Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccc(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
(2R,4S)-Methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (550 mg, 1.56 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 15 mL, 85.65 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx I, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(3,4-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (183 mg, 40%). 1H NMR (600 MHz, cd3od) δ 1.41 (q, 1H), 1.67 (dq, 1H), 1.99-2.08 (m, 2H), 2.77-2.95 (m, 4H), 3.17-3.24 (m, 1H), 3.26-3.34 (m, 1H), 5.49 (s, 1H), 7.00-7.05 (m, 1H), 7.14-7.22 (m, 2H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1253
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:15]=[CH:14][C:10]3[NH:11][N:12]=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:16]([O-])([OH:18])=[O:17]>>[N:1]1([CH2:6][C:7]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]3[NH:11][N:12]=[N:13][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])O
Reactant: c1cn(Cc2ccc3[nH]nnc3c2)cn1
Product: O=[N+]([O-])c1cc2[nH]nnc2cc1Cn1ccnc1
Reaction time: 8 h
Yield: 1.6 %

Procedure:
2.47 Parts of 5-(1H-imidazol-1-ylmethyl)-1H-benzotriazole were added portionwise to 30 parts of fuming nitric acid while stirring. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was poured into 100 parts of crushed ice and nitrogen was bubbled through the mixture during 30 minutes. The precipitated product was filtered off, washed with water and purified by reversed phase chromatography (HPLC) over Li Chroprep RP 18 using a mixture of methanol, acetonitrile and an ammonium acetate solution 0.5% (17:8:75 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was stirred in methanol and 2,2'-oxybispropane. The precipitated product was filtered off and boiled in methanol. The product was filtered off, washed with methanol and 2,2'-oxybispropane and dried in vacuo at 50°-60° C., yielding 0.05 parts (1.6%) of 5-(1H-imidazol-1-ylmethyl)-6-nitro-1H-benzotriazole; mp. 286.0° C. (decomp.) (compound 235).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([CH3:8])=O.Cl.[NH2:14][OH:15]>[OH-].[Na+].C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](=[N:14][OH:15])[CH3:8]
Reactant: CC(=O)COc1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(COc1ccccc1Cl)=NO
Yield: 3.9 %

Procedure:
1-(2-Chlorophenoxy)acetone (106.6 g, 0.58 mol) (J. Am. Chem. Soc., 75, 1953, 1134) was added to a solution of hydroxylamine hydrochloride (27.8 g, 4 mol) in 2N sodium hydroxide solution (420 ml) and sufficient ethanol to give a clear solution. The reaction mixture was refluxed for 30 minutes then concentrated in vacuo, the crude residue was extracted with diethyl ether (3×200 ml). The combined organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was distilled to give the title product (134-136° C./1.35 mmHg) (4.5 g, 3.9%); 1H NMR (CDCl3400 MHz) δ: 2.05 (s, 3H), 5.00 (s, 2H), 6.90-7.00 (m, 2H), 7.10 (t, 1H), 7.30 (d, 1H), 7.60 (s, 1H); Anal. Found C, 54.95; H, 5.05. C9H10NO2Cl requires C, 54.15; H, 5.05%.
Reaction SMILES: O=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].Cl.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][N:25]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CN1CCCC1=O)c1cccnc1
Reactant: NOCc1ccccc1
Agent: Cl
Product: O=C1CCCN1CC(=NOCc1ccccc1)c1cccnc1
Yield: 30.8 %

Procedure:
0.3 g (1.47 mmol) of 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one prepared from Example 20 and 0.35 g (2.21 mmol) of benzyloxyamine hydrochloride salt were treated as described in Example 22 to obtain 0.14 g (31% yield) of 1-(2-benzyloxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one as E/Z mixture (1.02:1).
Reaction SMILES: [C:1]12([C:11]3[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[K+].IC.C(OCC)(=O)C>C1COCC1>[C:1]12([C:11]3[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]([CH3:21])[CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1cc(C23CC4CC(CC(C4)C2)C3)c[nH]1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1cc(C23CC4CC(CC(C4)C2)C3)cn1C
Reaction time: 4 h
Yield: 298.2 %

Procedure:
Preparation C6, Step 1. Ethyl 3-(adamant-1-yl)-pyrrole-5-carboxylate (0.20 g, 0.7 mmol, 1 eq) was dissolved in THF (20 mL). Potassium bis(trimethylsilyl)amide (0.5 M in Tol, 1.62 mL, 0.81 mmol, 1.1 eq) was added thereto followed by iodomethane (0.102 mL, 1.6 mmol, 2.2 eq). The next day, the same amounts of potassium bis(trimethylsilyl)amide and iodomethane were again added to drive the reaction to completion. In 4 h, the reaction was finished. Ethyl acetate was added (100 mL) and the organic layer was washed with water (2×), brine, dried (MgSO4) and stripped to yield 600 mg of ethyl 3-(adamant-1-yl)-1-methylpyrrole-5-carboxylate, which was used as is in the next step. MS found: (M+H)+=288.16.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[C:12]([CH2:22]Br)=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>C(O)C>[F:10][C:11]1[C:12]([CH2:22][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)c1cccc(F)c1CBr
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc(F)c1COc1cccc(F)c1
Yield: 89.3 %

