Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH2:19][CH3:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)O)=[CH:4][CH:3]=1.[CH3:21][CH:22](C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)[CH3:23]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH2:19][CH3:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:23][CH:22]=[CH2:21])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(Br)cc1)C(O)c1ccc(Cl)cc1
Reactant: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Product: C=CCC(c1ccc(Cl)cc1)C(CCC)c1ccc(Br)cc1

Procedure:
The title compound was prepared from the intermediate from Step D using the conditions described in INTERMEDIATE 1, Step D. The title compound is obtained as a 2.1:1 mixture of diastereomers. 1H NMR for major diastereomer (500 MHz, CDCl3): δ 7.44 (d, J=8.5 Hz, 2H); 7.28 (d, J=8.3 Hz, 2H); 7.05 (d, J=8.2 Hz, 2H); 7.02 (d, J=8.4 Hz, 2H); 5.46-5.35 (m, 1H); 4.82-4.71 (m, 2H); 2.77-2.62 (m, 2H); 2.14-2.02 (m, 2H); 1.35-1.25 (m, 2H); 1.05-0.89 (m, 2H); 0.67 (t, J=7.3 Hz, 3H). LC1 4.66 min. Not ionized
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:63]([CH2:65][CH2:66][O:67][CH2:68]Cl)#[N:64].C(=O)(O)[O-].[Na+]>ClCCCl>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[O:21][CH2:68][O:67][CH2:66][CH2:65][C:63]#[N:64])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
N2-Phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (720 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethyl ether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxy methyl)guanosine (384 mg, yield 48%).
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].C[Li]>CCOCC>[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]1[CH2:4][CH:2]=1
Reactant: OCCCCCCCC1(Br)CC1(Br)Br
Agent: [Li]C
Solvent: CCOCC
Product: OCCCCCCCC1=CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
A solution of 1.0 g 1,1,2-tribromo-2-(7-hydroxyheptyl)cyclopropane (2.5 mmol) in 25 ml of ether was treated at −78° C. with 7.2 ml of methyllithium (1.4 M, 10 mmol). After 5 minutes, the reaction mixture was warmed to 0° C. and held at this temperature. The reaction was quenched with saturated ammonium chloride. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 240 mg of 1-(7-hydroxyheptyl)-cyclopropene (90% purity).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:40][CH2:41][CH2:42][CH3:43])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[N:38]([CH3:39])[N:37]=[N:36][N:35]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>C(Cl)Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH2:40]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[N:38]([CH3:39])[N:37]=[N:36][N:35]=2)[CH:22]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnnn2C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnnn2C)c1
Reaction time: 1 h

Procedure:
To a solution of 4-{6-butyl-5-[4-cyclohexyloxy-3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (0.52 mmol, 308 mg) in DCM (3 mL) was added 4 N HCl in dioxane (1 mL) and the reaction mixture was stirred for 1 h. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The yellow solid was dried overnight under high vacuum to give 3-butyl-4-[4-cyclohexyloxy-3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (229.3 mg).
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[S:4][C:5](C(Cl)(Cl)Cl)=[N:6][N:7]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]([Cl:13])([Cl:12])[C:3]1[S:4][CH:5]=[N:6][N:7]=1
Reactant: ClC(Cl)(Cl)c1nnc(C(Cl)(Cl)Cl)s1
Agent: O=S(=O)(O)O
Product: ClC(Cl)(Cl)c1nncs1
Yield: 83 %

Procedure:
A mixture of 6.4 parts of 2,5-bis-trichloromethyl-1,3,4-thiadiazole and 30 parts by volume of 91% sulfuric acid is heated for 0.1 hour at from 175° to 185° C. The reaction mixture is then carefully poured on to ice and the precipitated solid is suction filtered. The product is washed with water and treated with 20 parts by volume of methanol, and small amounts of undissolved starting material are filtered off. After concentration of the methanolic solution there is obtained 3.4 parts (83% of theory) of 2-trichloromethyl-1,3,4-thiadiazole; m.p.: 58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)[C:9]([C:25](=O)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+]>ClC(Cl)C.[Zn+2].[I-].[I-]>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)[C:9]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37][CH3:38])=[O:36])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)C(C)(C)Cc1c(Cc2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
Methyl 3-[N-(p-chlorobenzyl)-3-benzoyl-5-(benzoyloxy)indol-2-yl]-2,2-dimethylpropanoate (360 mg) (prepared in Step A of Example 9), 800 mg of ZnI2, and 500 mg of sodium cyanoborohydride were stirred in 5 mL of dichloroethane at RT under argon for 30 min. The temperature was then raised to 65° C. for 3 hr. After the solution had cooled, it was poured onto 10 mL of NH4OAc (25% solution), extracted with 3×15 mL of ether, washed with 10 mL of H2O and dried (MgSO4). The solution was evaporated to dryness and the residue was chromatographed on silica gel to yield the title compound as a white foam.
Reaction SMILES: [F:1][CH:2]([F:49])[O:3][C:4]1[CH:47]=[CH:46][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:11])=[CH:6][C:5]=1[F:48].C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[F:49][CH:2]([F:1])[O:3][C:4]1[CH:47]=[CH:46][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([C:27]([F:29])([F:30])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:36]=[CH:37][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:39][CH:40]=2)(=[O:33])=[O:34])=[O:11])=[CH:6][C:5]=1[F:48]
Reactant: O=C(NCc1ccc(OC(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(NCc1ccc(OC(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C(F)(F)F)ncc3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reaction time: 1 h
Yield: 71.8 %

