Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].[CH3:10][C:11]1[CH:12]=[C:13]([N:41]([CH3:45])[C:42]([NH2:44])=[S:43])[CH:14]=[C:15]([CH3:40])[C:16]=1[CH2:17][CH2:18][S:19]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]=[C:28]([CH:30]3[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]3)[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)(=[O:21])=[O:20]>C(O)(=O)C>[CH3:10][C:11]1[CH:12]=[C:13]([N:41]([CH3:45])[C:42]2[S:43][CH:1]=[CH:2][N:44]=2)[CH:14]=[C:15]([CH3:40])[C:16]=1[CH2:17][CH2:18][S:19]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]=[C:28]([CH:30]3[CH2:31][CH2:32][CH:33]([CH3:36])[CH2:34][CH2:35]3)[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)(=[O:20])=[O:21]
Reactant: CCOC(CBr)OCC
Reactant: Cc1cc(N(C)C(N)=S)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Solvent: CC(=O)O
Product: Cc1cc(N(C)c2nccs2)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Yield: 6.8 %

Procedure:
Bromoacetaldehyde diethylacetal (44.2 mg, 0.224 mmol) was added to a solution of 1-(3,5-dimethyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-1-methyl-thiourea (100 mg, 0.187 mmol) in acetic acid (2 ml) in a nitrogen stream. The mixture was heated under reflux for two hours and then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane, and the organic layer was then sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated, and the resulting residue was then purified by silica gel column chromatography (dichloromethane-methanol) to give 8-{2-[2,6-Dimethyl-4-(methyl-thiazol-2-yl-amino)-phenyl]-ethanesulfonyl}-2-(4-methyl-cyclohexyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (7.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][CH:10]=[O:11])[CH:7]=1.[CH:14]([Mg]Br)=[CH:15][CH2:16][CH3:17].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][CH:10]([OH:11])[CH2:17][CH2:16][CH:15]=[CH2:14])[CH:7]=1
Reactant: COc1ccc(F)cc1CCC=O
Reactant: CCC=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(O)CCc1cc(F)ccc1OC
Yield: 79.6 %

Procedure:
To a solution of 4 (3.0 g, 19.5 mmol) in THF (20 mL) at 0° C. was added a solution 1-butenylmagnesium bromide (0.5 M in THF, 45 mL, 22.5 mmol) dropwise for 15 min. The reaction mixture was poured into a solution of saturated ammonium chloride (80 mL) in a separatory funnel. The organic fraction was extracted with EtOAc (3×60 mL) and the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The product was purified by flash column chromatography (EtOAc/hexane, 15:85, v:v, Rf=0.2) to give the product as a colorless oil (3.7 g, 94%); 1H NMR (CDCl3, 500 MHz): δ 6.86-6.82 (m, 2 H), 6.76 (dd, J=4.6, 8.6 Hz, 1 H), 5.82 (m, 1 H), 5.04 (d, J=17.3 Hz, 1 H), 4.95 (d, J=10.2 Hz, 1 H), 3.81 (s, 3 H), 3.55 (m, 1 H), 2.75-2.69 (m, 2 H), 2.2 (m, 1 H), 2.1 (m, 1 H), 1.96 (bs, 1 H), 1.73-1.68 (m, 2 H), 1.6-1.53 (m, 3 H).
Reaction SMILES: [I-:1].[Zn+2:2].[I-].[C@@H:4]12[O:10][C@@H:7]([CH2:8][CH2:9]1)[CH2:6][C@H:5]2[CH2:11]O>C1COCC1>[I-:1].[C@@H:4]12[O:10][C@@H:7]([CH2:8][CH2:9]1)[CH2:6][C@H:5]2[CH2:11][Zn+:2]
Reactant: [Zn+2]
Reactant: OC[C@@H]1C[C@@H]2CC[C@H]1O2
Agent: [I-]
Solvent: C1CCOC1
Product: [Zn+]C[C@@H]1C[C@@H]2CC[C@H]1O2

