Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([Se]C2C=CC=CC=2)[CH3:10])[N:6]=[C:5]([NH2:18])[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.CCOCC>[CH:9](=[C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH2:18])[NH:6]1)[CH3:10]
Reactant: COc1cc(C(C)[Se]c2ccccc2)nc(N)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: CC=C1C=C(OC)N=C(N)N1
Temperature: 25 °C
Yield: 7.8 %

Procedure:
To a stirring solution of 4-methoxy-6-[1-(phenylselenyl)ethyl]-2-pyrimidinamine (14.3 mmol) in 100 ml of CH2Cl2 cooled to -78° C. was added in one portion m-chloroperbenzoic acid (14.3 mmol). The solution was warmed to room temperature, diluted with ether and filtered. A white crystalline solid (0.17 g), m.p. 119°-122° C. was isolated. NMR (200 MHz, CDCl3) δ 3.87 (s, 3H); 5.9 (br s, 2H); 5.5 (d, d, 1H); 6.0 (s, 1H); 6.2-6.6 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].C([N-]C(C)C)(C)C.[Li+].Cl([F:39])(=O)(=O)=O>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:39])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)isoindoline (1.0 g. 2.8 mmol) in tetrahydrofuran (10 mL) is added lithium diisopropylamide (1.5 mL, 3.0 mmol, 2 M) at. After 30 minutes, perchloryl fluoride (5 mmol) is bubbled into the mixture. The mixture is allowed to reach room temperature and the solvent then removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and 1N hydrochloric acid (10 mL) for one hour. The organic layer is separated and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through chromatography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][CH:26]=[C:27]([C:29]([NH2:31])=O)[N:28]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][CH:26]=[C:27]([C:29]#[N:31])[N:28]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(N)=O)cs3)cc12
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C#N)cs3)cc12
Yield: 91.4 %

Procedure:
A solution of tert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.32 g, 0.6 mmol) and cyanuric chloride (0.33 g, 1.8 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-6-(4-cyano-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.28 g, 93.3%) as crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([NH2:12])=[C:5]2[C:13]#[N:14].[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br)([O-:17])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([NH2:12])=[C:5]2[C:13]#[N:14])([O-:17])=[O:16]
Reactant: Cn1c(N)c(C#N)c2cc(O)ccc21
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(N)c(C#N)c2cc(OCc3cccc([N+](=O)[O-])c3)ccc21
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of 5-hydroxy-2-amino-1-methyl-1H-indole-3-carbonitrile (100 mg; 0.53 mmol) and 3-nitrobenzyl bromide (130 mg; 0.6 mmol) in DMF (5 ml) was treated with Cs2CO3 (520 mg; 1.6 mmol) and the mixture was stirred for 2 hours. Water (80 ml) was added and the precipitate was filtered, taken up in methanol, filtered, washed and dried to give 5-(3-nitrobenzyloxy)-2-amino-1-methyl-1H-indole-3-carbonitrile (96 mg).
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[IH:13]>>[I:13][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2
Reactant: I
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Product: O=C1C2CC3CC1CC(I)(C3)C2