Procedure:
Under an argon atmosphere, to a solution of the compound (912 mg) obtained in Step 6 and ammonium formate (750 mg) in ethanol (18 ml) was added 10% palladium carbon (912 mg). After stirring under refluxing conditions for 1 hr, the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and water. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=10:1-1:2) to give the title compound (625 mg).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[O:28][CH3:29])[N:13]=2)=[CH:8][CH:7]=1.Cl.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:29][O:28][C:18]1[N:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=1)=[N:13]2
Reactant: COc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cc12
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(1,3-dioxolan-2-yl)phenyl]-5-methoxy-3-phenyl-1,6-naphthyridine (760 mg, 1.98 mmol) in THF (8 mL) was added 1 N HCl (6 mL) and the solution was stirred for three hours. Ethyl acetate was added and the mixture was made basic with aqueous Na2CO3. The organic layer was dried (Na2SO4), filtered and the solvent evaporated. The residue was triturated with diethyl ether to give pure product. The mother liquors were purified by column chromatography on silica gel and elution with 10-30% ethyl acetate/hexane gave additional product. 1H-NMR (500 MHz, CDCl3): δ 10.10 (1H, s), 8.60 (1H, s), 8.26 (1H, d, J=6 Hz), 7.81 (2H, d, J=8.3 Hz), 7.62 (2H, d, J=8.3 Hz), 7.56 (1H, d, J=6.1 Hz), 7.30-7.32 (3H, m), 7.21-7.23 (2H, m), 4.17 (3H, s). m/e (m+1): 341.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[CH3:21].FC1C=CC([CH:27]=[O:28])=C(C)C=1C>Cl>[F:13][C:14]1[C:15]([CH3:21])=[C:16]([CH3:20])[CH:17]=[CH:18][C:19]=1[CH:27]=[O:28]
Reactant: Cc1c(F)ccc(C=O)c1C
Reactant: Cc1cccc(F)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(C=O)c(F)c1C
Temperature: 50 °C
Yield: 79.1 %

