Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]([CH3:33])([CH3:32])[CH:5]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:23][CH2:22]3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH:6]1[CH2:8][CH2:7]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]([CH3:33])([CH3:32])[CH:5]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:22][CH2:23]3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH:6]1[CH2:7][CH2:8]1)(=[O:3])[NH2:2]
Reactant: CC(C)(C(N)=O)C(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C(N)=O)C(NC(=O)c1c[nH]c2ncc(C3CC3)nc12)C1CC1
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-carbamoyl-1-cyclopropyl-2-methyl-propyl)-amide (108 mg, 0.23 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL). The yellow reaction mixture was stirred for 3 h then concentrated The residue was redissolved in CH2Cl2 (4 ml) and ethylenediamine (0.5 mL) was added. The reaction mixture was stirred for 1 h then concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc) followed by trituration with Et2O to afford 44 mg (56%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-carbamoyl-1-cyclopropyl-2-methyl-propyl)-amide as a white solid. MS: (M+H)+=342; mp=222.0-224.0.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-][C:9]#[N:10].[B]>>[C:9]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])#[N:10]
Reactant: Oc1ccccc1
Reactant: N#C[S-]
Agent: [B]
Product: N#Cc1ccccc1O

Procedure:
The phenol (II) is allowed to react with a thiocyanate in the presence of a boron trihalogenide to give an intermediate compound (IIIa), and the boron compound (IIIa) is then treated with a strong base to give a 2-cyanophenol (Ia). Alternatively, the 2-cyanophenol (Ia) can be prepared via the thiocarboxyimidic acid ester (IVa) by stepwise hydrolysis. Thus, IIIa is at first treated with a weak base to give IVa, which is then treated with a strong base to give the 2-cyanophenol (Ia).
Reaction SMILES: [Br:1][C:2]1[C:8]([Cl:9])=[C:7]([Br:10])[CH:6]=[C:5]([Cl:11])[C:3]=1N.N(OC(C)(C)C)=O>CCO>[Br:1][C:2]1[CH:3]=[C:5]([Cl:11])[CH:6]=[C:7]([Br:10])[C:8]=1[Cl:9]
Reactant: Nc1c(Cl)cc(Br)c(Cl)c1Br
Agent: CC(C)(C)ON=O
Solvent: CCO
Product: Clc1cc(Br)c(Cl)c(Br)c1
Temperature: 50 °C

Procedure:
A stirred mixture of 2,4-dibromo-3,6-dichloroaniline (5.0 g), tert-Butyl nitrite (3.3 g) and EtOH (50 mL) was heated in a sealed tube at 50° C. for 2 hrs. The mixture was concentrated and the residue was purified by silica gel flash chromatography (hexanes eluant) to afford the title compound. MS m/z: 303 (M+H)+.
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:46])[CH:15]([C:20]1[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].O.OO.[O-:52]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([F:35])[CH:31]=1)[CH2:27][O:26][C:24]1[CH:25]=[C:20]([C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:46])=[O:52])[CH:21]=[C:22]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][CH:37]=2)[CH:23]=1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)c1cc(OCc2cc(F)cc(F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
To a solution of 4-benzyl-3-{2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (23.40 g, 36.73 mmol) in THF (180 mL) was added water (60 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (1.54 g, 36.73 mmol) and 30% H2O2 (16.65 mL, 146.92 mmol), drop-wise, maintaining the internal temperature below 5° C. The resulting cloudy solution was stirred at 0° C. for 20 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (97.9 mL, 146.92 mmol) and stirred at room temperature for 15 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH 2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×200 mL), dried over MgSO4, and concentrated in vacuo resulting in a crude mixture which was purified by ISCO silica gel column chromatography to yield (R)-2-[5-(3,5-difluoro-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (12.25 g, 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:21]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: OCCn1ccc2cc(OCc3ccccc3)ccc21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OCCn1ccc2cc(OCc3ccccc3)ccc21