Procedure:
The title compound was prepared in an analogous manner to tetrahydro-2H-pyran-4-yl)zinc(II) iodide except that (1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-ylmethanol was used instead of tetrahydro-2H-pyran-4-ol in Step 1 to afford a 0.15M solution of ((1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)zinc(II) iodide in THF.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:25]([NH:27][C@H:28]([C:31]([NH:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])=[O:32])[CH2:29][OH:30])=[O:26])[NH:17]C(OC(C)(C)C)=O)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:25]([NH:27][C@H:28]([C:31]([NH:33][CH2:34][CH2:35][NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])=[O:32])[CH2:29][OH:30])=[O:26])[NH2:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of a 4M solution of hydrogen chloride in dioxane are added to a solution of 120 mg (0.191 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl-N-(2-{[(benzyloxy)carbonyl]amino}ethyl)-L-serinamide (Example 164A) in 5 ml of dioxane at RT. The mixture is stirred at RT for 1 h. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:17]=[C:18]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:19]=[CH:20][CH:21]=1.C(C1C=C(C=CC=1)CNC1C=CC(CCC(O)=O)=CC=1)(=O)C1C=CC=CC=1>>[C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1)(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: O=C(O)CCc1ccc(NCc2cccc(C(=O)c3ccccc3)c2)cc1
Product: O=C(c1ccccc1)c1cccc(CNc2ccc([C@@H]3C[C@H]3C(=O)O)cc2)c1
Yield: 39 %

Procedure:
It was prepared from (1R,2R)-2-(4-aminophenyl)cyclopropane carboxylic acid (0.7 g, 3.9 mmol) and [3-(bromomethyl)phenyl](phenyl)methanone (0.9 g, 3.2 mmol) by following the procedure described in Scheme 2 for Intermediate 5. (0.5 g, Yield: 39%). MS (ESI, 120 eV): m/z=372.0 (M+H)+.
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=O)[O].[K+].[K+].C([O-])(=[O:15])C.[Na+].[OH:18][C:19]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[C:21]([CH3:29])[C:20]=1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40]>CO.O.O>[OH:41][C:39]([CH3:42])([CH3:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:20]1[C:19](=[O:18])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[C:22](=[O:15])[C:21]=1[CH3:29]
Reactant: COc1cc(C)c(CCCCCCCCCC(C)(C)O)c(O)c1OC
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(C)(C)O)=C(C)C1=O
Temperature: 50 °C
Reaction time: 14 h
Yield: 68.1 %

Procedure:
Potassium nitrosodisulfonate (12 g) and sodium acetate (12 g) are suspended in methanol-water (5:2, 210 ml), and 11-(2-hydroxy-3,4-dimethoxy-6-methylpheyl)-2-methylundecan-2-ol (2.4 g) is added thereto. The mixture is stirred at 50° C. for 14 hours and then diluted with water (100 ml). The methanol is distilled off. The aqueous soliution is extracted with ethyl acetate (200 ml), and the extract is washed with water, dried and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography to give 1.7 g of 6-(10-hydroxy-10-methylundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as an orange oil.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][N:7]([CH:9]2[CH2:12][O:11][CH2:10]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)=[N:17][CH:18]=1)[CH3:2].Cl[C:38]1[C:43]([CH:44]=[O:45])=[C:42]([N:46]2[CH2:58][CH2:57][C:56]3[N:55]4[C:50]([CH2:51][CH2:52][CH2:53][CH2:54]4)=[CH:49][C:48]=3[C:47]2=[O:59])[N:41]=[CH:40][CH:39]=1.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH2:1]([CH:3]1[CH2:8][N:7]([CH:9]2[CH2:10][O:11][CH2:12]2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:21](=[O:36])[N:22]([CH3:35])[CH:23]=[C:24]([C:38]3[C:43]([CH:44]=[O:45])=[C:42]([N:46]4[CH2:58][CH2:57][C:56]5[N:55]6[C:50]([CH2:51][CH2:52][CH2:53][CH2:54]6)=[CH:49][C:48]=5[C:47]4=[O:59])[N:41]=[CH:40][CH:39]=3)[CH:25]=2)=[N:17][CH:18]=1)[CH3:2]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CCC1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 161f (200 mg, 0.40 mmol), 4-chloro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 139a (132 mg, 0.40 mmol), K3PO43 water (213 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (16 mg, 0.020 mmol), and acetonitrile (20 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. under N2 protection for 2 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 161g (150 mg, 57%) as yellow solid. MS-ESI: [M+H]+ 663
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:20][C:21](=[O:31])[CH2:22][C:23]([C:25]1[S:26][CH:27]=[CH:28][C:29]=1[Cl:30])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:29]1[CH:28]=[CH:27][S:26][C:25]=1[C:23]1[CH2:22][C:21](=[O:31])[NH:20][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1sccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2sccc2Cl)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 125.5 %

