Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5]([N:14]2[N:18]=[CH:17][CH:16]=[N:15]2)=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10].Cl>C1COCC1.CO>[F:3][C:4]1[C:5]([N:14]2[N:18]=[CH:17][CH:16]=[N:15]2)=[N:6][CH:7]=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cnc(-n2nccn2)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(-n2nccn2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A 5M potassium hydroxide aqueous solution (2 ml) was added to a THF/MeOH (2 ml/2 ml) solution containing methyl 5-fluoro-6-(2H-1,2,3-triazol-2-yl)nicotinate (250 mg), followed by stirring at room temperature for 1 hour. 6M hydrochloric acid was added to the reaction solution so as to acidify the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and a white solid of 5-fluoro-6-(2H-1,2,3-triazol-2-yl)nicotinic acid (198 mg) was thus obtained.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([O:18]C)=[O:17])=[CH:14][C:13]([S:20]([CH3:23])(=[O:22])=[O:21])=[N:12]2)=[CH:7][CH:6]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([S:20]([CH3:23])(=[O:22])=[O:21])=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(S(C)(=O)=O)nn1-c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nc(S(C)(=O)=O)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
A solution of lithium hydroxide (1.3 mL, 1.0 M, 1.3 mmol) was added to a suspension of methyl 1-(4-methoxyphenyl)-3-methylsulfonyl-pyrazole-5-carboxylate (272 mg, 0.88 mmol) in MeOH (10 mL) and stirred at room temperature 17 hours. The resulting mixture was concentrated and partitioned between EtOAc and H2O. The organic extracted was removed, and the aqueous extract was acidified with 1M HCl and extracted twice with EtOAc. The organic extracts from this extraction were combined, dried over Na2SO4, filtered, and evaporated to yield product (266 mg). 1H NMR (CDCl3 + few drops MeOD): δ7.45 (s, 1H), 7.38 (d, 2H, J=9.2), 6.96 (d, 2H, J=9.2), 3.86 (s, 3H), 3.25 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:14][N:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]=3[CH2:17][O:18][CH3:19])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[N:36]=[N:37][N:38](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:39]=1>CO.ClCCl>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:14][N:15]([CH2:20][C:21]([F:23])([F:22])[F:24])[C:16]=3[CH2:17][O:18][CH3:19])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:39][N:38]=[N:37][N:36]=1
Reactant: CCCCc1nn(CC(F)(F)F)c(COC)c1Cc1ccc2oc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(CC(F)(F)F)c(COC)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.8 %

Procedure:
dl-1-Camphor sulphonic acid (67 mg) was added to a solution of Intermediate 14a (268 mg) in methanol (5 ml) and dichloromethane (2 ml). The mixture was stirred at room temperature for 48 h. The solvent was evaporated and the residue purified by flash column chromatography eluting with System G (100:100:1) to give the title compound as a colourless foam (55 mg) after azeotroping with heptane to remove acetic acid.
Reaction SMILES: [OH-].[Li+:2].[CH3:3][N:4]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[CH:8][CH:7]=1)[CH3:5]>CO>[CH3:5][N:4]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:3].[Li+:2]
Reactant: CCOC(=O)COc1ccc(N(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(OCC(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.15 ml of a 1N aqueous solution of lithium hydroxide was added to a solution of 30 mg (0.13 mmol) of ethyl 4-(N,N-dimethylamino)phenoxyacetate (prepared as described in Preparation 18) in 1 ml of methanol, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, the resulting residue was mixed with benzene and the mixture was dehydrated by azeotropic distillation. This operation was repeated a further time, and then the residue was dried in vacuo for 2 hours, to give 26 mg of lithium 4-(N,N-dimethylamino)phenoxyacetate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.CC([O-])(C)C.[K+].C(OC([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[C:37]3[C:32](=[CH:33][C:34](F)=[CH:35][CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH2:24][CH2:23]1)=O)(C)(C)C>CS(C)=O.O>[NH:22]1[CH2:23][CH2:24][CH:25]([C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:35][CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: OCC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1nc(C2CCNCC2)c2ccc(OCC3CCOCC3)cc2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of (tetrahydro-pyran-4-yl)-methanol (0.2 mmol), KOtBu (0.2 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.1 mmol), prepared as described in Example 12b, in DMSO (1 mL), was stirred at 80° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h and then concentrated in vacuo.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:33])[C:9]([CH2:22][NH:23]S(C2C=CC=CC=2)(=O)=O)=[CH:10][C:11](=[O:21])[C:12]=1[O:13]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2].[C:34]1([S:40](C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:33])[C:9]([CH:22]([S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])[NH2:23])=[CH:10][C:11](=[O:21])[C:12]=1[OH:13])=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CC(C)NC(=O)c1c(O)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Yield: 48.56 %