Procedure:
Crude N-(2-hydroxyethyl)-5-benzyloxyindole (11.09 g, 42.1 mmol), acetic anhydride (4.36 mL, 46.3 mmol), triethylamine (6.50 mL,46.3 mmol), and DMAP (100 mg) were stirred together in THF for 1 hour before standard aqueous workup provided N-(2-acetoxyethyl)-5-benzyloxyindole in yield as a clear oil (13.0 g, 99%). 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J=8.1 Hz, 2H), 7.42 (t, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.27 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.01 (dd, J=2.4, 8.1 HZ, 1H), 6.47 (dd, J=0.8, 3.1 Hz, 1H), 5.14 (s, 2H), 4.37 (t, J=5.0 Hz, 2H), 4.31 (t, J=5.0 Hz, 2H), 2.02 (s, 3H). 13C NMR (50 MHz, CDCl3) δ 170.6, 153.3, 137.7, 131.6, 128.9, 128.5 (2 C's), 128.4, 127.7, 127.5 (2 C's), 112.8, 109.8, 104.,3 101.4, 70.9, 63.0, 45.0, 20.7. MS (EI, m/z) M+=309.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[O:1]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:18]([F:19])([F:20])[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
11 g of methyl 4-phenoxy-3-trifluoromethylbenzoate were dissolved in 200 ml of MeOH, 41 ml of a 1 N aqueous solution of NaOH were added and the mixture was stirred at RT for 24 h. The MeOH was then removed in vacuo, and the remaining mixture was diluted with 1 l of water and the whole adjusted to a pH of 2 with an aqueous solution of HCl; the precipitate was then filtered off. The latter was air-dried for 48 h, resulting in 9.2 g of an amorphous solid.
Reaction SMILES: C([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([OH:13])[SiH](C)C)=[CH:6][CH:5]=1)C=C.[Br:16]Br>C(O)CC1C=CC=CC=1>[Br:16][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH2:9][OH:13])=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: C=CCc1ccc(CC(O)[SiH](C)C)cc1
Solvent: OCCc1ccccc1
Product: OCCc1ccc(Br)cc1

Procedure:
Hydroboration of 4-allyldimethylsilylphenethyl alcohol (1 Scheme 8) followed by Suzuki coupling reaction with the linker (2 Scheme 29) resulted in polymer-bound phenethyl alcohol compound (3 Scheme 29) which can be cleaved with bromine to give 4-bromophenethyl alcohol (4 Scheme 29).
Reaction SMILES: C([O-])(O)=O.[Na+].OC(C(F)(F)F)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:32][NH2:33])=[O:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:34]#[C:35]Br>O1CCOCC1>[NH2:34][C:35]1[O:31][C:30]([C@@H:25]2[CH2:24][CH2:23][C@@H:22]3[CH2:29][N:26]2[C:27](=[O:28])[N:21]3[O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:32][N:33]=1
Reactant: NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.8 %

Procedure:
Saturated NaHCO3 (7.0 mL, 6.26 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide TFA salt (2.3 g, 5.69 mmol) in dioxane (11.4 mL) and the reaction mixture was stirred at rt for 5 minutes. Cyanic bromide (3 M solution, 2.3 mL, 6.90 mmol) was added and the reaction mixture was stirred at rt for 30 minutes. The reaction mixture was then loaded on a silica gel cartridge and purified by silica gel column chromatography (gradient elution 0-10% MeOH/DCM) to give (2S,5R)-2-(5-amino-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diazabicyclo[3.2.1]octan-7-one (0.57 g, 32%). ESI-MS (EI+, m/z): 316.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H+].[B-](F)(F)(F)F.CCOCC.C1C(=O)N([Br:28])C(=O)C1>C(#N)C.OS([O-])=O.[Na+]>[Br:28][C:8]1[CH:7]=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cccc(O)c1
Agent: F[B-](F)(F)F
Agent: O=S([O-])O
Agent: [H+]
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1cc(O)ccc1Br
Temperature: 19 °C
Yield: 88.4 %