Procedure:
Simple unit processes allow the conversion of several of the abovementioned X or X1 substituents, or others known in the art, to 5-X- or 5-X1 -adamantane-2-ones where X or X1 may be trialkylsilyloxy, iodo or cyano groups. These moieties are stable under the mild conditions used in step 4 of the foregoing reaction sequence. For example, when 5-hydroxyadamantan-2-one is refluxed for 7 hours with 57% hydriodic acid, 5-iodoadamantan-2-one (m.p. 73°-76° C.) is obtained. 5-Carboxyadamantan-2-one, prepared as described in Lantvoev, J. Obshch. Khim., 12, 2361 (1976) or Le Noble, et al., J. Org. Chem., 48, 1101 (1983), after saponification of the methyl ester, can be converted to 5-cyanoadamantan-2-one by the three step procedure of Tabushi, et al., J. Org, Chem., 38, 3447 (1973), used for access to the isomeric 1-cyanoadamantan-2-one through the intermediacy of a keto amide. 5-Trimethylsilyloxyadamantan-2-one (m.p. 34°-38° C.), useful as a protected version of 5-hydroxyadamantan-2-one, allows the use of only one equivalent of base in step 4 of the foregoing reaction sequence to prepare the corresponding enol ether, which can then be desilylated using standard techniques.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH3:3].[H-].[Na+].[Cl:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19].[ClH:22].[OH-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O>[ClH:14].[ClH:22].[CH2:16]([N:17]([CH2:20][CH3:21])[CH2:18][CH2:19][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][N:2]([CH3:1])[CH3:3])[CH3:15]
Reactant: CN(C)Cc1ccccc1O
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccccc1CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(N,N-dimethylaminomethyl)phenol (10.0 g, which contains 30% phenol by weight) in DMF (10 ml) was added dropwise with stirring to a suspension of sodium hydride (3.14 g, 60% dispersion in mineral oil) in DMF (75 ml) at ambient temperature under nitrogen. After the addition the mixture was stirred at ambient temperature for 30 minutes. A solution of 2-chloro-N,N-diethylethylamine in toluene (70 ml) [prepared by dissolving the hydrochloride (14.8 g) in water (20 ml), adding aqueous sodium hydroxide (5M) to basify the mixture and then extracting the mixture with toluene 3×20 ml, drying, filtering and then making up to 70 ml as required] was added dropwise over a period of 2 minutes and the resulting mixture heated on a steam bath for 18 hours under nitrogen. The mixture was poured into ice/water (500 ml) and sodium hydroxide solution was added until the mixture was basic (pH=14). The mixture was extracted with ether to give a residue which was distilled under vacuum. The highest boiling fraction (b.p. 105°-110° C. at 0.6 mbar) was dissolved in ether and acidified with ethereal hydrogen chloride. The solvent was removed under reduced pressure. The residue was dissolved in propan-2-ol and ether added to induce precipitation. The solid was collected by filtration and recrystallised from propan-2-ol to give 2-(2-diethylaminoethoxy)-N,N-dimethylbenzylamine dihydrochloride, m.p. 213°-214° C.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C@H:15]([O:17]C=O)[CH3:16])[C:9]1=[O:20])[C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+]>CO.C(O)(=O)C>[CH3:21][C:2]([CH3:1])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C@H:15]([OH:17])[CH3:16])[C:9]1=[O:20])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CC[C@@H]1[C@@H]([C@@H](C)OC=O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CC[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Methyl 3-methyl-2-[(3S,4R)-3-[(1R)-1-formyloxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate (23 mg) was dissolved in methanol (1 ml) and cooled to 0° C. To this solution was added a solution of sodium methoxide in methanol (0.49 M, 0.16 ml) and the mixture was stirred for 1 hour at the same temperature. An additional 0.08 ml of the sodium methoxide solution was added and the mixture was stirred for 30 minutes at the same temperature. Acetic acid (2 drops) was then added and the mixture was evaporated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography (silica gel) developing with methylene chloride and ethyl acetate (2:1) to give methyl 3-methyl-2-[(3S,4R)-3-((1R)-1-hyroxyethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (20 mg).
Reaction SMILES: [ClH:1].C([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8]1)=[O:6])C>O>[ClH:1].[CH3:16][O:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CCN(CCOC)CC1
Agent: Cl
Solvent: O
Product: COCCN1CCC(C(=O)O)CC1
Temperature: 100 °C
Yield: 81 %