Procedure:
6-(Benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropyl amide (18-01) (110.0 mg, 48.56%, purified by Prep-HPLC) was synthesized as an off white solid from 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropyl amide (17-01) (280.0 mg, 0.597 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[C:9]1[CH2:32][CH:31]=[CH:30][C:29](=[CH2:33])[CH:10]1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:28])[CH:20](Br)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1>C(Cl)(Cl)(Cl)Cl>[CH3:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:9]([CH3:8])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:28])[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: C=C1C=CCC(=C)C1COc1cccc(C(=O)C(Br)CC(=O)OCC)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (5.95 g, 58.9 mmol) was added to a solution of Ethyl 4-(3-(2,6-dimethlylbenzyloxy)phenyl)-4-oxo-3-bromo-butyrate (Step D, 2.47 g, 5.8 mmol) in carbon tetrachloride (50 ml). After stirring for 4 hours at room temperature, the reaction mixture was filtered through a pad of silica gel few times, and concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[CH:9][N:8]([C:11]3([CH3:14])[CH2:13][CH2:12]3)[C:4]=2[N:5]=[N:6][CH:7]=1.[CH2:15]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:16]>>[CH2:15]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:31]([F:32])=[CH:30][CH:29]=[C:28]([C:2]3[C:3]4[N:10]=[CH:9][N:8]([C:11]5([CH3:14])[CH2:13][CH2:12]5)[C:4]=4[N:5]=[N:6][CH:7]=3)[CH:27]=2)=[CH:24][CH:25]=1)(=[O:18])=[O:19])[CH3:16]
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)cc1
Reactant: CC1(n2cnc3c(Cl)cnnc32)CC1
Product: CCS(=O)(=O)c1ccc(-c2cc(-c3cnnc4c3ncn4C3(C)CC3)ccc2F)cc1
Yield: 32 %

Procedure:
Prepared according to the method described for Example 26 using 4-chloro-7-(1-methylcyclopropyl)-7H-imidazo[4,5-c]pyridazine (Preparation 97) and 2-(4′-ethylsulfonyl-6-fluorobiphenyl-3-yl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (Preparation 48) to afford the title compound as an off white solid in 32% yield, 20 mg
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][C@H:11]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12]1.[CH3:17]I>CN(C=O)C>[CH3:17][N:15]1[C@H:11]([CH2:10][O:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][O:3]2)[CH2:12][CH2:13][C:14]1=[O:16]
Reactant: CI
Reactant: O=C1CC[C@@H](COC2CCCCO2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@H]1COC1CCCCO1
Temperature: -40 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a mixture of NaH (0.48 g, 12 mmol, 60% mineral oil, Aldrich) in 15 mL of DMF was added a solution of (S)-5-((tetrahydro-2H-pyran-2-yloxy)methyl)pyrrolidin-2-one (2 g, 10 mmol) in 5 mL of DMF via a syringe at −40° C. The reaction was stirred at −40° C. for 1 hr. CH3I (0.9 mL, 12 mmol, Shanghai Jingchun Reagent Ltd.) was added dropwise via a syringe. The reaction was continued to stir at −40° C. for 4 hrs, and was quenched with 10 mL of saturated NaHSO3 aqueous solution. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the desired product as colorless oil (1.98 g, 92%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:21][C:22]1([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:34][C:31]1[CH:32]=[CH:33][C:28]([C:22]2([CH3:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:29][CH:30]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC1(c2ccc(O)cc2)CCCCC1
Product: COC(=O)C(Oc1ccc(C2(C)CCCCC2)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 79.6 %

Procedure:
In a manner similar to Example 16, 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate is reacted with 4.75 g of p-(1-methylcyclohexyl)phenol for 4 hrs. Chilling and filtering gives 7.4 g of product, mp 110°-112° C. Recrystallization from methanol-chloroform gives 6.3 g of white crystals, mp 111°-112.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:14][C:13]=1[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[N:7]([C:28](OC(C)(C)C)=O)[CH2:6][CH2:5]2.[AlH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:16]=[C:15]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[S:14][C:13]=1[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[N:7]([CH3:28])[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(-c2ccncc2)sc1-c1ccn[nH]1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCc2cc(Cl)ccc2C1c1cc(-c2ccncc2)sc1-c1ccn[nH]1
Temperature: 25 °C
Yield: 15.1 %

