Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:18][C:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OC(=Cc1ccncc1)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 152.9 %

Procedure:
To a suspension of NaH (0.81 g, 18.6 mmol) in DMF (30 mL) under argon atmosphere and cooled to 0° C., a solution of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (2.00 g, 9.3 mmol, obtained in reference example 1) in DMF (15 mL) was added and stirred to room temperature for 30 minutes. It was then cooled to 0° C. and a solution of 4-fluorobenzoyl chloride (2.95 g, 1.9 mmol) in DMF (10 mL) was added. It was stirred at room temperature overnight. Water was added and the solvent was evaporated off. The residue was dissolved in a mixture of CHCl3 and water and the phases were separated. The aqueous phase was extracted with CHCl3 (×3). The organic phase was washed with water (×2), dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.98 g of the desired compound as a yellow solid (yield: 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23].C(O)(=O)C(O)=O>CO.C(#N)C>[CH2:23]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([OH:14])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: C=CCBr
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: C=CCN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 51: Enantiomer E1 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.18 g, 0.92 mmol), acetonitrile (6 mL), potassium carbonate (0.25 g, 1.84 mmol) and allyl bromide (0.077 mL, 0.92 mmol). Flash chromatography on silica gel (ethyl acetate/methanol, 10:1). Yield: 0.1 g. [α]D=+22.4° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 104-105° C.; MS m/z (relative intensity, 70 eV) 239 (M+, 40), 83 (bp), 198 (84), 82 (13), 14 (33), 127 (31).
Reaction SMILES: [CH3:1][O:2][N:3]([CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](N2C=CN=C2)=[O:13])[S:9][CH:10]=1)[CH3:4].[C:19]([OH:23])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][N:3]([O:2][CH3:1])[CH3:4])[N:7]=1)=[O:13])([CH3:22])([CH3:21])[CH3:20]
Reactant: CON(C)Cc1csc(NC(=O)n2ccnc2)n1
Reactant: CC(C)(C)O
Product: CON(C)Cc1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A mixture of Intermediate 28: 2-(N-imidazocarbonylamino)-4-(N-methoxy-N-methyl-aminomethyl)thiazole (23.3 g, 87.2 mmol) and anhydrous tert-butanol (140 mL) was stirred under an inert atmosphere and heated to 80 C. After 20 minutes, a clear solution was obtained. tert-Butanol was evaporated at reduced pressure and the oily residue was dissolved in hexane (200 mL) and washed with water (2×100 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound as a colorless oil which crystallized on standing (21.4 g, 90% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][CH2:9][C:8]2[N:7]([C:11]3[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=3)[N:6]=[CH:5][C:4]=2[CH2:3]1.[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][CH:2]2[CH2:10][CH2:9][C:8]3[N:7]([C:11]4[S:12][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([CH3:16])[N:15]=4)[N:6]=[CH:5][C:4]=3[CH2:3]2)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(-n2ncc3c2CCC(N)C3)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(-n2ncc3c2CCC(NC(=O)c2nc(Cl)c(CC)[nH]2)C3)nc1C
Yield: 89.1 %

Procedure:
The same operation as in Example (217c) was performed using ethyl 2-(5-amino-4,5,6,7-tetrahydro-1H-indazol-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (242d) (50 mg, 0.16 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (28 mg, 0.16 mmol), WSC hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (22 mg, 0.16 mmol) and N-methylmorpholine (0.04 mL, 0.33 mmol), to obtain 66 mg of the title compound as a white solid (88%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:12]([O:14][CH:15]([O:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:18])[CH3:17])=[O:13])(=[O:7])=[O:6].[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:12]([O:14][CH:15]([O:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:18])[CH3:17])=[O:13])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)OC(=O)OC(OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl)C(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)OC(OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])C(C)C

