Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCOCC1.O>[OH:4][CH2:3][C@@H:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H](CO)C[C@H]1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@H](CO)C[C@H]1CCCOC1)OCc1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
To a solution of (5)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-1-ol (50 g, 312.5 mmol) and K2CO3 (129.375 g, 937.5 mmol) in dioxane (250 mL) and water (250 mL) at 0° C. was added CbzCl (106.6 g, 625 mmol) dropwise. The reaction mixture was stirred at room temperature until the staring material disappeared. The organic solvent was distilled and the residue was dissolved in AcOEt (200 mL). The organic phase was separated and the water was extracted with AcOEt (3×100 ml). The combined organic phase was washed with water (3×50 ml), dried over Na2SO4, and concentrated in vacuo to give the residue, which was purified by column to give the product (26 g). 1H NMR (CD3OD) 1.1-1.3 (m, 2H), 1.4-1.5 (m, 1H), 1.5-1.7 (m, 3H), 1.8-1.9 (m, 1H), 2.6-2.8 (m, 1H), 3.0-3.1 (t, 1H), 3.3-3.4 (m, 1H), 3.5-3.6 (m, 1H), 3.6-3.8 (m, 2H), 3.8-3.9 (m, 2H), 5.0-5.1 (s, 2H), 7.3-7.4 (m, 5H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([C:11]1[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.[Cl:31][C:32]1[CH:33]=[C:34]([OH:39])[CH:35]=[CH:36][C:37]=1[Cl:38]>CN(C=O)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][C:37]=1[Cl:38])[O:39][C:11]1[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Oc2ccc(Cl)c(Cl)c2)nc2oc(-c3cccc(C)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
103 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine were added to a solution of 49 mg of 3,4-dichlorophenol in 3 ml of DMF. The mixture was stirred at room temperature for 2 h. After filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 54 mg of the title compound.
Reaction SMILES: FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1.N1CC[C@H](O[N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])C1.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:22]1(=[O:31])[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29](=[O:30])[NH:21]1
Reactant: O=C1c2ccccc2C(=O)N1O[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
3-Trifluoromethylphenylsulfonyl chloride (1.96 g, 8.00 mmol) was added to a solution of (S)-2-(pyrrolidin-3-yloxy)isoindoline-1,3-dione) trifluoroacetic acid salt (2.77 g, 8.00 mmol) and N,N-diisopropylethylamine (3.10 g, 24.0 mmol) in CH2Cl2 (50 ml) and stirred at room temperature for 4 hours. The reaction mixture was washed with aqueous 1 N HCl solution (50 ml×2), H2O (50 ml×3) and brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 12.5/87.5 to 50/50) to give (S)-2-(1-(3-trifluoromethyl)phenylsulfonyl)pyrrolidin-3-yloxy)isoindoline-1,3-dione (1.87 g, 53%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][C@@H:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:17]([O:16][C:14]([C:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=1[NH:28][C@@H:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: C[C@@H](N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(N[C@H](C)c2ccccc2)CN(C(=O)OC(C)(C)C)CC1
Yield: 100.2 %

Procedure:
In a dry flask equipped with a Dean-Stark trap and reflux condenser, ethyl 1-(t-butoxycarbonyl)-3-oxo-4-piperidinecarboxylate (4.19 g, 15.4 mmol) was dissolved in toluene (50 mL). (R)-(+)-a-Methylbenzylamine (1.91 g, 15.8 mmol) and p-toluenesulfonic acid monohydrate (0.019 g, 0.1 mmol) were added and the mixture heated to reflux for 6 hours. The crude reaction mixture was concentrated in vacuo to give the desired amine (5.78 g, 100%) as a thick orange oil. 1H NMR (300 MHz, CDCl3), δ: 7.36 (t, J=3, 2H), 7.33 (t, J=4, 1H), 7.31 (dd, J=3, J′=4, 2H), 4.59 (m, 1H), 4.16 (q, J=7, 2H), 3.59 (m, 2H), 2.34 (m, 2H), 1.58 (bs, 2H), 1.52 (d, J=3, 3H), 1.29 (s, 9H), 1.26 (t, 3H, J=7). MS (ESI), m+/z: (M+H)+=375.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[CH:12])[CH:6]=1)[CH3:2].I[C:15]1[CH:27]=[CH:26][C:18]2[O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][C:17]=2[CH:16]=1.C1COCC1.C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCCCCC>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][C:15]2[CH:27]=[CH:26][C:18]3[O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][C:17]=3[CH:16]=2)[CH:6]=1)[CH3:2]
Reactant: CC1(C)COc2ccc(I)cc2OC1
Reactant: C#Cc1cccc(C(=O)OCC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)c1
Yield: 54.9 %

