mmol), followed by OsO4 (2.5 wt. % in tBuOH) (6.27 mL, 0.50 mmol) at rt. The resulting reaction mixture was stirred at rt overnight. Organic solvent were evaporated and the aqueous residue was extracted with EtOAc three times, dried over Na2SO4 and concentrated to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol as a pale brownish oil (5.52 g), which was used without further purification. HPLC-MS TR=2.48 min (UV 254 nm, 5 min method); mass calculated for formula C25H46N4O4Si2 522.3, observed LCMS m/z 523.3 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]#[C:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[CH:10][CH:9]=1.O.[OH-].[Li+].Cl>CO.C1COCC1.O>[NH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][C@@H:4]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:3]([OH:27])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](C#CCc1ccc(CCCCN)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCN)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
Compound 240 (0.40 g, 0.780 mmol) was dissolved in a mixture of methanol and THF (10 mL, 1/1, v/v). To the solution was added lithium hydroxide monohydrate (0.063 g, 1.561 mmol) dissolved in water (1 mL). The reaction mixture was stirred at room temperature for two hours, and then neutralized with 2N aqueous HCl solution to pH 5. The mixture was then concentrated under vacuum. The residue was taken into ethanol (3 mL) and the resulting solution was concentrated again under vacuum. The procedure was repeated two more times to ensure no aqueous solvent remained. The residue was chromatographed over silica gel, eluting with a mixture of concentrated ammonium hydroxide (0-10%), methanol (0-30%), and dichloromethane (100-60%), to afford the product 280 (0.29 g, 75%) as a white solid. 1H NMR (300 MHz, CD3OD): δ 1.46 (s, 9H), 1.58-1.78 (m, 8H), 2.54-2.68 (m, 4H), 2.85 (t, J=6.6 Hz, 2H), 3.98 (t, J=6.5 Hz, 1H), 7.08 (s, 4H), 8.50 (s, 1H). m/z (APCI) 365 [C20H32N2O4+H]+.
Reaction SMILES: [C:1]([N:8]=[N+]=[N-])(=[O:7])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[C:24]1([P:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8][C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:7])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of t-butyl carbonazidate in diethyl ether, 49.6 g (0.189 mol) of triphenylphosphine was added in small portions under cooling with ice, and the reaction solution was stirred at room temperature for 1 hour, and the precipitated solid was collected by filtration, washed with 200 mL of hexane and dried under reduced pressure to give 67 g of the desired product as white crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(C(C)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A stirred solution of methyl 5-acetyl-2-ethoxybenzoate (9.6 g, 0.043 mol) in a mixture of 1,4-dioxane (80 ml) and water (80 ml) was treated with 5N aqueous sodium hydroxide solution (44 ml, 0.217 mol). The mixture was stirred at room temperature for 18 hours then the solvents evaporated under vacuum. The residue was dissolved in water (100 ml), then this solution was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (4×100 ml). The organic extracts were combined, dried (Na2SO4) and evaporated under vacuum. Crystallization of the residue from ethyl acetate gave the title compound as a colorless solid (5.4 g, 60%), m.p. 122°-125° C. Found: C,63.20; H,5.81. C11H12O4 requires C,63.45; H,5.81%.