Procedure:
To a solution of 1.3 g of sodium metal in 100 ml of ethanol are added 6.3 g of 3-fluorophenol and 13 g of ethyl 3-fluoro-2-bromomethylbenzoate and the mixture is refluxed with heating for 8 hours. After cooling, 300 ml of water is added and the mixture is extracted with toluene. After the extract is washed with water and a saturated saline solution and dried over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to silica-gel chromatography and eluted with toluene to give 13 g of ethyl 3-fluoro-2-[(3-fluorophenyl oxy)methyl]benzoate (oil). Mass spectrum m/z: 292(M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>O1CCCC1.ClCCl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[NH:29][C:30](=[O:31])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: COc1ccc(C)cc1N=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C)cc1NC(=O)Nc1ccc(-c2c(C(N)=O)[nH]c3cnccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 100 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide in 5 mL of tetrahydrofuran are added dropwise 54.4 μL of 2-methoxy-5-methylphenyl isocyanate. The reaction mixture is stirred for 16 hours at room temperature under an argon atmosphere and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 2 mL of dichloromethane. The suspended solid is filtered off, washed with water and drained by suction. After drying under vacuum, at 40° C., 40 mg of 3-{4-[3-(2-methoxy-5-methylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:28]1[C:32]([CH3:34])([CH3:33])[C:31](=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[C:38]([C:45]([F:48])([F:47])[F:46])[CH:37]=2)[C:29]1=[O:49])[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[C:7]1=[O:27].Cl[Sn]Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.CCCCCCC.CCOC(C)=O>[CH2:5]([N:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=2)[C:7]1=[O:27])[CH2:4][CH2:3][CH2:2][CH2:1][N:28]1[C:32]([CH3:34])([CH3:33])[C:31](=[O:35])[N:30]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([C:45]([F:46])([F:47])[F:48])[CH:37]=2)[C:29]1=[O:49]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)N1CCCCCN1C(=O)N(c2ccc(N)c(C(F)(F)F)c2)C(=O)C1(C)C
Temperature: 80 °C
Yield: 78 %

Procedure:
A mixture of the compound of Example 2 (410 mg, 0.58 mmole) and SnCl2, 2H2O (1.32 g, 5.8 mmoles) in AcOEt (10 ml) is heated at 80° C. for 90 minutes. The reaction medium is then cooled down to 0° C. before being poured into a saturated aqueous solution of Na2CO3 (40 ml). The heterogeneous mixture thus obtained is filtered on celite and rinsed with AcOEt (2×50 ml). After decantation, the organic phases are combined, dried over Na2SO4, filtered and the solvent is evaporated off under reduced pressure. The residue obtained is taken up in a mixture of heptane/AcOEt in order to produce a white solid, after filtration, with a yield of 78% (290 mg). Melting point: 108-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].O=S(Cl)[Cl:19].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][Cl:19])[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11]
Reactant: O=S(Cl)Cl
Reactant: C[C@H](Oc1ccc(CO)cc1Cl)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C[C@H](Oc1ccc(CCl)cc1Cl)C(F)(F)F

Procedure:
A solution of {3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}methanol (284 mg) and SOCl2 (179 μL) in DCM (7 mL) was stirred at room temperature for 2 hours. The reaction liquid was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain 2-chloro-4-(chloromethyl)-1-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzene (285 mg) as a colorless liquid.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([CH2:19][CH2:20][C:21](O)=O)[CH2:18]CCCC1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([CH:18]2[CH2:13][CH2:19][CH2:20][CH2:21]2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCCC1CCCCC1
Reactant: O=C(O)CCC1CCCCC1
Product: O=C(CCCC1CCCCC1)C1CCCC1

Procedure:
The title compound was prepared analogously to Example A(44), where cyclohexanebutyric acid was substituted in place of 3-cyclohexylpropionic acid in Step 1 of that example. 1H NMR (DMSO-d6): δ 0.79-0.91 (m, 2H), 1.11-1.27 (m, 7H), 1.55-1.85 (m, 14H), 2.41 (t, J=7.4, 2H), 2.81-2.91 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccc(F)cc1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′ ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-fluorobenzyl chloroformate.
Reaction SMILES: C[O:2][C:3]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].B(Cl)(Cl)Cl>>[OH:2][C:3]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(C(=O)OC)c1OC
Agent: ClB(Cl)Cl
Product: COC(=O)c1cccc(C(=O)OC)c1O