Procedure:
Following the general procedure for the preparation of azides of Description 16, a mixture of 2-methyl-1-(methylethoxycarbonyloxy)propyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoate (47a) (0.6 g max.) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 69 mg (1.1 mmol) of sodium azide (NaN3). After work-up, the crude title compound (47b) was used in the next step without further purification. MS (ESI) m/z 590.22 (M+Na)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]1)=[N+:2]=[N-:3].[C:17]1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=CC(C)=O)[CH:22]=CC=C[CH:18]=1>C1(C)C=CC=CC=1>[CH3:22][C:17]1[N:1]([CH2:4][CH:5]2[CH2:9][N:8]([C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[C:7](=[O:16])[CH2:6]2)[N:2]=[N:3][CH:18]=1
Reactant: CC[C@@H](C(N)=O)N1CC(CN=[N+]=[N-])CC1=O
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC[C@@H](C(N)=O)N1CC(Cn2nncc2C)CC1=O
Temperature: 80 °C

Procedure:
In a 50 ml 3 necked flask, fitted with magnetic stirrer and reflux condenser under inert atmosphere, 1 g (4.44 mmoles, 1 eq) of (2S)-2-[4-(azidomethyl)-2-oxo-1-pyrrolidinyl]butanamide 32 is suspended in 20 ml of toluene. 1.55 g (4.88 mmoles, 1.1 eq) of 1-(triphenylphosphoranylidene)acetone are added, and the mixture is heated up to 80° C. for 24 hours. After cooling down, the mixture is concentrated to dryness and purified by Prep LC (1 kg SiO2, CH2Cl2/MeOH/NH4OH, 94.5:5:0.5). It is suspended in 15 ml of water and lyophilised to give 240 mg of pure 52 as a clear oil, 42%. 7.3.4. Synthesis of of (2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1-pyrrolidinyl]butanamide 49
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[O:20].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[O:20]
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NC(=O)NCCC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-glucose and L-(+)-citrulline using Raney nickel or palladium/activated carbon as a catalyst and heating for 2 hours to 50° C. and 4 hours to 70° C. A product was obtained which had a melting point of 176° C. and an RF -value of 0.7 (determined on DC-finished plates of silica gel G (Merck) with a transporting liquid made up of 50 parts by volume of methanol and 50 parts by volume of water).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:12]([NH:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:14])[CH3:13]>>[C:12]([NH:15][C:16]([CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:14])[CH3:13]
Reactant: COC(=O)CCC/C=C\CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Product: CCOC(=O)C(CC=CCCCC(=O)OC)(NC(C)=O)C(=O)OCC

Procedure:
cis-Methyl 7-bromohept-5-enoate (prepared by the method of Brit. Pat. No. 1 355 991) and diethyl acetamidomalonate reacted under the conditions described in Example 1A to give diethyl acetamido-(6-methoxycarbonylhex-2-enyl)malonate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of methyl 3-(4-chlorophenyl)-2-phenylpropionate (Step A, 20 g, 74 mmol) in acetonitrile (100 mL) and water (100 mL) was added lithium hydroxide monohydrate (8.8 g, 0.21 mol). After stirring at room temperature for 3 days, the volatile materials were removed by concentrating on a rotary evaporator and the residue was partitioned between water (300 mL) and hexane/ether (1:1, 200 mL). The water layer was separated, acidified to pH=2-3, and extracted with EtOAc (2×200 mL) The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.34-7.10 (m, 9H), 3.82 (dd, 1H), 3.36 (dd, 1H), 2.98 (dd, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24](I)=[C:25]([CH:34]=1)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(NCC)C.[CH2:41]([N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54])[C:42]#[CH:43]>[Pd](Cl)Cl.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:43]#[C:42][CH2:41][N:44]2[C:48](=[O:49])[C:47]3=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]3[C:45]2=[O:54])=[C:25]([C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=1
Reactant: C#CCN1C(=O)c2ccccc2C1=O
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1I
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g (0.20 mole) of 5-chloro-2-iodobenzophenone, 200 ml of diethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 40.0 g (0.22 mole) of N-propargylphthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of iospropanol. The resulting percipitate was collected by filtration to give crude end product. Recrystallization from acetone gave cream colored prisms, mp 148°-150° C.
Reaction SMILES: [S:1]([O:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:14][CH:13]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:39]([NH2:42])[CH2:40][CH3:41]>>[CH2:39]([NH:42][C:15]1[C:16]2[C:17](=[O:27])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:26])[C:25]=2[C:12]([O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[CH:13][CH:14]=1)[CH2:40][CH3:41]
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OS(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Product: CCCNc1ccc(OS(=O)(=O)c2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Yield: 73 %