Procedure:
To a stirred solution of 3-cyanophenol (2.00 g, 18.0 mmol) in anhydrous acetonitrile (20 mL) under N2 at −30° C. was added dropwise 54% HBF4.Et2O (2.48 mL, 18.0 mmol). The temperature was maintained below −20° C. during addition. To this stirred solution was added NBS (3.27 g, 18.0 mmol) portion wise keeping the temperature below −10° C. After the addition was complete, the solution was allowed to warm to 19° C. The reaction mixture was diluted with 38% NaHSO3 (10 mL) and extracted with MTBE (2×25 mL). The organic layer was washed with H2O (2×25 mL) and brine (25 mL), dried (MgSO4), filtered, and concentrated to give a white solid (3.15 g). Purification of a portion of this product (1.0 g) by radial chromatography (30% EtOAc/hexane) gave 0.51 g of the title compound as a white solid. mp 183-184° C. Anal. Calculated for C7H4BrNO: C, 42.46; H, 2.04; N, 7.07. Found: C, 42.44; H, 1.93; N, 6.90.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11](=[O:44])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[CH:16][CH:15]=[C:14]([O:27][CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[CH:13]=3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[F:26][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[CH:13][C:14]([O:27][CH2:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]4)=[CH:15][CH:16]=3)[C:11](=[O:44])[C:10]=2[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc3C2=O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1F
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(3-(2-(3-fluoro-4-methoxyphenyl)-3-(3,5-difluorophenyl)-1-oxo-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate (96 mg, 0.2 mmol) obtained in Step 1 in CH2Cl2 was added trifluoroacetic acid (20 eq, 2.4 mmol). After being stirred for 1 h, the mixture was diluted with CH2Cl2 and basicified to pH 9 with a 3N NaOH solution. The organic layer was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[C:19]#[N:20]>C1COCC1>[NH2:20][C:19]([C:18]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=1[F:16])=[CH:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: COc1ccc(F)c(C#N)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)C=C(N)c1cc(OC)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Following the procedure of Huckin and Wilson (Can. J. Chem. 1974, p 1346), 850 mg of methyl acetoacetate (7.32 mmol, 1 eq.) were added slowly to a cooled (0° C.) and stirring suspension of NaH (60% dispersion in mineral oil, 1 eq.) in dry THF. When evolution of H2 had ceased (10 min.), 1.05 equivalents of n-butyllithium (2.5M in hexanes) were slowly added, producing an orange solution. After an additional 10 minutes at 0° C., 1 equivalent of 2-fluoro-5-methoxybenzonitrile (1.11 grams, 7.32 mmol) was added dropwise and the resulting red solution was allowed to come to room temperature. After stirring overnight (20 h) the reaction mixture was brought to 0° C. and quenched with 1.5 mL of 12M HCl followed by H2O (20 mL). The mixture was extracted with ether (4×) and the combined ether layers were washed (4×) with saturated aqueous NaCl solution, dried (Na2SO4) and concentrated to give a red oil. Purification via column chromatography (Silica gel, EtOAc/Hexanes eluent) afforded methyl 5-amino-3-oxo-5-(2-fluoro-5-methoxyphenyl)-pent-4-enoate as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:9]/[C:10](/[C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:26]\[OH:27])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1cnccn1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cnccn1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 3-(4-bromo-phenyl)-1-pyrazin-2-yl-3-o-tolyl-propan-1-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing about 10% of the corresponding Z isomer as a colorless foam, MS (ESI−): m/z=393.8 [M−H]−.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[CH2:6](Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C>C(OCC)(=O)C>[O:8]=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][O:4][C:1](=[O:5])[CH2:2][OH:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CO)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61 %

Procedure:
A mixture of 7.61 g of glycolic acid, 19.90 g of phenacylbromide and 13.9 ml of triethylamine in 300 ml of ethyl acetate was stirred for 20 hours at room temperature. Then, the mixture was filtered. The filtrate was washed with 2N HCl, saturated sodium bicarbonate, and brine. Then, the filtrate was dried, filtered again, and evaporated to dryness. The resulting white solid was purified by recrystallization to yield 11.85 g of colorless crystals.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH2:7][C:8]([P:14]([OH:17])([OH:16])=[O:15])([P:10]([OH:13])([OH:12])=[O:11])[OH:9])[CH:2]=1.C([O-])([O-])=O.[Na+:22].[Na+]>O>[CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH2:7][C:8]([P:10]([O-:12])([OH:13])=[O:11])([P:14]([OH:17])([OH:16])=[O:15])[OH:9])[CH:2]=1.[Na+:22]
Reactant: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(O)(Cc1cccnc1)P(=O)(O)O
Yield: 173.7 %