Procedure:
To a solution of tert-butyl 6-chloro-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (41 mg, 0.083 mmol) in tetrahydrofuran (3.0 mL, 37 mmol) was added lithium tetrahydroaluminate (0.249 mmol, 0.249 mmol) in THF (2.0 mM) at −78° C. After the addition, the temperature of the reaction was raised to rt for 30 min and then heated at 85° C. for 5 h. The mixture was quenched with water, diluted with methanol, and extracted with ethyl acetate. The organic phase was dried, filtered and evaporated. The residue was loaded onto silica gel and purified by chromatography to afford 6-chloro-2-methyl-1-[2-(1H-pyrazol-5-yl)-5-pyridin-4-yl-3-thienyl]-1,2,3,4-tetrahydroisoquinoline (5.1 mg, 15%). LCMS AA ES+ 407.2, 409.1; 1H NMR (400 MHz, d4-methanol) δ: 8.48 (d, J=5.06 Hz, 2H), 7.89-7.66 (m, 1H), 7.61 (s, 2H), 7.50-7.31 (br, 1H), 7.17 (s, 1H), 7.00 (d, J=7.98 Hz, 1H), 6.87-6.48 (m, 2H), 5.16-4.94 (m, 1H), 3.34 (s, 1H), 3.28-3.10 (m, 2H), 2.94-2.79 (m, 1H), 2.72-2.56 (m, 1H), 2.26 (s, 3H)
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Si:19]([O:26][C@H:27]([CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[C:54]([F:59])[CH:53]=1)[CH2:28][O:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH3:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CI>O1CCCC1.O>[Si:19]([O:26][C@H:27]([CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[C:54]([F:59])[CH:53]=1)[CH2:28][O:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([CH3:1])([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH3:31])([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(C)Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C)(C)Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To diisopropylamine (0.21 mL, 1.52 mmol), a 2.69 M solution of n-butyl lithium in hexane (0.57 mL, 1.52 mmol) was added at −78° C. followed by stirring for 15 minutes. After adding anhydrous tetrahydrofuran (1.5 mL), the mixture was further stirred for 15 minutes at −78° C. Subsequently, a solution of methyl 3-{2-[(1R)-1-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}-2-methylpropanoate (445 mg, 0.76 mmol), which had been obtained in Example 179 (179b), in tetrahydrofuran (1 mL) was added thereto and stirred at −78° C. for 1 hour. After adding methyl iodide (0.14 mL, 2.28 mmol), the mixture was stirred at room temperature for 17 hours. Upon the completion of the reaction, water was added. After extracting the mixture with ethyl acetate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=85/15) to give the title compound as a pale yellow oily substance (309 mg, yield 68%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH2:15][CH3:16])=[C:6]1[CH3:17])[CH:2]=[CH:3][CH3:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=3)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH2:15][CH3:16])=[C:6]1[CH3:17])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1ccc(F)cc1
Reactant: CC=CCn1c(C)c(CC)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(CC)c2cnnc(OCc3ccc(F)cc3)c21
Yield: 63.1 %