Procedure:
A potassium salt of a phenol is needed for the next step in the reaction. The preferred potassium salt of a phenolic ester is made in two steps starting from commercially available 2-methoxyisophthalic acid. It is first reacted with trimethyloxonium tetrafluoroborate (Me3OBF4) and diisopropylethylamine ("iPr2NEt") under conditions effective to produce dimethyl 2-methoxyisophthalate. Gerecke, et al. Helv. Chim. Acta., 59:2551 (1976), which is hereby incorporated by reference. Then, the methyl ether is cleaved with BCl3 under conditions effective to yield dimethyl 2-hydroxyisophthalate. The potassium salt of dimethyl 2-hydroxyisophthalate is prepared by treating it with potassium hydride (KH) in toluene for about 20 minutes at about 0° C. under conditions effective to produce the potassium salt.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH:9]=[CH:8][C:7](=[O:11])[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[S:4][C:3]=1[C:18]#[N:19].I[C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.CN(C)CCO>[O:11]=[C:7]1[N:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]2[S:4][C:3]([C:18]#[N:19])=[C:2]([NH:1][C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: Cc1cccc(I)c1
Reactant: N#Cc1sc2c(ccc(=O)n2-c2ccccc2)c1N
Agent: [Cu]I
Agent: CN(C)CCO
Agent: O=P([O-])([O-])[O-]
Product: Cc1cccc(Nc2c(C#N)sc3c2ccc(=O)n3-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
The compound of Example 3 (5.00 g), 3-iodotoluene (4.85 ml), copper(I) iodide (0.36 g), K3PO4 (7.90 g), and N,N-dimethylethanolamine (50 ml) were placed in a pre-dried 250 ml round-bottom flask fitted with a reflux condenser. The flask was sealed, then evacuated and back-filled with nitrogen three times. The white/pink suspension was stirred by the action of a magnetic stirring bar and heated to 80° C. The reaction developed into a brown suspension and then on to a brown solution. After 1.5 hours at this temperature the reaction was shown to be complete by hplc. The reaction was cooled to room temperature, quenched by the addition of 100 ml of water, and stirred for a further 1 h at room temperature. Filtration of the resultant suspension, washing with a further 100 ml of water, gave, after drying, a crude green/brown solid (6.78 g). The crude product (6.00 g) was recrystallised from 4 volumes of AcOH, washed with EtOAc (50 ml) and then dried under vacuum to give the title compound as a yellow solid (4.16 g). δH (DMSO-d6) 7.60-7.70 (3H m), 7.40 (2H m), 7.35 (1H, d, J 9.7 Hz), 7.25 (1H, m), 6.85-7.00 (3H, m), 6.50 (1H d, J 9.7 Hz), 6.40 (1H, s), 2.35 (3H, s). LCMS (ES+) RT 3.85 minutes, 358 (M+H)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1([C:17]2[CH:31]=[CH:30][C:20]3[NH:21][C:22]([CH2:24][C:25]([O:27]CC)=O)=[N:23][C:19]=3[CH:18]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]#[N:40]>C1COCC1>[NH2:40][C:39]1[C:34]2[C:33](=[CH:38][CH:37]=[N:36][CH:35]=2)[NH:32][C:25](=[O:27])[C:24]=1[C:22]1[NH:21][C:20]2[CH:30]=[CH:31][C:17]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[CH:18][C:19]=2[N:23]=1
Reactant: N#Cc1cnccc1N
Reactant: CCOC(=O)Cc1nc2cc(N3CCOCC3)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(-c2nc3cc(N4CCOCC4)ccc3[nH]2)c(=O)[nH]c2ccncc12
Reaction time: 8 h

Procedure:
LiHMDS (3.3 eq) was added to ethyl (5-morpholin-4-yl-1H-benzimidazol-2-yl)acetate (1.0 eq) and 4-aminopyridine-3-carbonitrile (see J. Chem. Soc. 1967, p 1558–1564; 1.0 eq) in THF at 0° C. The reaction was stirred overnight. The resulting mixture was quenched with an aqueous saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. The crude material was washed successively with CH2Cl2 and MeOH, and then was purified by reverse phase HPLC to provide the desired product. LC/MS m/z 363.2 (MH+), Rt 1.55 minutes.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)C(=O)[C:2]1=[O:3].[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:18][O:17][C:12]1([O:15][CH3:16])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: COC(OC)OC
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC1(OC)C(=O)Nc2ccccc21
Yield: 76.2 %