Procedure:
18.0 g of risedronic acid and 730 ml of deionized water are charged into a 1-liter reactor, equipped with mechanical stirrer and thermometer. The suspension, under stirring, is added with 3.4 g of Na2CO3. The admixture is kept under stirring for 30′, up to complete dissolution of the undissolved solids. The solution, whose pH is 4.57, is filtered on a paper filter and put into Lioguard chambers. The chambers are introduced into a lyophilizer and processed according to example 1. At the end 17 g of lyophilized amorphous sodium risedronate are thus obtained (yields 87.6%).
Reaction SMILES: N1([C:6]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=3[S:8](=[O:20])(=[O:19])[N:7]=2)C=CN=C1.[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>>[CH:21]([NH:25][C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:9]=2[S:8](=[O:20])(=[O:19])[N:7]=1)([CH2:23][CH3:24])[CH3:22]
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Reactant: CCC(C)N
Product: CCC(C)NC1=NS(=O)(=O)c2cc(C(=O)O)ccc2N1

Procedure:
3-(Imidazol-1-yl)-4H-1,2,4-benzothiadiazine-7-carboxylic acid 1,1-dioxide was treated with sec-butylamine according to the general procedure Method A to give the title compound; m.p. >310° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[C:10]([O:14][C:15](=[O:31])[CH2:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1)([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([O:14][C:15](=[O:31])[CH2:16][N:17]1[CH:21]=[C:20]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:9])[CH:19]=[N:18]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cc(-c2ccc(Br)cc2F)cn1
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-2-fluoro-1-iodobenzene (380 mg, 1.3 mmol) in THF (10 mL) was added tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate (390 mg, 1.3 mmol), 2M sodium carbonate in water (2.5 mL) and tetrakis(triphenylphosphine)palladium (40 mg, 0.04 mmol). The solution was degassed with N2, and heated at 80° C. overnight. The mixture was cooled to RT, poured into water, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatograph on a silica gel column with EtOAc in Hexanes (30%) to afford the desired compound. LCMS: (M+57)=299.0.
Reaction SMILES: [N:1]1[N:12]2[C:4]([N:5]=[C:6]3[C:10](=[C:11]2[C:13]2[CH:14]=[CH:15][C:16]4[O:20][C:19]([CH2:21][CH2:22]OS(C)(=O)=O)=[CH:18][C:17]=4[CH:28]=2)[CH2:9][CH2:8][CH2:7]3)=[CH:3][CH:2]=1.[CH3:29][N:30]([CH3:36])[C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:29][N:30]([CH3:36])[C@@H:31]1[CH2:35][CH2:34][N:33]([CH2:22][CH2:21][C:19]2[O:20][C:16]3[CH:15]=[CH:14][C:13]([C:11]4[N:12]5[C:4](=[CH:3][CH:2]=[N:1]5)[N:5]=[C:6]5[C:10]=4[CH2:9][CH2:8][CH2:7]5)=[CH:28][C:17]=3[CH:18]=2)[CH2:32]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3c4c(nc5ccnn35)CCC4)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)[C@@H]1CCN(CCc2cc3cc(-c4c5c(nc6ccnn46)CCC5)ccc3o2)C1
Temperature: 70 °C

Procedure:
Methanesulfonic acid 2-[5-(6,7-dihydro-5H-1,4,8a-triaza-s-indacen-8-yl)-benzo-furan-2-yl]-ethyl ester (0.085 mmol) described above was dissolved in acetonitrile (2 ml) followed by addition of 3-(R)-dimethylaminopyrrolidine (0.85 mmol) and potassium carbonate (0.425 mmol) and heated to 70° C. for 24 hours. The reaction was cooled, filtered and concentrated. The residue was purified via preparative HPLC to give 8-{2-[2-(3-(R)-Dimethylamino-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-6,7-dihydro-5H-1,4,8a-triaza-s-indacene.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>>[CH2:9]([CH2:8][CH:7]([NH2:6])[C:13]([OH:15])=[O:14])[CH2:10][CH2:11][NH2:12]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Product: NCCCCC(N)C(=O)O