Procedure:
The title compound (cis/trans=22/78) was prepared as a white powder in 63.1% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-3-ethyl-2-methylpyrrolo[2,3-d]pyridazine (cis/trans=26/74) and 4-fluorobenzyl alcohol.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]3[CH2:14][O:13]3)=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[CH:16]=[CH:15][C:9]([O:10][CH2:11][C@H:12]([OH:13])[CH2:14][NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[Cl:21])=[CH:8][CH:7]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: NCc1ccccc1Cl
Reactant: c1ccc2c(-c3ccc(OCC4CO4)cc3)csc2c1
Solvent: CCO
Product: O[C@H](CNCc1ccccc1Cl)COc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from a mixture of 2-(4-benzo[b]thiophen-3-yl-phenoxymethyl)-oxirane, 2-chlorobenzylamine and ethanol essentially as described above in Example 94. Purity by LC/MS=99%, [M+H]+=424.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[O:16][C:17]1[CH:29]=[CH:28][C:20]2[C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][O:23][C:19]=2[C:18]=1[CH2:30][CH2:31][CH3:32])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[OH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[O:16][C:17]1[CH:29]=[CH:28][C:20]2[C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][O:23][C:19]=2[C:18]=1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1c(O[C@H]2CCCC[C@H]2CO[Si](C)(C)C(C)(C)C)ccc2c(C(F)(F)F)noc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(O[C@@H]2CCCC[C@@H]2CO)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-{[(1S,2S)-2-({[tert-butyl(dimethyl)silyl]oxy}-methyl)cyclohexyl]oxy}-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (550 mg, 1.17 mmol), from this Example step 2, in dry THF (17 ml) was added tetrabutylammonium fluoride (1M THF, 1.75 mL, 1.75 mmol) at 0° C. The reaction mixture was stirred at room temperature for two hours. Saturated NaHCO3 was added. The mixture was extracted with ethyl acetate three times and the combined organic layers washed with brine, dried over Na2CO3 and filtered. The solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate and hexane (20:80) to give the title compound.
Reaction SMILES: ClC1C(OC(=O)[C@H:10]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=C(Cl)C(Cl)=C(Cl)C=1Cl.[CH2:35]([O:42][C:43](=[O:71])[C@H:44]([CH2:67][CH2:68][S:69][CH3:70])[NH:45][C:46](=[O:66])[C@H](CC1C2C(=CC=CC=2)NC=1)NC(OC(C)(C)C)=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43](=[O:71])[C@H:44]([CH2:67][CH2:68][S:69][CH3:70])[NH:45][C:46](=[O:66])[C@H:10]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:24][CH:25]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(C)(C)C)cc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccc(C(C)(C)C)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-p-t-butyl-L-phenylalanine pentachlorophenyl ester is substituted for the N-t-butoxycarbonyl-L-tryptophan 2,4,5-trichlorophenyl ester of Example 5 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-p-t-butyl-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: P(=O)([O-])[O-].[CH3:5][C:6](=[CH:17][CH2:18][C:19]1[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][CH2:21][C:20]=1[CH3:27])[CH:7]=[CH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH3:5][C:6]([CH:17]=[CH:18][C:19]1[C:24]([CH3:25])([CH3:26])[CH2:23][CH2:22][CH2:21][C:20]=1[CH3:27])=[CH:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: CCOP(=O)(C=CC(C)=CCC1=C(C)CCCC1(C)C)OCC
Agent: O=[PH]([O-])[O-]
Product: CCOP(=O)(CC=C(C)C=CC1=C(C)CCCC1(C)C)OCC

Procedure:
A mixture of the vinyl phosphonate produced in accordance with Example VIII (943 mg, 2.77 mmoles) and 99 mg (0.88 mmoles) of potassium tert-butoxide in 12 mL of anhydrous dimethyl sulfoxide (DMSO) was stirred, protected from atmospheric moisture, at 20° C. for 80 minutes. The product was isolated by dilution of the reaction mixture with 100 mL of ether and subsequent washing with 120 mL portions of 10% aqueous sodium chloride (4×120 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Removal of the ether by evaporation at reduced pressure afforded 718 mg (76% yield) of the desired allylic phosphonate, whose structural integrity was confirmed by NMR analysis [δ 2.75, doublet of doublets, J=8 Hz and 22 Hz, CH2P]. In a similar manner, this allylic phosphonate could be prepared by isomerization of 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-pentadienylphosphonic acid, diethyl ester, produced in accordance with Example VI.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O>C(Cl)Cl>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]1[N:12]([CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(-c3ccccc3Cl)n(CC(OC)OC)c12
Temperature: 55 °C
Yield: 36.7 %

Procedure:
Methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (498 mg, 2.0 mmol) from Step C of Example 13, 2-chlorobenzaldehyde (303 mg, 2.15 mmol) and 4 {acute over (Å)} molecular sieves were stirred in methylene chloride (6 mL) at room temperature for 1 h. To this mixture was added iodobenzene 1,1-diacetate (1.26 g, 3.92 mmol) and the reaction mixture was heated (external temperature=55° C.) for 10 min. The reaction was quenched with saturated aqueous sodium bicarbonate, 10% aqueous sodium thiosulfate and pH adjusted to 8. The organic phase was extracted with methylene chloride, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 3:1 hexanes/ethyl acetate) to give methyl 2-(2-chlorophenyl)-1-(2,2-dimethoxyethyl)-1H-benzo[d]imidazole-7-carboxylate as a brown oil (275 mg, 38%): 1H NMR (500 MHz, MeOD) δ 7.91 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.66-7.60 (m, 3H), 7.56 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 1H), 4.28 (t, J=4.5 Hz, 1H), 4.27-4.08 (m, 2H), 3.98 (s, 3H), 3.12 (s, 3H), 3.09 (s, 3H); MS (ESI+) m/z 375 (M+H).