Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[NH2:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:39]#[N:40]>C1COCC1>[C:39]([C:38]1[CH:37]=[C:36]([NH:35][C:15]([C@@:11]2([CH:18]([CH3:19])[CH3:20])[CH2:12][C:13](=[O:14])[N:9]([C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10]2)=[O:16])[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=1)#[N:40]
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(C#N)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (25 mg, 0.091 mmol) and methanesulfonyl chloride (9 μL, 0.12 mmol) in THF (0.9 mL) at 0° C. was added diisopropylethylamine (0.047 mL, 0.27 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-amino-5-(trifluoromethyl)benzonitrile (34 mg, 0.18 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC, which failed to provide the desired product in sufficient purity. To a solution of the crude mixture (14 mg) in 2 mL THF was added aqueous NaOH (3 mL, 1.0 M) and the solution was stirred at 50° C. overnight. The following day, the solution was quenched with 10% HCl, partitioned with ethyl acetate, and the organic layer was separated. The organics were subsequently dried with sodium sulfate, concentrated in vacuo, and purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 10.28 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.04-7.17 (m, 3H), 3.99 (d, J=11.2 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 3.05 (d, J=17.2 Hz, 1H), 2.70 (d, J=17.2 Hz, 1H), 2.38 (septet, J=6.8 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H), 0.98 (t, J=6.8 Hz, 6H). LC-MS Rt (retention time): 2.81 min; MS: (ES) m/z 444 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[N:11]=[N:10][C:9]2[N:5]([CH:6]=[N:7][C:8]=2[C:12]([NH2:14])=[O:13])[C:3]1=[O:4].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O>>[CH3:1][N:2]1[C:3](=[O:4])[N:5]2[CH:6]=[N:7][C:8]([C:12]3[O:13][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=3)=[C:9]2[N:10]=[N:11]1
Reactant: Cn1nnc2c(C(N)=O)ncn2c1=O
Reactant: O=C(CBr)c1ccccc1
Product: Cn1nnc2c(-c3nc(-c4ccccc4)co3)ncn2c1=O
Temperature: 130 °C
Yield: 1 %

Procedure:
Temozolomide (0.200 g; 1.03 mmol) and 2-bromoacetophenone (0.246 g; 1.24 mmol) were stirred in a sealed tube under nitrogen, and heated to 130° C. for 1 hour. The mixture was cooled, and then concentrated in vacuo before being applied directly to the head of a chromatography column (SiO2) and purified by column chromatography (DCM:MeOH, 5:1), to give the title compound as a yellow powder (0.003 g; 1%). δH (DMSO-d6) 8.97 (1H, s), 8.88 (1H, s), 7.91 (2H, t, J=7.4), 7.50 (2H, t, J=7.4), 7.39 (1H, t, J=7.4), 3.90 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:16][C:17]([F:20])([F:19])[F:18])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[F:18][C:17]([F:20])([F:19])[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of commercially available 4-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.561 g; 19.70 mmol), and Cs2CO3 (8.004 g; 24.60 mmol) in anh. DMF (30 ml) was stirred at rt, under nitrogen, for 1 h. Water and AcOEt were added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 4-(2,2,2-trifluoroethoxy)benzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.72 min.; no ionisation.
Reaction SMILES: Cl.[C:2](=[NH:6])([NH2:5])[CH2:3][CH3:4].C[O-].[Na+].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH3:33])[C:26](OC)=[O:27])=[CH:20][CH:19]=1)#[N:11]>CO>[CH2:3]([C:2]1[NH:6][C:26](=[O:27])[C:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:13]3[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:19][CH:20]=2)=[C:30]([CH2:31][CH2:32][CH3:33])[N:5]=1)[CH3:4]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: CCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 74.5 %

Procedure:
A solution of propanimidamide hydrochloride (20 g), 28% sodium methoxide (56 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (34 g) in methanol (350 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (27 g, 82%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CN(C=O)C.Cl>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>[CH3:10][O:11][C:12](=[O:24])[CH:13]=[CH:14][C:15]1[CH:16]=[CH:17][C:18]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[CH:19][CH:20]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: COC(=O)/C=C/c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=Cc1ccc(-c2ccc(O)cc2C)cc1
Temperature: 80 °C
Yield: 20 %