Procedure:
Prepared from {3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K20) (100 mg, 0.21 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (93 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[N:5]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:4][N:3]=1.FC(F)(F)C(O)=O.C([SH:40])C>ClCCl>[CH3:1][C:2]1[NH:3][C:4](=[S:40])[N:5]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(c2cccc([N+](=O)[O-])c2)N(S(=O)(=O)c2ccccc2)CN=C1C
Reactant: CCS
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=C(C)NC(=S)N(S(=O)(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 0.95 g (0.0016 mole) of 1, 6-dihydro-2-[(4-methoxyphenyl)methyl]thio]-4-methyl -6-(3-nitrophenyl)-1-(phenylsulfonyl)-5pyrimidinecarboxylic acid, ethyl ester, 0.6 ml (0.0066 mole) of trifluoroacetic acid and 0.24 g (0.0037 mole) of ethanethiol in 20 ml of dichloromethane was stirred at room temperature overnight. The solvent was evaporated and the residue (solid) was treated with isopropyl ether to give 0.68 g of the title compound as a colorless solid, melting point 162°-164° C. Analysis Calc'd. for C20H19N3O6S2 : C, 52.04; H, 4.14; N, 9.10; S, 13.89. Found: C, 51.77; H, 4.09; N, 8.96; S, 13.71.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1)=O>CCOCC>[OH:1][CH2:2][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:10][CH:11]=1
Reactant: CC(CCCC1CCCCC1)c1ccc(CCC(=O)O)cc1
Solvent: CCOCC
Product: CC(CCCC1CCCCC1)c1ccc(CCCO)cc1

Procedure:
Next, 0.82 g of Li[AlH4 ] was added to 50 ml of dried (C2H5)2O, and the resulting mixture was stirred. Thereto was gradually added 5 g of 4-[p-(2-hydroxycarbonylethyl)phenyl]pentylcyclohexane. Thereafter, the thus obtained mixture was stirred for 5 hours, and filtered. The (C2H5)2O was distilled off from the filtrate, and the residue was recrystallized from n--C6H14 to obtain 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C. To a mixture of 3.6 g of SOCl2, one drop of pyridine and 50 ml of benzene was added 4.3 of the 4-[p-(3-hydroxypropyl)phenyl]pentylcyclohexane obtained above, and the resulting mixture was refluxed for 5 hours. Thereafter, the surplus SOCl2 was distilled off to obtain 4-[p-(3-chloropropyl)phenyl]pentylcyclohexane. The melting point of this compound was 70.7° to 72.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C@@H:22]2[C@@H:17]([CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21]2)[CH2:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:7]([N:14]1[C@@H:22]2[C@@H:17]([CH2:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21]2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1C[C@@H]2Cc3ccccc3C[C@@H]2N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CC[C@@H]3Cc4ccccc4C[C@@H]32)cc1
Yield: 75.9 %

Procedure:
To a stirred suspension of lithium aluminium hydride (0.96 g, 25 mmol) in dry tetrahydrofuran (30 ml) at 0° C. under argon, was added cis-1-benzyl-1,3,3a,4,9,9a-hexahydro-2H-benz[f]indol-2-one (1.75 g, 6 mmol) in dry tetrahydrofuran (5 ml). The resultant mixture was then heated at reflux for 6 h, cooled to 0° C. and, with vigorous stirring, water (1 ml) was added, followed by aqueous 10% sodium hydroxide (5 ml) and water (2 ml). The resultant mixture was filtered and the solid residue was washed with dichloromethane (10 ml). The filtrate was dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound as a yellow oil (1.2 g, 72%).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)C=CC=CC=1>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Yield: 96.8 %

Procedure:
To a solution of 1,1-dimethylethyl {[(2S)-4-(phenylmethyl)-2-morpholinyl]methyl}carbamate (4.9 g, 16 mmol) in ethanol (160 mL) was added 10% Pd/C (1.5 g). The suspension was hydrogenated at 50 psi using a Parr Shaker apparatus for 8 h. The reaction was filtered through a pad of Celite® and the pad was washed several times with methanol. The filtrate was concentrated to afford the title compound (3.35 g, 97%) as a colorless solid which was not purified further: LC/MS (ES) m/e 217 (M+H)+. The absolute stereochemistry of the title compound was determined by vibrational circular dichroism (VCD).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[O:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (66 mg, 60%), MS (ISP) m/z=439.4 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and tetrahydro-pyran-4-carboxylic acid.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].[Br-].C([O:11][C:12]1[C:13]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:14]([CH:35]=[CH:36][CH:37]=1)[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=O)C.C=O.Cl>O>[OH:11][C:12]1[CH:37]=[CH:36][CH:35]=[C:14]([CH:15]=[CH2:1])[C:13]=1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cccc1OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Br-]
Solvent: O
Product: C=Cc1cccc(O)c1C(=O)OCC
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A solution of 12.7 g of sodium carbonate in 115 ml of water was added dropwise, while stirring vigorously at room temperate, to 33.8 g of (3-acetoxy-2-ethoxycarbonylbenzyl)triphenylphosphonium bromide (e.g. Eicher et al. Synthesis (1988) 525) in 264 ml of 36.5% by weight aqueous formaldehyde solution. The reaction mixture was stirred at 55° C. for 6 h and then poured into ice-water at pH 1 (hydrochloric acid) and extracted with ethyl acetate, after which the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Further purification was carried out by chromatography on silica gel with toluene/ethyl acetate (20:1) as eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH:17]1(/[CH:23]=[C:24](\B2OC(C)(C)C(C)(C)O2)/[CH2:25][OH:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:17]1(/[CH:23]=[C:24](\[C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=2)/[CH2:25][OH:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1OC(F)(F)F
Yield: 88.9 %