Procedure:
Concentrated hydrochloric acid (200 ml) was added to a suspension of the product of Example 4 Step 1 (20 g, 93 mmol) in water (120 ml). The mixture was heated at 100° C. for 60 hours, cooled to room temperature and the solvent concentrated in vacuo. The residue was azeotroped with toluene (×5) and dried over phosphorus pentoxide. The resulting solid was triturated with diethyl ether and acetone to yield the title compound (14.0 g, 81%); MS (ES−) m/e 186 [M−H]−.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][OH:26])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Si:11]([O:18][C@@H:19]1[CH2:20][CH2:21][C@H:22]([CH:25]=[O:26])[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C=O)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
16.4 g (129.47 mmol) oxalyl chloride are dissolved in 600 ml of dichloromethane and cooled to −78° C. 20.2 g (258.95 mmol) of dimethyl sulfoxide are then slowly added dropwise. The mixture is stirred for 5 min. After addition of a solution of 21.1 g (86.32 mmol) of the compound from Example 53A in 200 ml of dichloromethane the mixture is stirred at −78° C. for 1 h. 60 ml (431.58 mmol) of triethylamine are then slowly added dropwise. Over a period of one hour, the reaction mixture is then warmed to RT, and 500 ml of saturated aqueous sodium bicarbonate solution are then added. The phases are separated, the organic phase is dried over sodium sulfate and the solvent is removed on a rotary evaporator. The residue is purified chromatographically on silica gel 60 (mobile phase: gradient petroleum ether→petroleum ether/ethyl acetate 9:1).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]3)[N:27]=[C:26]([O:39][CH3:40])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:32][CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH2:36]3)[N:27]=[C:26]([O:39][CH3:40])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCN(c2nc(OC)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)CC1
Solvent: CO
Product: CCN1CCN(c2nc(OC)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC1
Yield: 97.9 %

Procedure:
A solution of ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(4-ethyl-1-piperazinyl)-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-3-oxopropyl)[(phenylmethyl)oxy]formamide (0.145 g, 0.26 mmol), and Pd(C) (0.030 g) in MeOH (10 mL) was run under standard hydrogenation conditions as in General Procedure A, Part C, to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(4-ethyl-1-piperazinyl)-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide as a red solid (0.119 g, 98%). LCMS: (M+H)+=468.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[F:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1O>CCOC(C)=O>[F:18][C:19]1[C:20]([O:12][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:21]([F:28])[C:22]([F:27])=[C:23]([F:26])[C:24]=1[F:25]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)c1ccccc1NCc1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.9 %

Procedure:
To a stirred suspension of 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid (preparation 1, 300 mg) in EtOAC (10 ml) was added 2,3,4,5,6-pentafluorophenol (413 mg) followed by drop-wise addition of a solution of N,N-dicyclohexyl-carbodiimide (461 mg) in EtOAc (5 ml). The reaction mixture was stirred at room temperature for 15 hours. The formed precipitate was removed by filtration and the filtrate was evaporated under reduced pressure. The remaining material was subjected to column chromatography on silica gel (petroleum ether/EtOAc as eluent) and gave the title compound (352 mg). 13C-NMR (DMSO-d6) δ 163.2, 151.4, 149.7, 148.1, 140.9, 138.9, 137.6, 136.9, 131.9, 124.7, 121.9, 115.6, 112.5, 105.5, 44.7.
Reaction SMILES: [CH3:1][C:2](=[CH2:7])[C:3]#[C:4][CH2:5][OH:6].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[CH:24]([SiH:27]([CH:29]([CH3:31])[CH3:30])Cl)([CH3:26])[CH3:25]>>[CH3:7][C:2](=[CH2:1])[C:3]#[C:4][CH2:5][O:6][SiH:27]([CH:29]([CH3:31])[CH3:30])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: C=C(C)C#CCO
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: C=C(C)C#CCO[SiH](C(C)C)C(C)C
Yield: 89.5 %