Procedure:
The culture broth was adjusted to pH 3.0 with addition of sulfuric acid and then loaded on a cation exchange resin, DIAION SK1BL (Mitsubishi Chemical) so that L-lysine should be adsorbed on the resin. After the adsorption of L-lysine, the resin was washed with water, and L-lysine was eluted with aqueous ammonia. The eluent containing L-lysine was then concentrated in a rotatry evaporator until L-lysine concentration became 50% by weight to obtain an L-lysine base solution.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](OC)=[O:5].[H-].[Na+].[CH3:13][C:14]#[N:15]>C1COCC1>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:5])[CH2:13][C:14]#[N:15]
Reactant: COC(=O)C(C)(CF)CF
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CF)(CF)C(=O)CC#N
Temperature: 70 °C
Yield: 80.1 %

Procedure:
According to the procedure described in Example 161B Step 1, methyl 3-fluoro-2-(fluoromethyl)-2-methylpropanoate (5.21 g, 34.2 mmol), NaH (1.248 g, 52 mmol), and MeCN (2.791 g, 68 mmol) in THF (40 mL) were heated at 70° C. overnight, to afford 5-fluoro-4-(fluoromethyl)-4-methyl-3-oxopentanenitrile as oil (4.412 g, 80%). 1H NMR (300 MHz, CDCl3) δ 4.67 (m, 2H), 4.52 (m, 2H), 3.80 (s, 2H), 1.27 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:10]2[C:11](=[O:15])[NH:12][CH:13]=[CH:14][C:9]=2[S:8][C:7]=1[CH3:16]>S(=O)(=O)(O)O.C1N(COCCO)C2NC(N)=NC(=O)C=2N=1>[Br:5][C:6]1[C:10]2[C:11](=[O:15])[NH:12][CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[C:9]=2[S:8][C:7]=1[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1sc2cc[nH]c(=O)c2c1Br
Agent: Nc1nc(=O)c2ncn(COCCO)c2[nH]1
Agent: O=S(=O)(O)O
Product: Cc1sc2c([N+](=O)[O-])c[nH]c(=O)c2c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
A solution of nitric acid (1.68 mL, 70%, 26. 8 mmol) in sulfuric acid (5 mL) was added dropwise to a 0° C. solution of Example 66A (3.27 g, 13.4 mmol) in sulfuric acic (15 mL). The resulting mixture was stirred at 0° C. for 1 hour, warmed to room temperature overnight, and poured into ice water. The resulting precipitate was collected by filtration, washed with water, and dried in a vacuum oven to provide 2.47 g (64% yield) of the desired product. MS (ESI(+)) m/e 290 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>>[OH:15][CH:10]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CC(C)(C)C=O
Product: CC(C)(C)C(O)C(C#N)c1ccccc1
Yield: 87 %

Procedure:
Reaction of phenylacetonitrile and pivalaldehyde on a 30 mmol scale according to the procedure in Example 1, and recrystallization from toluene/hexane gave 5.34 g of the desired anti-aldol product (87%), m.p.: 70.7-71.2° C. NMR (1H, 13C), IR, and Mass spectra were consistent with the assigned structure. Analysis: Calculated for C13H17NO: C, 76.81; H, 8.42; N, 6.89. Found: C, 76.80; H, 8.43; N, 6.83.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 5-bromo-3-(trifluoromethyl)-1H-pyrazole-1-acetate (i.e. the product of Example 11, Step C) (2.84 g, 9.4 mmol) in tetrahydrofuran (10 mL) was treated with a 50 wt. % aqueous sodium hydroxide solution (1.0 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was treated with concentrated aqueous hydrochloric acid to lower the pH to 1 and then extracted with ethyl acetate. The extract was dried (MgSO4) and concentrated under pressure to give 2.26 g of the title compound as a light brown solid. Recrystallization from 1-chlorobutane (20 mL) gave 0.68 g of the title compound as lustrous light pink plates.