Procedure:
67.60 g of aluminum chloride (mol. Wt. 133.34; 507.0 mmol), 450.0 g of 1,2-dichlorobenzene (mol. Wt. 147.00; 3,061 mmol), and about 503.54 g of 3-fluoro-o-xylene (mol. Wt. 124.16; 789.3 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 50° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 28 hours (the reaction temperature was maintained at 50° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluoro-o-xylene, 1,2-dichlorobenzene, and left about 94.98 g of a benzaldehyde mixture consisting of 4-fluoro-2,3-dimethylbenzaldehyde (89.1 %) and 2-fluoro-3,4-dimethylbenzaldehyde (10.9%) (mol. Wt. 152.17; 624.2 mmol; yield of approximately 79.1%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:13])[C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[Br:16]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:16][CH2:11][C:10](=[O:12])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=1)=[O:13]
Reactant: BrBr
Reactant: CC(=O)C(=O)c1ccc(C(F)(F)F)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CBr)C(=O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a chloroform (6.0 mL) solution of 1-[4-(trifluoromethyl)phenyl]propane-1,2-dione (0.65 g), bromine (0.62 mL) was added, and the resultant was stirred at 70° C. for 6 hours. After standing to cool to room temperature, a 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure to obtain the title compound (1.1 g) as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]Cl)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:18]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][C:9]([C:10]#[N:11])([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCC1CCN(Cc2ccccc2)CC1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC(CC1CCN(Cc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Sodium hydride (1.69 g, 42.1 mmol; 80% dispersion in oil) was added portionwise over 10 minutes to a solution of diphenylacetonitrile (7.4 g, 38.3 mmol) in toluene (40 ml) and the mixture was heated under reflux for 45 minutes, treated with 1-benzyl-4-chloromethylpiperidine (4.3 g, 1.92 mmol; prepared by partitioning the hydrochloride salt, which was obtained by the method described in J. Het. Chem., 1978, 15, 675, between 10% aqueous sodium carbonate solution and dichloromethane, drying the organic layer over magnesium sulphate and evaporating), heated under reflux for one hour, allowed to cool to room temperature and partitioned between toluene and water. The organic layer was dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (7.57 g, 52%) as a colourless foam which was characterised by its 1H-NMR spectrum.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>ClCCl>[CH2:31]([NH:38][C:11](=[O:13])[CH:10]([OH:14])[C@@H:9]([NH2:8])[CH2:15][CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC[C@H](N)C(O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxypentanoic acid (300 mg, 1.29 mmol) was combined with EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.6 mmol). A solution of benzylamine (0.22 mL) and 4-methylmorpholine (0.5 mL) in dichloromethane (4 mL) was added in one portion. The reaction mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (150 mL), the solution was washed with 1 N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine. The resultant mixture was dried with magnesium sulfate and evaporated under vacuum to yield 3(S)-amino-2-hydroxy-pentanoic acid benzylamide (380 mg) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[C:14]([CH3:16])[N:15]=[C:8]2[N:7]=1)(=O)C.NC(N)=[S:19]>C(O)C>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([SH:19])[N:9]2[N:13]=[C:14]([CH3:16])[N:15]=[C:8]2[N:7]=1
Reactant: CC(=O)OCc1cc(Cl)n2nc(C)nc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1nc2nc(CO)cc(S)n2n1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
In 600 ml of ethanol was dissolved 31 g of 5-acetoxymethyl-7-chloro-2-methyl-s-triazolo[1,5-a]pyrimidine, and 29.5 g of thiourea was added thereto and the mixture was refluxed for 10 minutes. The reaction mixture was ice-cooled and resulting precipitated crystal was collected by filtration. The crystal was dissolved in 600 ml of a 5 % potassium hydroxide and the mixture was stirred for 30 minutes, ice-cooled and adjusted to pH 2 with 2N hydrochloric acid. Precipitated crystal was collected by filtration, washed with water and dried to obtain 16.33 g of the title compound.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:26])[C@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[OH:27]O.O[Li].O>C1COCC1.O>[CH2:19]([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:26])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CC[C@@H](CCCCCCC)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](CCCCCCC)C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of 8.69 g (0.024 mol) of the product from Example 3 in 425 mL of THF/H2O (3:1), cooled to 0 degrees, was added 10.8 mL (0.097 mol) of 30% hydrogen peroxide solution followed by 2.03 g (0.049 mol) of LiOH-H2O. The resulting solution was stirred at 0° C. for 1.5 h and then quenched with a solution of 15.4 g of sodium sulfite in 100 mL of H2O. The reaction mixture was then acidified to pH 3 with aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.33 g (90%) of the desired product as a colorless oil. CI Mass Spec: 199 (M+H).
Reaction SMILES: [S:1]1[C:5]([CH:6](O)[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=2)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[O:15][CH3:16])[CH2:6][C:5]1[S:1][C:2]2[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=2[CH:4]=1
Reactant: COc1cc(C(O)c2cc3ccccc3s2)cc(OC)c1OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2cc3ccccc3s2)cc(OC)c1OC

Procedure:
2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene was prepared in the same manner as described in Example 47B. Reaction of a-(2-benzo[b]-thienyl)-3,4,5-trimethoxybenzyl alcohol (4.5 mmoles, 1.5 g), triethylsilane (5.0 mmoles, 0.80 mls), CH2Cl2 (50 ml) and TFA (9.1 mmoles, 0.70 mls) yielded, after flash chromatography using 20% ethyl acetate/hexanes, 0.77 g (54%) of a white solid.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([NH:7][C:8]2[CH:17]=[CH:16][N+:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[CH:5][CH:4]=1>[OH-].[Na+]>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:7]=[C:8]2[CH:17]=[CH:16][N:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[CH:9]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(Nc2cc[n+]3ccccc3c2)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(N=c2ccn3ccccc3c2)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(4-chloroanilino)quinolizinium bromide (30 g., 0.09 mole) in 500 ml of 1N NaOH solution was warmed to 50° and stirred for 30 minutes. The crude product was removed by filtration and dried. The product (20 g., 87%) was recrystallized from ethanol to give material which melted at 183°-184°.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[NH:26]>>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH2:21][CH2:22][O:23][CH2:24][C:25]1[NH:27][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([F:11])=[N:3][C:2]=2[N:26]=1
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N=C(N)COCCc1c(F)cccc1Cl
Agent: Cl
Product: O=c1[nH]c(COCCc2c(F)cccc2Cl)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(2-chloro-6-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride. Off-white solid. MS: m/e=352.2 [M+H+].
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:21]1([S:27]([C:30]2[S:34][C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:32][CH:31]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([S:27]([C:30]2[S:34][C:33]([N:35]3[CH2:40][CH2:39][N:38]([C:9]([C:8]4[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:7]=4[O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[O:11])[CH2:37][CH2:36]3)=[N:32][CH:31]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ncc(S(=O)(=O)c4ccccc4)s3)CC2)c1
Yield: 57 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(5-benzenesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 4(d)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 57%). MS (m/e): 576.0 (M+H+, 100%), 593.3 (M+NH4+, 94%).