Procedure:
To a mixture under N2 of 3-ethynyl-benzoic acid ethyl ester (9) (50 mg), 7-iodo-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (5) (87 mg) (example 1b), [PdCl2(PPh3)2] (10 mg) and copper(I) iodide (5.5 mg) is added a degassed mixture of THF (2.5 ml) and diisopropylamine (2.5 ml). After 5.5 h stirring at RT hexane (15 ml) is added and the mixture is washed with 1 N aq. HCl sol. (2×15 ml), H2O (15 ml) and brine (15 ml). After drying over MgSO4 the solvent is evaporated and the product is purified by flash chromatography (silica gel, hexane/1% AcOEt). 55 mg of 3-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-benzoic acid ethyl ester (10) are obtained as a colourless gum, MS (ESI) 350.2 (M•)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH:40][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:39][CH2:38]5)[CH:17]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: NC1(c2ccccc2)CC1
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclopropanamine hydrochloride (0.040 g, 0.20 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.40 (s, 1H), 8.90 (d, J=7.32 Hz, 1H), 8.35 (s, 1H), 8.11 (d, J=1.22 Hz, 1H), 8.03 (d, J=7.93 Hz, 1H), 7.98 (d, J=7.63 Hz, 2H), 7.90 (dd, J=8.70, 5.65 Hz, 2H), 7.65 (t, J=7.78 Hz, 1H), 7.49 (dd, J=7.32, 1.83 Hz, 1H), 7.28-7.35 (m, 4H), 7.23-7.26 (m, 2H), 7.15-7.20 (m, 1H), 2.81 (d, J=4.58 Hz, 3H), 1.32 (d, J=9.16 Hz, 4H). LCMS: retention time: 3.053 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 505 (MH+).
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([O:3][CH3:4])=[O:2].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](=[O:7])[CH2:5][C:1]([O:3][CH3:4])=[O:2]
Reactant: CNc1ccccc1
Reactant: COC(=O)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC(=O)N(C)c1ccccc1
Reaction time: 0.07 h

Procedure:
The carbomethoxy acetyl chloride mixture is cooled in an ice-salt bath to -5 to 0° and N-methyl aniline (55.64 g, 0.52 mol) in methylene chloride (200 ml) is added at a rate so as to maintain the temperature of the reaction mixture between -5 to 0°. The addition is performed using an addition funnel and can normally be carried out over a 3-5 min time period to control the slight exotherm. Pyridine (66.36 g, 0.84 mol) in methylene chloride (200 ml) is then added to the above mixture. The addition rate is adjusted so as to keep the temperature of the reaction between -5 to 0° during the addition. The addition is performed using an addition funnel and can normally be carried out over a 3-5 min time period to control the slight exotherm. After the addition is complete (as measured by HPLC) the reaction is quenched by pouring the reaction mixture into water (500 ml) and stirring continued for 30 min. The reaction is equilibrated and the methylene chloride layer separated. Additional methylene chloride (400-500 ml) is added and the methylene chloride mixture is washed successively with hydrochloric acid (1N, 2×300 ml), saturated sodium bicarbonate solution (2×300 ml), saline (1×600 ml) and the methylene chloride mixture dried through anhydrous sodium sulfate. Concentration of the mixture under reduced pressure at 40-45° gives the title compound, HPLC (Nucleosil column; acetonitrile/water, 45/55, 1 ml/min, UV=229 nm; Retention times for N-methyl-N-phenyl-α-carbomethoxyacetamide~6.0 min; N-methyl aniline~11.0-12.0 min.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)#[N:8]>CN(C=O)C>[NH:1]1[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]2)=[N:8][N:3]=[N:2]1
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)CC1
Reaction time: 24 h
Yield: 19.3 %

Procedure:
NaN3 (1.7 g, 26.14 mmol) and NH4Cl (1.75 g, 32.7 mmol) were added to the solution of benzyl 4-cyanopiperidine-1-carboxylate (1.6 g, 26.14 mmol) in DMF (16 mL) and stirring was continued at 90° C. for 24 h. The reaction mixture was quenched with 10% aqueous citric acid solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 1.45 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:21][CH:22](OC)[CH:23]=[CH2:24].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:24]=[CH:23][CH:22]=[O:21])[CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2ccn1Cc1ccccc1
Reactant: C=CC(OC)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=CC=Cc1ccc2c(=O)n(Cc3ccccc3)ccc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-benzyl-6-bromo-1,2-dihydro-1-oxoisoquinoline (1 g, 3.2 mmol), acrolein dimethyl acetal (2.6 mL, 22.4 mmol), Pd(OAc)2 (15 mg, 0.064 mmol), P(o-tolyl)3 (78 mg, 0.26 mmol) and Et3N (0.5 mL, 3.84 mmol) in DMF (2 mL) is heated in a sealed tube apparatus at 120° for 48 hours. After cooling to room temperature, the reaction mixture is diluted with EtOAc, filtered, washed with saturated NaCl solution, dried over MgSO4 concentrated in vacuo, and the residue is chromatographed (silica gel 1:4 EtOAc/hexane) to yield 3-[2-benzyl-1-oxo-1,2-dihydroisoquinolin-6-yl]-acrolein.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9](CO)[CH:8]=[CH:7]2.[C-]#[N:15].[K+].C1O[CH2:33][CH2:32]OCCOCCOCCOCCOC1.P(CCCC)(CCCC)CCCC.C(Cl)(Cl)(Cl)Cl>C(#N)C.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:32][C:33]#[N:15])=[CH:9][CH:8]=[CH:7]2
Reactant: [C-]#N
Reactant: OCc1ccc2cccc(Br)c2c1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: N#CCc1cccc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 637.7 %