Procedure:
A mixture of 4-bromo-3-methyl-phenol (460 mg, 2.01 mmol), [4-(E-3-methoxy-3-oxo-1-propen-1-yl)phenyl]boronic acid (486 mg, 2.21 mmol), tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.201 mmol) cesium carbonate (1.31 g, 4.02 mmol) and DMF (4.8 mL) is heated to 80° C. for 4.5 hours. The reaction is cooled to room temperature and diluted with water and acidified with 1 N HCl. The resulting solution is extracted with ether. The combined organic layers are dried over anhydrous magnesium sulfate and are purified via flash chromatography eluting with 15% ethyl acetate/heptane to give the title compound (108 mg, 20%). ES/MS m/e 267.3 (M−1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]1(C)C=CC=CC=1.[Cl:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[C:22]([CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])=[CH:21][CH:20]=1.BrC[C:35]#[N:36]>C1COCC1>[Cl:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[C:22]([C:27]([CH3:11])([CH2:32][C:35]#[N:36])[C:28]([O:30][CH3:31])=[O:29])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1
Reactant: N#CCBr
Reactant: COC(=O)C(C)c1ccc(Cl)nc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC#N)c1ccc(Cl)nc1OC
Reaction time: 0.67 h
Yield: 84.1 %

Procedure:
In a dry flask containing lithium bis(trimethylsilyl)amide/toluene (1.0 M, 13.1 mL, 13.1 mmol) and THF (18 mL) at −78° C. was added methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (2.39 g, 10.4 mmol) dropwise via syringe over 12 min resulting in a bright yellow solution. After 40 min, the resulting solution was added dropwise to a dry flask containing a solution of 2-bromoacetonitrile (1.38 mL, 20.8 mmol) in THF (18 mL) at 0° C. over 15 min, resulting in a color change from colorless to yellow to dark red-brown. Subsequent rinses with THF (2×1.5 mL) were cannulated over. After 50 min, the reaction was quenched with saturated aqueous ammonium chloride (18 mL). The mixture was diluted with heptanes (4× the reaction volume). The aqueous layer was extracted 2× with 1:1 EtOAc/heptanes (200 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification by silica gel column chromatography (220 g RediSep Gold column, 5-18% EtOAc/heptanes) provided methyl 2-(6-chloro-2-methoxypyridin-3-yl)-3-cyano-2-methylpropanoate (2.35 g, 84%) as a white solid. 1H NMR (600 MHz, CDCl3) δ: 1.74 (s, 3H), 3.07 (d, 1H), 3.14 (d, 1H), 3.67 (s, 3H), 3.95 (s, 3H), 7.00 (d, 1H), 7.57 (d, 1H); MS (AP+)(M+H) 269.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[F:9][C:10]([F:14])([F:13])[CH2:11]I.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:9][C:10]([F:14])([F:13])[CH2:11][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: Oc1ccccc1Br
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccccc1Br
Temperature: 25 °C

Procedure:
A solution of 0.35 g (2 mmol) of 2-bromophenol, 0.63 g (3 mmol) of 2,2,2-trifluoroethyliodide, 0.55 g (4 mmol) of potassium carbonate in 2 Ml of DMF was reacted at 150° C. in a microwave system (Personal Chemistry, Smithcreator) for 30 min. After cooling to RT, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (5%, 10% successively EtOAc:hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1cc(N)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)cc(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture solution of 3-amino-5-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-5-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+]336.0 & 338.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:40][C:41]1[N:45]2[C:46](=[O:55])[N:47]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[CH2:48][C:44]2=[CH:43][N:42]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:40][C:41]1[N:45]2[C:46](=[O:55])[N:47]([CH:49]3[CH2:54][CH2:53][N:52]([C:10]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:12])[CH2:51][CH2:50]3)[CH2:48][C:44]2=[CH:43][N:42]=1
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CCCCC(NC(=O)OC(C)(C)C)C(=O)N1CCC(N2Cc3cnc(C)n3C2=O)CC1
Yield: 81.2 %

