Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].CCOCC>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of the indole of Step 1 (8.9 g, 45 mmol) in DMF (150 mL) at 0° C. was added portionwise NaH (2.2 g, 55 mmol, 60% in oil). The reaction mixture was stirred for 30 minutes at 0° C. and triisopropylsilyl chloride (10.5 g, 55 mmol) was added. The reaction mixture was stirred for 30 minutes and 400 mL of Et2O was added. The reaction was quenched with saturated aqueous NH4Cl and extracted with Et2O. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 100% Hexanes to provide 16 g of the title compound as a white solid.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[C:5]([C:10]([NH:13][C:14]2[N:15]=[N:16][C:17]([C:20]3[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=3)=[CH:18][N:19]=2)([CH3:12])[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1.C([O-])([O-])=[O:29].[K+].[K+].CS(C)=O.OO>C(O)(=O)C>[F:27][CH:2]([F:1])[O:3][C:4]1[C:5]([C:10]([NH:13][C:14]2[N:15]=[N:16][C:17]([C:20]3[S:21][C:22]([C:25]([NH2:26])=[O:29])=[CH:23][N:24]=3)=[CH:18][N:19]=2)([CH3:12])[CH3:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Nc1ncc(-c2ncc(C#N)s2)nn1)c1ncccc1OC(F)F
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC(C)(Nc1ncc(-c2ncc(C(N)=O)s2)nn1)c1ncccc1OC(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 148.6 %

Procedure:
2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carbonitrile (15 mg, 38 μmol), K2CO3 (50 mg, 0.35 mmol), and DMSO (1 mL) were combined in a vial and cooled to 0° C. H2O2 (0.1 mL of 35% solution) was then added and the reaction was warmed to rt and stirred for 1 h. Acetic acid (0.1 mL) was added, and the reaction was filtered and then purified using reverse phase chromatography to afford 23 mg of 2-(3-(2-(3-(difluoromethoxy)pyridin-2-yl)propan-2-ylamino)-1,2,4-triazin-6-yl)thiazole-5-carboxamide as a white solid, m/z=408.3 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:12]([CH3:25])[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][NH2:20])[C:14]=2[C:21]([F:24])([F:23])[F:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:32][C:33]([F:39])([F:38])[CH2:34][C:35](Cl)=[O:36]>CCOC(C)=O.C1COCC1>[F:32][C:33]([F:39])([F:38])[CH2:34][C:35]([NH:20][NH:19][C:15]1[C:14]([C:21]([F:24])([F:22])[F:23])=[C:13]([N:12]([CH2:11][C@@H:9]2[CH2:10][C@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:25])[CH:18]=[CH:17][N:16]=1)=[O:36]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(NN)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C[C@@H]1C[C@H]1c1ccc(F)cc1)c1ccnc(NNC(=O)CC(F)(F)F)c1C(F)(F)F
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a mixture of trans-N-((2-(4-fluorophenyl)cyclopropyl)methyl)-2-hydrazinyl-N-methyl-3-(trifluoromethyl)pyridin-4-amine (0.5 g, 1.411 mmol) in EtOAc (6 mL), THF (6 mL) and 2.0 M of aqueous sodium carbonate (3.53 mL, 7.06 mmol) was added 3,3,3-trifluoropropionyl chloride (0.248 g, 1.693 mmol) dropwise at rt. The resulting mixture was stirred at under nitrogen for 10 min. The reaction mixture was partitioned between EtOAc/aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography using 0-30% EtOAc/hexane as the eluent to give trans-3,3,3-trifluoro-N′-(4-(((2-(4-fluorophenyl)cyclopropyl)methyl)(methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)propanehydrazide (0.46 g, 66.7% yield) as a white solid. 1H NMR (500 MHz, METHANOL-d4) δ 7.88 (d, J=6.0 Hz, 1H), 7.08-7.01 (m, 2H), 6.99-6.91 (m, 2H), 6.58 (d, J=6.1 Hz, 1H), 3.41 (dd, J=14.0, 5.6 Hz, 1H), 3.36-3.24 (m, 2H), 3.13 (dd, J=14.0, 7.6 Hz, 1H), 1.81-1.71 (m, 1H), 1.32-1.21 (m, 1H), 0.99 (dt, J=8.6, 5.2 Hz, 1H), 0.87 (dt, J=8.8, 5.4 Hz, 1H). LCMS: M+1=465.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][C:14]([O:17]C)=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.B(Br)(Br)Br.C(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9]2=[CH:10][C:11]3[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][C:14]([OH:17])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(OC)cc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC1CCn2c1cc1c(S(C)(=O)=O)cc(O)cc12
Reaction time: 2.5 h
Yield: 57 %

Procedure:
To a solution of the methyl ether from Step 1 (0.35 g, 1.03 mmol) in CH2Cl2 (5 mL) at 0° C. was added 1M BBr3/CH2Cl2 (5.2 mL, 5.2 mmol) over a period of 55 minutes. The dark gummy suspension was then brought to RT for 2.5 hours. MeOH (≈5 mL) was then added at −78° C. followed by saturated NaHCO3 solution. The cold bath was removed and the mixture was stirred for 30 minutes. The product was then extracted with CH2Cl2 and the organic phase was washed with H2O. After drying (MgSO4), filtering, and evaporating, the residue was purified by flash chromatography (1:2, 1:1 EtOAc:hexane) to give a light brown solid (0.19 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH3:18])=[O:16])=[C:11]([F:19])[CH:10]=2)[CH2:4]1.[C:20](SCC)(=[S:22])[CH3:21]>CN(C=O)C>[C:20]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH3:18])=[O:16])=[C:11]([F:19])[CH:10]=2)[CH2:4]1)(=[S:22])[CH3:21]