Procedure:
According to the procedure of A. Mizuno, et al. Synthesis 1007 (1980), a mixture of 8-bromo-2-hydroxymethylnaphthalene (1.70 g, 7.17 mmol), KCN (0.93 g, 14.34 mmol) and 18-crown-6 (0.19 g, 0.72 mmol) in acetonitrile (24 mL) was stirred at room temperature for 15 minutes. A mixture of n-Bu3P (1.60 g, 7.89 mmol) and acetonitrile (7 mL) was added. The mixture was cooled to 0° C., and a solution of CCl4 (1.21 g, 7.89 mmol) in acetonitrile (7 mL) was added. The resulting mixture was stirred at room temperature for two days. Ether (300 mL) was added and the mixture was washed with 10% aqueous citric acid (150 mL). CCl4 (20 mL) was added and the mixture was washed with H2O (2×150 mL); saturated aqueous NaCl (150 mL), dried (MgSO4), and concentrated. The crude material was purified by flash chromatography (eluant EtOAc/hexane (5:95), to EtOAc/hexane (20:80)) to give a yellow solid (1.13 g, 64%), m.p. 55°-56° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:21][NH:20][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc2c(c1)ncn2-c1ccnc(NCC2CCCCC2)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with aminomethylcyclohexane according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): 308.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.64 (s, 1H); 8.39 (br s, 1H); 8.23 (br s, 1H); 7.87 (m, 1H); 7.41 (m, 2H); 6.78 (d, J=5.5 Hz, 1H); 5.50 (br s, 1H); 3.39 (t, J=6.3 Hz, 2H) 1.70-1.93 (m, 6H); 1.18-1.38 (m, 3H); 1.02-1.12 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:6][CH:7]=1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>O>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:5]1[N:6]=[CH:7][C:2]([CH:17]=[O:16])=[CH:3][CH:4]=1
Reactant: Fc1ccccc1Oc1ccc(Br)cn1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccccc2F)nc1
Temperature: 0 °C
Yield: 53 %

Procedure:
To a mixture of 5-bromo-2-(2-fluoro-phenoxy)-pyridine (500 mg, 1.9 mmol) described in Manufacturing Example 74-1-1 and tetrahydrofuran (7 mL) was added n-butyl lithium (1.7 mL, 1.5 M n-hexane solution, 2.6 mmol) under nitrogen atmosphere at −78° C. N,N-dimethylformamide (0.29 mL, 3.7 mmol) was added to the reaction mixture at the same temperature, and the temperature was then gradually raised to 0° C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (210 mg, 53%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]([P:17](=[O:22])([O:20]C)[O:18]C)([P:11](=[O:16])([O:14]C)[O:12]C)[OH:10])C(=O)C2=CC=CC=C12.Cl>>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]([P:17](=[O:18])([OH:20])[OH:22])([P:11](=[O:12])([OH:14])[OH:16])[OH:10]
Reactant: COP(=O)(OC)C(O)(CCCN1C(=O)c2ccccc2C1=O)P(=O)(OC)OC
Agent: Cl
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O

Procedure:
contacting tetramethyl phthalimido-1-hydroxybutylidene-bisphosphonate from Step (b) with aqueous hydrochloric acid at a temperature range of 80° C. to reflux to form 4-amino-1-hydroxybutylidene-bisphosphonic acid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([SH:13])[CH2:11][SH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:14]([O:16][CH:17](OCC)OCC)[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH:10]1[CH2:11][S:12][CH:17]([O:16][CH2:14][CH3:15])[S:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(S)CS
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC1SCC(CO[Si](C)(C)C(C)(C)C)S1
Reaction time: 6 h
Yield: 94 %