Procedure:
Heat a suspension of 4-bromo-1-methanesulfonyl-2-trifluoromethoxy-benzene (0.71 g, 2.23 mmol), (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (0.77 g, 2.91 mmol), 2 M aqueous sodium carbonate solution (2.2 mL, 4.4 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (164 mg, 2.13 mmol) in 5.7 mL DMF to 80° C. for 2 h. Dilute the mixture with ethyl acetate, separate the organic layer, wash it with water followed by saturated sodium chloride solution. Filter through a hydrophobic filter paper and remove the solvent under vacuum. Further purify the resulting residue by column chromatography, eluting with a gradient from 100:0 to 30:70 hexanes:ethyl acetate to afford the title compound (0.75 g) as a yellow oil. MS (m/e): 396 (M+4H2O).
Reaction SMILES: [OH-].[Na+:2].[CH:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([P:15]([OH:18])([OH:17])=[O:16])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1>O.CC(O)C.CO.C(O)C.CN(C=O)C>[CH:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([P:11]([O-:14])([O-:13])=[O:12])([P:15]([O-:17])([OH:18])=[O:16])[OH:10])[CH:4]=1.[Na+:2].[Na+:2].[Na+:2]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: CC(C)O
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (1.4 g) in a mixture of water (20% v/v)/Ethanol or Methanol or IPA (80% v/v, 10 volumes per grams of ZLD-Ac form XII) (10 ml) was added drop-wise to a suspension of Zoledronic acid form XII (5.0 g) in a mixture of water (20% v/v)/Ethanol or Methanol or IPA (80% v/v, 10 volumes per grams of ZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50° C. for 24 hours to give Zoledronate trisodium crystal form IX.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Br:10]Br>CN(C=O)C>[Br:10][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:9]
Reactant: BrBr
Reactant: COc1ccc(O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-methoxyphenol (13.00 g, 104.84 mmol) in DMF (50 mL) was added bromine (5.40 mL, 104.84 mmol) at 0° C. The reaction was allowed to warm to room temperature. After stirring for 2 h the reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 21.28 g of the crude title compound as a dark oil: 1H NMR (250 MHz, CDCl3) d 7.49 (b, 1H), 6.96 (d, 1H), 6.72-6.62 (m, 2H), 3.71 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])=[CH:7][CH:6]=1.Cl.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](Cl)=[O:38].C(N(CC)CC)C>CC#N>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH2:14][CH2:15][N:16]2[C:24](=[O:25])[NH:23][C:22]3[C:17]2=[N:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[N:20][C:21]=3[NH2:26])[C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])=[CH:7][CH:6]=1
Reactant: CN(C)CC(=O)Cl
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCc3ccc(CC(=O)OC)cc3)c2n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(Cc3ccc(CC(=O)OC)cc3)C(=O)CN(C)C)c2n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The product of example 1, step (ix) (200 mg) was suspended in MeCN. N,N-dimethylglycyl chloride hydrochloride (110 mg) and triethylamine (0.19 ml) were added and the mixture stirred at rt for 10 h. The mixture was purified by RPHPLC. Yield 100 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:26])([CH3:25])[CH2:8][CH:7]=1)=[O:5])[CH3:2]>C(O)C.[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:25])([CH3:26])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CCC(C)(C)c2cc(O[Si](C)(C)C(C)(C)C)c(C)cc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(C)(C)c2cc(O[Si](C)(C)C(C)(C)C)c(C)cc21
Reaction time: 8 h

Procedure:
A solution of 6-(tert-butyl-dimethyl-silanyloxy)-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 190, 0.95 g, 2.54 mmol) in ethanol was treated with a slurry of 5% palladium on carbon (0.3 g) in ethyl acetate (0.5 mL) and the resulting reaction mixture was stirred under an atmosphere of hydrogen overnight. The solids were filtered over a bed of celite and the filtrate was evaporated in vacuo to aford the title compound as a viscous oil (0.95 g, ˜100%).