Procedure:
1-(n-propylamino)-4-tosyloxyanthraquinone was prepared by reaction of 1,4-ditosyloxyanthraquinone with n-propyl amine. The isolated and purified reaction product has the structure illustrated below (where "Ts" is ##STR9## The yield was 73% and the m.p. 163°-164° C. Mass spec m/e 435 (M+), 406 (M-C2H5), 280 (M-C7H7SO2), 252 (280-CO), 155 (C7H7SO2), 91 (C7H7); 1H-NMR (CD2Cl2)δ10.01 (br s, 1H), 8.21-7.87 (m, 2H), 7.81-7.65 (m, 4H), 7.35-6.96 (m, 4H), 3.41-3.20 (m, 2H), 2.31 (s, 3H), 1.91-1.67 (m, 2H), 1.16-1.00 (t, 3H); IR (Nujol) 1368 cm-1 (asymmetrical stretch), 1170 cm-1 (symmetric stretch), 932, 898, 865, 830, 785 cm-1 (S--O--C stretch); UV/VIS max (Xylenes) 501 nm (ε6380).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Br)c1)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-chloro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=10.05 min. MS (ESI−): mass calcd. for C22H15Br2ClN4O5S2, 674.77; m/z found, 673/675 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.77 (s,1H), 8.46-8.42 (m,1H), 8.34-8.29 (m,1H), 8.19-8.13 (m,1H), 7.93-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.73-7.69 (m, 1H), 7.54-7.46 (m, 2H), 7.40-7.35 (m, 1H), 7.17-7.12 (m, 1H), 4.97-4.88 (m, 1H), 3.40-3.32 (m, 1H), 3.22-3.14 (m, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13].Cl>C1COCC1>[C:1]1([CH2:7][CH2:8][S:9]([NH2:13])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=S(=O)(Cl)CCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-phenylethanesulfonyl chloride (40.94 g) in THF (250 ml) was cooled to −20° C. before it was treated with sat. aq. ammonia (50 ml). The brown suspension was stirred at rt for 16 h. The mixture was neutralised with aq. HCl and the organic solvent was evaporated. The remaining suspension was diluted with water and extracted four times with EA. The organic layers were combined and evaporated to give 2-phenyl-ethanesulfonic acid amide (33.06 g) as orange solid. 1H-NMR(300 MHz, CDCl3): 3.15–3.21(m, 2H), 3.38–3.45(m, 2H), 4.59(s br, 2H), 7.21–7.37(m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:6]([C:5]1[C:4]([CH3:11])=[CH:3][C:2]([O:1][CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[CH:9][C:8]=1[CH3:10])=[O:7]
Reactant: CN(C)C(=O)CCl
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC(=O)N(C)C)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-2,6-dimethylbenzaldehyde (100 mg) and 2-chloro-N,N-dimethylacetamide (89 mg) in DMF (2 mL) was added K2CO3 (185 mg) and the mixture was stirred at room temperature for 48 h. The mixture was poured into water and extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using 30% EtOAc/CH2Cl2 as eluent to give 2-(4-formyl-3,5-dimethylphenoxy)-N,N-dimethylacetamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.O([NH2:20])C>C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([NH2:20])[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccc(F)c1)c1cccnc1
Reactant: CON
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: NC(Cc1cccc(F)c1)c1cccnc1
Reaction time: 14 h

Procedure:
The intermediate oxime was prepared from 2-(3-fluoro-phenyl)-1-pyridin-3-yl-ethanone (crude) and methoxylamine hydrochloride (6.50 g, 77.83 mmol) according to the protocol described in general procedure B. The oxime was then dissolved in acetic acid (10.00 mL) and Pd/C (0.80 g) was added. The reaction mixture was hydrogenated under 50 psi for 14 hours, then filtered and concentrated. The residue was basified with 5M sodium hydroxide and extracted with methylene chloride. The combined organic phases were dried over potassium carbonate and concentrated to yield the title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.83 ((dd, J=7.04, 3.22 Hz, 2 H) 4.07 (t, J=7.04 Hz, 1 H) 6.96-7.08 (m, 2 H) 7.11 (td, J=5.86, 2.64 Hz, 1 H) 7.14-7.23 (m, 1 H) 7.27 (dd, J=7.48, 5.13 Hz, 1 H) 7.70 (ddd, J=7.77, 2.20, 2.05 Hz, 1 H) 8.36 (dd, J=4.84, 1.61 Hz, 1 H) 8.41 (t, J=3.08 Hz, 1 H).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.C(#N)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:acetonitrile (40:60 v/v, 12.33 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:acetonitrile (40:60 v/v, 71 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 1 hour to obtain a pH of 4.05. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2×20 ml), and dried in a vacuum oven at 50° C. for 20 hours to obtain 3.9 g of ibandronate sodium crystal form Q5. Form Q5 can exhibit a weight loss of about 5% to about 11% in TGA.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:16])[NH:9][N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH2:23]([N:9]1[C:8](=[O:16])[C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)n1[nH]c(=O)c2cnc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)n1c2cc(Cl)ncc2c(=O)n1Cc1ccccc1