Procedure:
To a solution of 1-t-butyldimethylsilyloxy-2,3-dimercaptopropane (example 47) (32.00 g, 134 mmol) in toluene (400 mL) were added triethylorthoformate (29.0 mL, 174 mmol, 1.3 eq) and pyridinium p-toluenesulfonate (200 mg). The solution was strirred at 120°-130° C. for 6 hr then was quenched at room temperature with a solution of saturated sodium bicarbonate. The aqueous phase was extracted with dichloromethane and the organic layer was dried with magnesium sulfate and evaporated under reduced pressure. The crude product was obtained in 94% yield (37.17 g) as a 1:1 mixture and was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:7]2=[N:8][C:9]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:10][C:11](=[O:12])[N:6]2[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][N:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](Cl)=[O:37])=[CH:35][C:30]=2[N:29]=[N:28]1.O>O1CCCC1>[CH3:26][N:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]([NH:1][CH:2]3[C:7]4=[N:8][C:9]([C:13]5[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=5)=[CH:10][C:11](=[O:12])[N:6]4[CH2:5][CH2:4][CH2:3]3)=[O:37])=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: NC1CCCn2c1nc(-c1ccncc1)cc2=O
Reactant: Cn1nnc2cc(C(=O)Cl)ccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nnc2cc(C(=O)NC3CCCn4c3nc(-c3ccncc3)cc4=O)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
To a solution of 0.050 g (0.21 mmol) of (+/−)9-amino-2-pyridin -4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one dissolved in 2.2 mL of tetrahydrofuran was added 30 μl (0.25 mmol) of triethylamine and 0.0484 g (0.25 mmol) of 1-methyl-1H-1,2,3-benzotriazole-5-carbonyl chloride. The resulting mixture was stirred at room temperature for 16 h. Water was added and the mixture extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of ammonium chloride, dried and evaporated. The residue was purified by silica gel chromatography, eluting with dichloromethane/methanol/ammonia in the proportions 95/5/0.5 to give 0.041 g of pure product obtained in the form of free base.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=[O:15])[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=1)[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc(C(=O)O)c1
Reaction time: 3 h

Procedure:
A suspension of mono-methyl 5-nitro-isophthalate (22.5 g, 100 mmol) and palladium on carbon (5%, 2.00 g) in methanol (100 mL) is shaken in a hydrogenation apparatus under hydrogen (50 psi) for 3 hours. The mixture is then filtered through diatomaceous earth and concentrated to give the title compound, NMR (300 MHz, CDCl3) beta 7.67, 7.41, 7.40 and 3.83; MS (ESI−) for C9H9NO4 m/z (M−H)−=194.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1>CCOCC>[Br-:11].[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P+:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: [Br-]
Product: c1ccc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 145 g. of 4-phenyl-1-bromobutane and 179 g. of triphenylphosphine in 350 ml. of toluene is heated at reflux under nitrogen for 16 hours. The mixture is then cooled slowly and ether is added giving a precipitate of (4-phenylbutyl)triphenylphosphonium bromide which is washed thoroughly with benzene/ether and dried 18 hours at 50° C. under reduced pressure, 268 g., m.p. 139°-140° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH3:22])[CH:16]=1.C(Cl)CCl>C(Cl)Cl>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(N)ccc1O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To 3-(trifluoromethyl)benzoic acid (380 mg, 2.00 mmol), 4-amino-2-methylphenol (271 mg, 2.20 mmol) and EDC (767 mg, 4.00 mmol) was added CH2Cl2 (80 mL). The resulting mixture was stirred for 66 hours at RT, concentrated, dissolved in EtOAc and washed with water. The organics were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc/hexanes) to yield N-(4-hydroxy-3-methylphenyl)-3-(trifluoromethyl)benzamide as a white solid. MS m/z=296 [M+1]+. Calc'd for C15H12F3NO2: 295.26.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1)(C)C.[SiH](CC)(CC)[CH2:21][CH3:22].C(=O)C.C([O-])(O)=O.[Na+]>CC#N>[CH2:21]([O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1)[CH3:22]
Reactant: CCOC(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC[SiH](CC)CC
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)[C@H]1CC[C@H](OCC)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis/trans Ethyl 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1, 35 g, 122 mmol) was dissolved in CH3CN (250 mL) and Et3SiH (1.2 eq., 146 mmol, 23 mL), BiBr3 (4% mol, 4.9 mmol, 2.2 g) were added portionwise at room temperature followed by acetaldehyde (1.2 eq., 8.2 mL) that was slowly added at 25° C. The mixture was stirred at room temperature for 1 hour. The mixture was subsequently poured onto an aqueous saturated solution of NaHCO3 and the mixture obtained was then extracted with EtOAc (3×). Organics were combined, washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude mixture that was purified by silica chromatography (Biotage 65i column, EtOAc-nhex) to afford the title compound, 21 g, 87%.