Procedure:
To a solution of 2-((tert-butoxycarbonyl)amino)hexanoic acid (0.46 g) obtained in Example 80a), HOBt (0.46 g) and WSC (0.58 g) in acetonitrile (20 ml) was added a solution of 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.6 g), DBU (0.6 ml) and triethylamine (0.61 ml) in acetonitrile (20 ml), and mixed for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate/methanol=10/1) to obtain the title compound as colorless powder (0.7 g, 75%).
Reaction SMILES: [CH2:1]([N:8]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[S:28][C:27]3[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:25][C:24](Cl)=[N:23][C:22]=3[CH:21]=2)[CH2:15][CH2:14]1)[CH2:9][CH2:10][O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:45]=2[CH:46]=[CH:47][NH:48]3)O1>>[CH2:1]([N:8]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[S:28][C:27]3[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[N:25][C:24]([C:44]4[CH:52]=[CH:51][CH:50]=[C:49]5[C:45]=4[CH:46]=[CH:47][NH:48]5)=[N:23][C:22]=3[CH:21]=2)[CH2:15][CH2:14]1)[CH2:9][CH2:10][O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: COCCN(Cc1ccccc1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COCCN(Cc1ccccc1)C1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Benzyl-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl)-piperidin-4-yl]-(2-methoxy-ethyl)-amine (150 mg), was used in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (141 mg), to give after flash silica purification the title compound (105 mg) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C-]#N.[Na+].Cl>CS(C)=O.C(Cl)Cl.O>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C@H:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[CH3:15])=[N:17][CH:18]=1
Reactant: COc1ccc([C@@H](C)NC(=O)Cc2ccc(C(C)C)cc2)nc1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(O)cn2)cc1
Temperature: 175 °C
Reaction time: 16 h

Procedure:
2-(4-Isopropylphenyl)-N-[(1R)-1-(5-methoxypyridin-2-yl)ethyl]acetamide (3.8 g, 12.2 mmol) (Example 11) was dissolved in DMSO (20 mL) and transferred to a sealed tube. To this solution was added NaCN (3.6 g, 73.0 mmol) and the mixture was stirred at 175° C. for 16 h. The mixture was cooled to room temperature and diluted with CH2Cl2 (200 mL) and water (100 mL). The pH of the aqueous layer was brought to neutral by the addition of 2N HCl and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL), concentrated, and purified by normal phase chromatography (2-10% MeOH/CH2Cl2) to give N-[(1R)-1-(5-hydroxypyridine-2-yl)ethyl]-2-(4-isopropylphenyl)acetamide as a tan solid. 1H NMR (CDCl3, 400 MHz) δ 8.06 (t, J=1.65 Hz, 1H), 7.17 (m, 4H), 7.02 (m, 2H), 6.67 (d, J=7.50 Hz, 1H), 5.03 (quint., J=6.96 Hz, 1H), 3.53 (d, J=2.20 Hz, 2H), 2.88 (sept., J=6.69 Hz, 1H), 1.38 (d, J=6.77 Hz, 3H), 1.23 (d, J=6.95, 6H); MS (Electrospray): m/z 299.3 (M+H).
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>O>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH:13][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][CH:7]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NNC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 50 ml of dichloromethane and 2.76 g of free 4-methoxyphenyl-hydrazine there are added first 2.2 g of triethylamine and then, dropwise, at a temperature of from 0° to 5°, 2.65 g of pivaloyl chloride. The reaction mixture is stirred for 12 hours at room temperature and then discharged into water. The aqueous mixture is extracted with dichloromethane, the extract is concentrated and the residue is recrystallised from toluene/pentane, yielding N-(4-methoxyphenyl)-N′-pivaloyl-hydrazine which melts at from 126° to 127°.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O1CCCCC1ONC([C@H]([C@@H](CC(C)C)C(NNS(C)(=O)=O)=O)C/C=C/C1C=CC=CC=1)=O.BrCCC1C=CC=CC=1>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CCc1ccccc1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: BrCCc1ccccc1
Agent: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Product: CC(C)C[C@@H](C(=O)NN(CCc1ccccc1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
The (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-(2-phenylethyl)valerohydrazide used as the starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-(2R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide by reaction with 2-bromoethyl-benzene.
Reaction SMILES: [OH-:1].[Na+:2].C([OH:5])C.[CH:6]1[N:10]=[CH:9][N:8]([CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH:7]=1.CO>O>[CH:6]1[N:10]=[CH:9][N:8]([CH2:11][C:12]([P:14]([O-:17])([OH:16])=[O:15])([P:18]([O-:20])([OH:21])=[O:19])[OH:13])[CH:7]=1.[OH2:5].[OH2:1].[OH2:5].[OH2:5].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: CCO
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (0.7 g) in a mixture of water (X % v/v)/Methanol (Y % v/v, 10 volumes per grams of ZLD-Ac form XII) (13-15 ml) was added drop-wise to a suspension of Zoledronic acid form XII (4.98 g) in a mixture of water (X % v/v)/Methanol (Y % v/v, 10 volumes per grams of ZLD-Ac) (70-85 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50° C. for 24 hours to give Zoledronate disodium crystal form V.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4]1>CCO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:22])[CH3:1])[CH2:4]2)=[C:10]([C:18]([F:21])([F:19])[F:20])[CH:11]=1
Reactant: CN(C)[C@@H]1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)C1
Agent: [Pd]
Solvent: CCO
Product: CN(C)[C@@H]1CCN(Cc2ccc(N)cc2C(F)(F)F)C1