Procedure:
In 500 ml of methanol were dissolved 14.7 g of isatin and 10.6 g of trimethyl orthoformate, and 100 mg of p-toluenesulfonic acid was added thereto. The mixture was heated under reflux for 7 hours, followed by concentration. To the residue was added chloroform, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=10/1) to give 14.7 g (76%) of the title compound as an oil.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
2-Acetylthiomethyl-3-phenylpropionic acid (18.5 g) is mixed with 70% aqueous methanol (100 ml), and the mixture is stirred at room temperature for one hour under nitrogen while maintaining at pH 13.0 with 20% aqueous sodium hydroxide solution, and thereafter the mixture is adjusted to pH 2.0 with 20% hydrochloric acid, and methanol is distilled off under reduced pressure. The residue is purified by a column chromatography using Diaion HP-20 (eluant, water-acetonitrile). The fractions containing the desired compound are collected and acetonitrile is distilled off under reduced pressure. The aqueous solution is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure to give 2-mercaptomethyl-3-phenylpropionic acid (8 g) as a colorless oily substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].FC(F)(F)S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O>>[F:20][C:19]([F:22])([F:21])[CH2:18][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:2])=[O:4])=[N:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cn1
Product: O=C(O)c1ccc(OCC(F)(F)F)cn1
Yield: 83.1 %

Procedure:
Analogous to the preparation of intermediate 49, 5-hydroxy-2-pyridinecarboxylic acid methyl ester (0.253 mL, 2.122 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.739 mL, 3.18 mmol) were combined to afford the title compound (390 mg, 1.764 mmol, 83%) as a white solid. MS m/z=222.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][N:12]=[C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:10]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][N:12]=[C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:16][CH2:15]2)[N:10]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COc1ccccc1-c1nc(N2CCNCC2)ns1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nc(N2CCN(C(=O)OCC(C)C)CC2)ns1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine (80 mg, 0.29 mmol) and triethylamine (61 μL, 0.43 mmol) in CH2Cl2 (0.5 mL) at 0° C. was added isobutyl chloroformate (59 mg, 0.43 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at 0° C. for 1 h, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield isobutyl 4-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate. LC/MS: m/z 377.5 (M+H)+ at 3.81 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>ClCCl>[CH3:14][S:15]([O:6][CH2:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:17])=[O:16]
Reactant: OCCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a solution of 2-cyclopropylethanol (2.1 g, 24.4 mmol) in dichloromethane (50 ml) at 0° C. under nitrogen was added triethylamine (4.1 ml, 1.3 mol equiv). Methanesulphonyl chloride (2.5 ml, 1.3 mol equiv) was added dropwise and the reaction stirred for 16 hours at room temperature. Water (30 ml) and dichloromethane (30 ml) were added. The organic phase was washed with water (2×50 ml) and then dried over anhydrous MgSO4. The solution was then filtered and the solvent removed in vacuo to give the title compound as an oil (4.0 g).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10]([P:16](=[O:19])([OH:18])[OH:17])([P:12](=[O:15])([OH:14])[OH:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+:21]>C(O)C>[K+:21].[C:1]1([C:7]2[CH2:11][C:10]([P:16](=[O:17])([OH:19])[O-:18])([P:12](=[O:13])([OH:14])[OH:15])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=P(O)(O)C1(P(=O)(O)O)CC(c2ccccc2)=NO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=P([O-])(O)C1(P(=O)(O)O)CC(c2ccccc2)=NO1

Procedure:
The free acid, [3-phenyl-5(4H)-isoxazolylidene]bisphosphonic acid, is then dissolved in ethanol (15 ml), treated with a solution of potassium hydroxide (560 mg, 10 mmol) in ethanol (10 ml), the precipitate collected and washed with ether to give the title compound, mp dec>250°; MS (m/e) 422, 384, 346 and 308; IR (mineral oil mull) 3054, 3029, 2317, 1609, 1572, 1497, 1206 and 1068 cm-1 ; NMR (D2O) 3.94 δ.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:23][N:24](C)C=O>O.Cl>[OH:16][C:15]1[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:23]#[N:24])=[CH:3][CH:4]=2)=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: O=C(c1ccc(Br)cc1)c1ncccc1O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)c2ncccc2O)cc1
Temperature: 90 °C
Yield: 45 %

Procedure:
10 g (35.96 mM) of (4-bromophenyl)(3-hydroxy-2-pyridinyl)methanone are mixed with 6.44 g (71.92 mM) of cuprous cyanide in 90 ml of dimethylformamide. The mixture is refluxed for 21 h. A solution of 19.25 g of ferric chloride in 42.5 ml of water and 6.7 ml of concentrated hydrochloric acid is prepared and added to the cooled reaction medium and the resulting mixture is then heated at 90° C. for 30 minutes. After cooling, ethyl acetate and water are added and the mixture is filtered on Celite. The product is then extracted with ethyl acetate and the organic phase is washed with saturated sodium chloride solution. The solvent is evaporated off under reduced pressure to give the desired product in the form of a yellow solid with a yield of 45%.