Reactant: CCSC(C)=S
Reactant: CCS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Solvent: CN(C)C=O
Product: CCS(=O)c1ccc(N2C[C@H](CNC(C)=S)OC2=O)cc1F

Procedure:
Prepared analogously to the Method A of General Methods of Preparation of 5-(S)-Thioamidomethyloxazolidinones (Example 1) from 5-(S)-aminomethyl-3-[4′-ethylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.0885 g, 0.309 mmol) and ethyl dithioacetate. Reaction was performed in DMF overnight. Yield 0.104 g (98%). M.p. 138-9° C. MS (m/z): [M+H]+=345.
Reaction SMILES: N1CCCCC1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].[N:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH:34]=O)[CH:32]=3)[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=2)=[CH:19][CH:18]=1>CCO>[N:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([CH:34]=[C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[NH:7][C:8]4=[O:16])[CH:32]=3)[N:27]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:26]=2)=[CH:19][CH:18]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2cc(C=O)ccc21
Solvent: C1CCNCC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2cc(C=C3C(=O)Nc4ccccc43)ccc21
Temperature: 75 °C

Procedure:
A solution of piperidine (0.2M in EtOH, 0.10 mL, 0.02 mmol) was added to a suspension of oxindole (16.5 mg, 0.12 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-5-carbaldehyde (42.5 mg, 0.11 mmol) in EtOH (4 mL). The reaction was then heated to 75° C. for 15 hrs. The solvent was evaporated in vacuo. MeOH was added and the resulting suspension was sonicated, but the solution was still cloudy even after EtOAc was added. The solid was removed by filtration and the solvent evaporated in vacuo. Chromatography (5 g silica SPE tube, Silicycle, 2% MeOH in CH2Cl2) gave a yellow solid (35 mg, 64%, 55:45 mixture of E/Z isomers). 1H NMR (400 MHz, CDCl3 plus a drop of CD3OD) δ 9.77 (s, 0.45H), 8.63 (m, 1.9H), 8.42 (s, 0.55H), 8.18 (s, 0.45H), 8.14 (dd, J=8.8, 1.2 Hz, 0.45H), 8.00 (s, 1H), 7.83-7.42 (m, 7H), 7.26 (t, J=7.6 Hz, 1H), 7.09 (t, J=7.6 Hz, 0.45H), 6.94-6.88 (m, 1.6H), 5.80 (s, 0.55H), 5.77 (s, 0.45H), 3.64 (m, 2H), 0.95 (m, 2H), −0.02 (s, 5H), −0.03 (s, 4H).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[C:7]1([C:13]2[CH:14]=[C:15]3[N:20]([CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[O:3]=[C:2]([C:21]1[N:20]2[C:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:14][C:13]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([Cl:6])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(-c2cc3n(c2)CCCC3)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Oxalyl chloride (17.2 mL, 0.19 mol) was added to an ice-cold solution of 2-phenyl-5,6,7,8-tetrahydro-indolizine (32 g, 0.16 mol) in a mixture of toluene (20 mL) and THF (30 mL). The reaction mixture was allowed to warm to room temperature and stirred for 30 min. then concentrated under vacuum. The residue was triturated with petrol (5×300 mL) to afford oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (42 g, 89%) as a dark yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][CH2:9][C:8]3[S:12][CH2:13][CH2:14][S:15][C:7]=3[C:6]=2[C:5]([CH3:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[C:20](Cl)(=[O:24])[C:21](Cl)=O>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1[C:11]2[S:10][CH2:9][C:8]3[S:12][CH2:13][CH2:14][S:15][C:7]=3[C:6]=2[C:5]([CH3:16])=[C:4]([C:17]([O:19][C:2]2[CH2:3][CH2:4][CH2:21][C:20](=[O:24])[CH:1]=2)=[O:18])[CH:3]=1
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCC1=C2SCCS1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1SCC1=C2SCCS1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.78 g of the title compound of Step A in 35 mL of methylene chloride was added 0.66 mL of oxalyl chloride (purchased from Aldrich Chemical Co.) and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 2 h and was then concentrated under reduced pressure to dryness. The resulting residue was redissolved in 30 mL of methylene chloride and the solution was evaporated to dryness again. Another 30 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. To this solution was added 0.31 g of 1,3-cyclohexanedione (purchased from Aldrich Chemical Co.) followed by addition of 1.0 mL of triethylamine. The mixture was stirred overnight while warming to room temperature. Saturated aqueous sodium bicarbonate was then added to the reaction mixture and the mixture was extracted with methylene chloride. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. Chromatography of the crude product on silica gel eluting with a mixture of hexanes:ethyl acetate (8:1 and then 4:1) yielded 0.58 g of the title compound of Step B as a yellow solid melting at 120°-126° C. 1H NMR (CDCl3): δ 2.15 (m, 2H), 2.36 (s, 3H), 2.46 (t, 2H), 2.66 (t, 2H), 2.67 (s, 3H), 3.07 (m, 2H), 3.24 (br s, 2H), 3.41 (m, 2H), 6.00 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]1[NH:21][C:20]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[N:11]=1.Cl.[NH2:23][CH2:24][C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1)[OH:26].CN1CCOCC1>C(#N)C>[Br:33][C:29]1[CH:28]=[C:27]([C@H:25]([OH:26])[CH2:24][NH:23][C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=2[C:10]2[NH:21][C:20]3[CH:19]=[C:18]4[C:14]([CH:15]=[N:16][NH:17]4)=[CH:13][C:12]=3[N:11]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]ccc(Cl)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Reactant: NC[C@@H](O)c1cccc(Br)c1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=c1[nH]ccc(NC[C@@H](O)c2cccc(Br)c2)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-bromo-phenyl)-ethanol hydrochloric acid salt (96 mg, 0.37 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (73 mg, 63%). 1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.21–7.40 (m, 5H), 6.14 (d, J=7.5 Hz, 1H), 4.97 (m, 1H), 3.60–3.68 (m, 2H). LCMS (t=1.46 min), [M+H]+465.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:9])(=[O:8])[CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32](O)[CH:33]4[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]4)=[CH:28][CH:27]=3)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C(OCC)(=O)C>[C:6]([O:9][CH:32]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=3)=[CH:18][CH:19]=2)=[O:24])=[CH:31][CH:30]=1)[CH:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)(=[O:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(O)c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC(c1ccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)cc2)cc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Concentrated sulfuric acid (0.0562 ml) was added to an acetic acid solution (3.5 ml) of tert-butyl 3-[[4-[[(4′-chloro[1,1′-biphenyl]-4-yl)carbonyl]amino]phenyl](hydroxy)methyl]-1-piperidinecarboxylate (366 mg, 0.702 mmol) obtained in Example 128, which was stirred under room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, which was washed with potassium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by alumina B column chromatography (development solvent; ethyl acetate: methanol=3:1), and powdered with diisopropyl ether, to give the titled compound (210 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cccc(C#N)c2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (3-cyanophenyl)boronic acid (205 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 298 mg, 94%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([S:12]([O-:15])(=[O:14])=[O:13])=[N:3][CH:4]=1.[Na+:16]
Reactant: O=S([O-])O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)cn1
Yield: 85.6 %

Procedure:
In a flask, 2-chloro-5-(trifluoromethyl)pyridine (54.5 g, 0.3 mol), sodium hydrogen sulfite (125 g, 1.2 mol), ethanol (600 ml) and water (600 ml) were charged and heated under reflux for 198 hours. After evaporating off the solvent, to the solid residue, conc. hydrochloric acid was added. The mixture was evaporated to dryness. The residue was extracted with methanol and filtrated. The filtrate was evaporated to dryness to obtain sodium 5-(trifluoromethyl)pyridine-2-sulfonate (64.0 g). Yield, 86%. Decomposition point, 356°-370° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.O1CCCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:6][OH:7])=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1c(F)cc(Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a mixture of 4-chloro-2,6-difluoro-benzaldehyde (5.7 g, 32 mmol), tetrahydrofuran (150 mL) and ethanol (20 mL) was added sodium borohydride (1.2 g, 32 mmol) at 0° C. The mixture was stirred for 30 minutes, warmed to ambient temperature, and additional sodium borohydride (0.40 g, 11 mmol) was added to drive the reaction to completion (TLC). The mixture was concentrated in vacuo, diluted with ether and treated cautiously with 1M aqueous HCl. The aqueous phase was extracted 3× with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated. Trituration of the residue with pentane afforded 4.8 g (83%) of (4-chloro-2,6-difluoro-phenyl)-methanol as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.04 (d, 2H, J=7.1 Hz), 4.73 (s, 2H) ppm.