Procedure:
To a solution of (R)-N,N-dimethyl-1-(4-nitro-2-(trifluoromethyl)benzyl)pyrrolidin-3-amine (1.20 g, 3.79 mmol) in 20 mL of wet EtOH was added 0.26 g of Pd/C (10% Pd on C) and the mixture shaken in a Parr apparatus (pressure reaction vessel purged thoroughly with H2 and pressure regulated at 45 psi throughout) for 2-3 h. The reaction mixture was filtered through a small pad of celite, washed with EtOAc, and the combined organics concentrated to provide a quantitative yield of a light yellow oil. This material was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.[NH2:25][CH2:26][C:27]([NH2:30])([CH3:29])[CH3:28].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:15]([OH:17])=[O:16].[NH2:30][C:27]([CH3:29])([CH3:28])[CH2:26][NH:25][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])=[CH:7][C:8]([CH3:19])=[CH:9][C:10]=12)=[O:17]
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: CC(C)(N)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)NCC(C)(C)N)c2c1
Product: O=CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.3 %

Procedure:
A mixture of 78.0 mg (0.235 mmol, 1.0 eq.) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A, 49 μl (0.47 mmol, 2.0 eq.) of 1,2-diamino-2-methylpropane [CAS No.: 811-93-8] and 0.20 ml (1.2 mmol, 5.0 eq.) of N,N-diisopropylethylamine in 2.4 ml of DMF was admixed with 116 mg of HATU (0.305 mmol, 1.3 eq.) and stirred at RT for 6 h. Subsequently, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was stirred with water, and the precipitated solids were filtered off and purified by means of preparative HPLC (Method 4). 22.3 mg of the title compound were obtained (24% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9](Br)[CH2:10][CH3:11])=[CH:4][CH:3]=1.FCCCC(C1C=CC=CC=1)=O.[CH3:26][NH:27][CH3:28]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]([N:27]([CH3:28])[CH3:26])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(Br)C(=O)c1ccc(F)cc1
Reactant: CNC
Agent: O=C(CCCF)c1ccccc1
Solvent: CCOCC
Product: CCC(C(=O)c1ccc(F)cc1)N(C)C
Reaction time: 12 h

Procedure:
240 g (0.98 mol) of 1-(4-fluorophenyl)-2-bromobutan-1-one (prepared by bromination of 4-fluorobutyrophenone by the method described in EP-A-3,002) are dissolved in 250 ml of diethyl ether. This solution is slowly added dropwise to a mixture of 265 g (5.87 mol) of the dimethylamine in 1250 ml of diethyl ether at 0°. After the mixture has been stirred at 0° for 12 hours, the excess dimethylamine is removed at room temperature by blowing through N2 and the suspension is poured onto water. The ether phase is washed with water and dried over MgSO4. After filtration and evaporation of the solution, 202.8 g of crude produce remain as a colourless oil, which is used without further purification for the subsequent reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26](O)=[O:27])=[C:19]3[N:18]=2)[C:6]1=[O:29].CN(C=O)C.C(Cl)Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O>[F:11][C:9]1[CH:8]=[C:7]2[C:6](=[O:29])[N:5]([CH:10]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:27])[C:25]1=[C:19]3[N:18]=[C:17]([CH:22]=[CH:21][N:20]3[N:23]=[CH:24]1)[N:13]1[C@@H:12]2[CH2:16][CH2:15][CH2:14]1
Reactant: NCCCn1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1NCCCn2cc(F)cc(c2=O)[C@H]2CCCN2c2ccn3ncc1c3n2
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To a solution of (R)-5-(2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.24 mmol) in 1:2 DMF/DCM (9 mL) was added EDCI (0.14 g, 0.71 mmol) followed by HOBT (96 mg, 0.71 mmol) at ambient temperature. After stirring for 10 minutes, TEA (0.099 mL, 0.71 mmol) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was treated with EtOAc, washed with saturated NH4Cl, saturated NaHCO3, and brine, then dried (MgSO4), filtered, concentrated. The crude material was purified by silica column chromatography, eluting with 4% MeOH/DCM to yield the title product (35 mg, 39% yield). MS (apci) m/z=383.2 (M+H).