Procedure:
Ethyl 6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (Intermediate 1B; 582 mg, 2.41 mmol), potassium carbonate (666 mg, 4.82 mmol), and benzyl bromide (0.345 mL, 2.9 mmol) were stirred in DMF (10 mL) at room temperature for 16 h. Water was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (6-50% EtOAc-hexanes) gave ethyl 2-benzyl-6-chloro-3-oxo-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate. MS ESI calc'd. for C16H14ClN3O3 [M+1]+ 332. found 332. Ethyl 3-(benzyloxy)-6-chloro-1H-pyrazdo[4,3-c]pyridine-1-carboxylate was also obtained. MS ESI calc'd. for C16H14ClN3O3 [M+1]+ 332. found 332.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](OC2C=CC=CC=2)=[O:21])=[N:17][CH:18]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:6][C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([Br:12])=[CH:18][N:17]=1)=[O:21])=[O:5]
Reactant: O=C(Nc1ccc(Br)cn1)Oc1ccccc1
Reactant: NC(=O)c1c(F)cccc1Cl
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Br)cn1

Procedure:
A portion of 2-chloro-6-fluorobenzamide is dissolved in an organic solvent, and 5-bromo-2-pyridinylaminocarboxylic acid, phenyl ester is added. The reaction mixture is stirred with heating for a period of time, and is then evaporated under vacuum. The product, identical to the product of Example 2 above, is isolated from the residue by recrystallization:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:18][O:17]2)=[CH:10][CH:9]=1.[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.Cl>O.CS(C)=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH2:18][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)([OH:17])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:10][CH:9]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(CCc2ccc(Cl)cc2)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C(O)(CCc1ccc(Cl)cc1)Cn1cncn1
Temperature: 110 °C
Yield: 41.6 %

Procedure:
5.3 g (0.05 mole) of sodium carbonate were added to a mixture of 245.2 g (1 mole) of 2-(4-chlorophenylethyl)-2-tert.-butyl-oxirane (97.2% pure), 72.5 g (1 mole) of 1,2,4-triazole (95.2% pure) and 380 ml of dimethylsulphoxide at room temperature, while stirring, and the mixture was then heated at 110° C. for 4 hours. Thereafter, the reaction mixture was poured into 1 liter of water and neutralized with dilute aqueous hydrochloric acid. The liquid phase was decanted off from the solid and the residue was dissolved in 1 liter of toluene. The solution was extracted with water, the phases were separated and the organic phase was dried and concentrated by stripping off the diluent under reduced pressure. 128 g (42% of theory) of 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-ylmethyl)-4,4-dimethyl-pentan-3-ol were obtained in this manner in the form of a solid.
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17]>C(OCC)(=O)C>[C:5]([C:4](=[C:3]([NH:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH3:11])[CH:14]=1)[S:9][CH3:10])[C:7]#[N:8])#[N:6]
Reactant: COc1cccc(CN)c1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCOC(C)=O
Product: COc1cccc(CNC(SC)=C(C#N)C#N)c1

Procedure:
A mixture of 17.03 g (0.1 mol) of 3,3-bis-methylmercapto-2-cyano-acrylonitrile, 12.78 ml (0.1 mol) of 3-methoxy-benzylamine and 60 ml of ethyl acetate is heated under reflux for 2 hours and then concentrated by evaporation in vacuo, yielding the oily title compound; TLC-Rf 32 0.28 (toluene/isopropanol [9:1]).