Reaction SMILES: [H-].[Na+].[CH2:3](P([O-])(=O)[O-])[P:4]([O:9][CH2:10][CH3:11])(=[O:8])[O:5][CH2:6][CH3:7].C([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)C1C=CC=CC=1>O1CCCC1>[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:3][P:4](=[O:8])([O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH2:25][CH2:24]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCOP(=O)(CP(=O)([O-])[O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC1CCNCC1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.11 g (528 mmol) of 60% strength sodium hydride are initially charged in 50 ml of absolute tetrahydrofuran, and 15.7 g (52.8 mmol) of diethyl methanediphosphonate are added dropwise. The mixture is stirred at room temperature for another 30 minutes, and 10.1 g (52.8 mmol) of 1-benzyl-4-piperidone are then added. The mixture is stirred for one hour at room temperature and for one hour under reflux, concentrated, admixed with water and extracted three times with dichloromethane, and the organic phases are dried over sodium sulphate and concentrated. The residue is hydrogenated in 50 ml of ethanol over 1.7 g 10% palladium-carbon at room temperature and 3 bar. The catalyst is filtered off with suction and the filtrate is concentrated.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[P:11]([OH:14])([OH:13])[OH:12].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:11]([OH:14])([OH:13])=[O:12])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 87.5 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
3-Pyridine acetic acid (25 g) in 500 ml of chlorobenzene added to phosphorous acid (35.5 g). The reaction mixture was heated up to 85-90° C. To the reaction mixture phosphorous trichloride (58.97 g) was added slowly to obtain a yellowish rigid, thick mass. The reaction mass was cooled to ambient temperature. The solvent was decanted. Demineralized water (200 ml) was added to the reaction mass and refluxed azeotropically, to remove residual chlorobenzene. Filtered through hyflo bed while hot, washed with hot demineralized water. The reaction mass was cooled to 0-5° C., stirred for 1.0 hour, filtered the solid and washed to get risedronic acid (30.0 g, yield 58%) having purity of 83.98% by HPLC.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[C:10]([OH:12])[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C)C=O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:12][C:10]2[CH:9]=[N:8][N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=3)[CH:11]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(-n2cc(O)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cc(Oc3ccc([N+](=O)[O-])cc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
1-p-Tolyl-1H-pyrazol-4-ol (1.0 g, 5.75 mmol) in dimethylformamide was added to the cold slurry of sodium hydride (344 mg, 8.61 mmol). Reaction mixture was stirred for 0.5 hour followed by addition of 4-fluoro nitro benzene (810 mg, 5.74 mmol) in cold condition. Reaction mixture was stirred at 20-35° C. for 20 minutes. Water was then added to quench the reaction. The aqueous layer was extracted with diethylether and the combined organic layer was washed with brine solution and dried over anhydrous Na2SO4. The solvent was evaporated under vacuum at 40° C. and the product was purified by column chromatography using mixture of petroleum ether and ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[C-:15]#[C-:16].[Na+].[Na+]>C1COCC1>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:6]([OH:7])[C:15]#[CH:16])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: [C-]#[C-]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A solution of 3,4,5-trimethoxybenzaldehyde (1.0 g, 5.0 mmol) in THF (50 mL) was stirred at 0° C. Sodium acetylide (18% w.t. slurry in xylene, 1.63 g, 6.1 mmol) was added via syringe. The reaction mixture was stirred overnight at room temperature and quenched by water. It was then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a crude product, which was purified by flash column chromatography eluting with EtOAc/n-hexane (1:2) to afford 1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol as a white solid (815 mg, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](O)=[O:12])[N:8]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:7]=1)=[O:5])[CH3:2].CO>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 40 °C

Procedure:
To a solution of 4 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrazole-3,5-dicarboxylic acid 3-ethyl ester in 50 ml THF 26 ml BH3*THF (1M in THF) were added slowly at RT. Then the mixture was warmed to 40° C. for 6 h. After cooling to 0° C. 20 ml MeOH were added cautiously and the mixture was concentrated to dryness. The residue was again codistilled with 20 ml of MeOH and then purified by chromatography on silica gel eluting with n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.9 g.