Procedure:
4-Methylpent-4-en-2-yn-1-ol (2.0 g, 20.80 mmol), dimethylaminopyridine (0.252 g, 2.1 mmol), triethylamine (2.126 g, 21.01 mmol) and diisopropylchlorosilane (3.135 g, 20.80 mmol) were used according to the general procedure described above. The resulting clear, light yellow colored crude compound was purified by flash chromatography to yield pure product (3.914 g, 18.62 mmol, 89.5%) as clear colorless solution: Rf 0.82 (hexanes/Et2O, 9:1); 1H NMR (500 MHz, CDCl3) δ 5.28 (bs, 1H, H-5), 5.22 (bs, 1H, H-5), 4.49 (s, 1H, H-1), 4.21 (s, 1H, H-7), 1.88 (s, 3H, H-6), 0.74-1.37 (m, 14H, H-8, 9); 13C NMR (300 MHz, CDCl3) δ 126.5 (C-4), 121.8 (C-5), 86.5 (C-3), 86.3 (C-2), 54.3 (C-1), 23.2 (C-6), 17.3 (C-9), 17.2 (C-9), 12.3 (C-8); Anal. calcd for C12H22OSi: C, 68.51; H, 10.54. Found: C, 68.32; H, 10.73.
Reaction SMILES: [Na:1].[NH2:2][C:3]([P:9]([OH:12])(=[O:11])[OH:10])([P:5]([OH:8])(=[O:7])[OH:6])[CH3:4].[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[Na:1].[C:13]([NH:2][C:3]([P:5]([OH:8])(=[O:6])[OH:7])([P:9]([OH:12])(=[O:10])[OH:11])[CH3:4])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)(P(=O)(O)O)P(=O)(O)O
Agent: [Na]
Solvent: O
Product: CC(=O)NC(C)(P(=O)(O)O)P(=O)(O)O

Procedure:
22.7 g. (0.1 mole) of the mono-sodium salt of 1-amino ethane-1,1-diphosphonic acid are boiled under reflux in 30.6 g. (0.3 moles) of acetic acid anhydride for about 30 minutes. A clear solution is obtained. On cooling, a viscous yellowish sirup is produced. The sirup can be diluted with water and the aqueous solution can be used directly. In order to recover the crystalline reaction product, the sirup is added with stirring to 40 cc. of glacial acetic acid and the resulting crystalline product is filtered off by suction. After drying, 20.3 g. of the mono-sodium salt of N-acetyl-1-amino ethane-1,1-diphosphonic acid, corresponding to 75.4 % of the theoretical yield, are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@@H:13]([CH:15]=[C:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[NH:12][CH2:11][C@@H:10]2[O:22][CH:23]([C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][N:39]([CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]=3[CH:48]=2)[S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:5][CH:4]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:14][C@@H:13]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[NH:12][CH2:11][C@@H:10]2[O:22][CH:23]([C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][N:39]([CH2:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]=3[CH:48]=2)[S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(C(O[C@H]3CN[C@H](C=C4CCOCC4)C[C@@H]3c3ccc(OC)cc3)S(=O)(=O)c3ccc(C)cc3)cc21
Solvent: CCO
Product: COCCCN1CCOc2ccc(C(O[C@H]3CN[C@H](CC4CCOCC4)C[C@@H]3c3ccc(OC)cc3)S(=O)(=O)c3ccc(C)cc3)cc21

Procedure:
According to general procedure E (using ethanol as solvent), 6-[(3R,4R,6S)-4-(4-methoxy-phenyl)-6-(tetrahydro-pyran-4-ylidenemethyl)-1-(toluene-4-sulfonyl)-piperidin-3-yloxymethyl]-4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazine is used to afford the title compound, which is identified based on its Rf value.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15]1([N:21]2[C:33]3C=C(B4OC(C)(C)C(C)(C)O4)C=C[C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.COCCOC>[C:15]1([N:21]2[C:22]3[CH:23]=[C:24]([C:2]4[CH:3]=[CH:4][C:5]5[NH:6][C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)[CH:25]=[CH:26][C:27]=3[C:28]3[C:33]2=[CH:3][CH:2]=[CH:14][CH:13]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: CC1(C)OB(c2ccc3c4ccccc4n(-c4ccccc4)c3c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: c1ccc(-n2c3ccccc3c3ccc(-c4ccc5[nH]c6ccccc6c5c4)cc32)cc1
Temperature: 25 °C
Yield: 156.6 %

Procedure:
Next, a mixed solution of 4.0 g of 3-bromocarbazole, 6.6 g of 9-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-9H-carbazole, 18 ml of a 2M aqueous potassium carbonate solution, 80 ml of 1,2-dimethoxyethane, 72 mg of palladium acetate and 243 mg of tris(2-methylphenyl)phosphine was refluxed for 6 hours under a nitrogen flow. The solution was cooled to room temperature, and then extracted with toluene. The organic layer was washed with water twice, dried over magnesium sulfate, and then evaporated. The resultant concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 5.2 g of 9-phenyl-9H,9′H-2,3′-bicarbazole.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].N[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH2:23][CH3:24])=[CH:21][C:20]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[N:19]2)=[CH:14][CH:13]=1>C(O)(=O)C.[Ni]>[CH2:23]([C:22]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:5][CH2:4][C:3]3[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=3[F:1])=[CH:13][CH:14]=2)[N:19]=[C:20]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=1)[CH3:24]
Reactant: Cc1cccc(F)c1C#N
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [Ni]
Solvent: CC(=O)O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(NCc2c(C)cccc2F)cc1
Reaction time: 7 h
Yield: 49.7 %

Procedure:
A mixture of 2-chloro-6-methylbenzonitrile (5 g, 33.0 mmol) and CsF (14 g, 92.2 mmol) in DMSO (30 ml) was heated at 140° C. for 15 hr and then allowed to cool to room temperature. It was diluted with water, extracted with dichloromethane, washed with brine, dried (Na2SO4) and concentrated to give 2-fluoro-6-methylbenzonitrile (2.93 g, 66%). A mixture of the above nitrile (250 mg), 1-(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (200 mg, 0.76 mmol) and Raney Ni (50% in water, 100 mg) in glacial acetic acid (15 ml) was shaken in a Parr apparatus under H2 (40 psi) for 7 hr. The catalyst was removed by filtration and the solvent was evaporated. Chromatography on silica gel (hexane/ethyl acetate=2:1) afforded the title compound (146 mg). 1H-NMR (CDCl3): 1.30 (t, J=7.5 Hz, 3H), 2.46 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 3.92 (bs, 1H), 4.38 (s, 2H), 6.58 (s, 1H), 6.78 (d, J=8.6 Hz, 2H), 6.99 (t, J=6.8Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.19-7.38 (m, 4 H), 8.20 (d, J=7.8 Hz, 1H), 8.56 (d, J=3.7Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([CH:32]1[C:36](=[O:37])[O:35][C:34](Cl)([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:34]2([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[CH2:33][CH:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:36](=[O:37])[O:35]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Reactant: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC(Cc3ccccc3)C(=O)O2)C1=O)OCc1ccccc1
Yield: 51 %

Procedure:
In 1 ml of dichloromethane were dissolved 55 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 0.07 ml of triethylamine. To the solution was added, under ice-cooling while stirring, 100 mg of the Compound (74) obtained in Example 74. The reaction solution was stirred at room temperature for 30 minutes, to which was added 25 ml of ethyl acetate. The mixture was washed with water, an aqueous solution of sodium hydrogen carbonate and water, successively, which was then dried (MgSO4), followed by evaporating off the solvent. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1) to give 70 mg of the subject Compound (75) as a pale yellow oily product. The IR and NMR spectra are in agreement with those of the Compound (75) obtained in Example 75.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1nccc2cnccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2cnccc12

Procedure:
1-Hydroxy-2,6-naphthyridine (550 mg) [prepared according to the method of Sakamoto, T. et al Chem, Pharm. Bull. 33, 626, (1985)] was stirred with phosphorous oxychloride (10 ml) at 110° for 5 h. The volatiles were removed in vacuo and the residue treated carefully with ice. After diluting with water (to ˜25 ml), solid NaHCO3 was added to effect neutralisation and the product extracted into EtOAc (2×80 ml). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the crude product chromatographed (SiO2; EtOAc) affording the title compound as a slightly yellow solid (420 mg, 68%). δH (CDCl3) 9.35 (1H, s), 8.82 (1H, d, J 5.9 Hz), 8.48 (1H, d, J 5.6 Hz), 8.00 (1H, d, J 5.9 Hz), 7.74 (1H, d, J 5.6 Hz); m/z (ES+, 70V) 165 and 167 (MH+).