Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]([CH3:11])(OC(=O)C)[CH:5]=[CH2:6]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:3]([O:12][CH2:6][CH:5]=[C:4]([CH3:11])[CH:3]([O:2][CH3:1])[O:12][CH3:13])(=[O:2])[CH3:4]
Reactant: C=CC(C)(OC(C)=O)C(OC)OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: COC(OC)C(C)=CCOC(C)=O
Temperature: 152 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
1,800 parts of 1,1-dimethoxy-2-methyl-2-acetoxy-but-3-ene together with 3.6 parts of copper (II) acetate were heated, with stirring, for 12 hours at 152° C. in the reaction vessel described under (A). The low-boiling products formed distilled off continuously over the entire reaction period. Subsequent working up of the reaction mixture by distillation gave 1,278 parts of 4,4-dimethoxy-3-methyl-crotyl acetate, corresponding to a yield of 71% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[C:21]3[O:23][CH2:24][O:25][C:20]3=[CH:19][C:18]=2[N+:26]([O-])=O)[CH2:12]1)=[O:9])=[O:5]>[Pd].CO>[NH2:26][C:18]1[CH:19]=[C:20]2[O:25][CH2:24][O:23][C:21]2=[CH:22][C:17]=1[CH2:16][N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:8](=[O:9])[CH2:7][NH:6][C:4](=[O:5])[C:3]2[CH:29]=[C:30]([C:33]([F:35])([F:34])[F:36])[CH:31]=[CH:32][C:2]=2[NH2:1])[CH2:12]1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2cc3c(cc2[N+](=O)[O-])OCO3)C1
Agent: [Pd]
Solvent: CO
Product: Nc1cc2c(cc1CN1CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C1)OCO2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine (30.5 mg), 10% Pd-activated carbone (6 mg), and methanol (3 mL) was stirred under a hydrogen atmosphere at room temperature for 10 h. The Pd catalyst was filtered off through Celite, and the filtrate was concentrated. Solid phase extraction (Bond Elut™ SI, 20% methanol/AcOEt) afforded (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 2127) (21.9 mg, 76%): The purity was determined by RPLC/MS (95%); ESI/MS m/e 480.1 (M++H, C22H24F3N5O4).
Reaction SMILES: C12C=C3N=C(C=C3)C=C3NC(C=C3)=CC3=NC(C=C3)=CC(N1)=CC=2.[NH2:25][C:26]1[CH:27]=[C:28]([C:32]2[C:33]3[NH:37][C:36]([C:38]([C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:39]4[N:67]=[C:42]([C:43]([C:61]5[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=5)=[C:44]5[NH:60][C:47](=[C:48]([C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[C:49]6[CH:50]=[CH:51][C:52]=2[N:53]=6)[CH:46]=[CH:45]5)[CH:41]=[CH:40]4)=[CH:35][CH:34]=3)[CH:29]=[CH:30][CH:31]=1.[Br:74][CH2:75][C:76](Br)=[O:77]>>[Br:74][CH2:75][C:76]([NH:25][C:26]1[CH:27]=[C:28]([C:32]2[C:33]3[NH:37][C:36]([C:38]([C:68]4[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=4)=[C:39]4[N:67]=[C:42]([C:43]([C:61]5[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=5)=[C:44]5[NH:60][C:47](=[C:48]([C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[C:49]6[CH:50]=[CH:51][C:52]=2[N:53]=6)[CH:46]=[CH:45]5)[CH:41]=[CH:40]4)=[CH:35][CH:34]=3)[CH:29]=[CH:30][CH:31]=1)=[O:77]
Reactant: Nc1cccc(-c2c3nc(c(-c4ccccc4)c4ccc([nH]4)c(-c4ccccc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)c1
Reactant: O=C(Br)CBr
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Product: O=C(CBr)Nc1cccc(-c2c3nc(c(-c4ccccc4)c4ccc([nH]4)c(-c4ccccc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)c1

Procedure:
A porphyrin (5-(3-aminophenyl)-10,15,20-triphenylporphyrin is derivatized by reacting with excess bromoacetyl-bromide (dissolved in acetone containing sodium carbonate) to form (5-(3-bromoacetamidophenyl)-10,15,20-triphenylporphyrin. 10 μmol of the derivatized porphyrin and 10 mg of the scFv-4-helix bundle-cys are dissolved separately in 20 ml of dry dimethyl formamide. These two solutions are added over a period of 3 hours to 50 ml dry dimethyl formamide containing 25 mg sodium carbonate. These reactions are performed in the dark, under argon. The final product is scFv-4-helix bundle-cys with optimally conjugated porphyrins (scFv-4-helix bundle-cys/porphyrin). The scFv-4-helix bundle-cys/porphyrin is dialysed into PBS and concentrated as above.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1.[CH3:23][CH:24]([CH:28]([CH3:31])[CH2:29][CH3:30])[C:25](Cl)=[O:26]>N1C=CC=CC=1>[CH3:23][CH:24]([CH:28]([CH3:31])[CH2:29][CH3:30])[C:25]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1)=[O:26]
Reactant: CCOC(=O)c1cnc2c3cc(N)ccc3c(C)cn2c1=O
Reactant: CCC(C)C(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2c3cc(NC(=O)C(C)C(C)CC)ccc3c(C)cn2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of ethyl 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (1.5 g) in pyridine (110 ml) was added 2,3-dimethylpentanoyl chloride (1.4 g) under ice cooling. After stirring for 2 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue in chloroform (100 ml) was washed with water, a cold 1N hydrochloric acid and water in turn and dried over magnesium sulfate. After removal of the solvent, the residue was chromatographed on a silica gel column using chloroform as an eluent to give ethyl 10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (1.94 g).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2>CN(C=O)C>[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:25]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: Nc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4ccc(N)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 56.2 %

Procedure:
157 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 242 mg of 5-aminoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 124 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]2[N:10]=[CH:11][C:12]([CH:13]=[O:14])=[C:4]2[N:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH2:32](O)[CH2:33][CH2:34][OH:35].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]2[N:10]=[CH:11][C:12]([CH:13]3[O:35][CH2:34][CH2:33][CH2:32][O:14]3)=[C:4]2[N:3]=1
Reactant: OCCCO
Reactant: Cc1c(Cl)nc2c(C=O)cnn2c1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(Cl)nc2c(C3OCCCO3)cnn2c1Cl

Procedure:
To 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (290 mg) in toluene (40 mL) was added pyridinium p-toluenesulfonate (60 mg) and propan-1,3-diol. The mixture was then heated under reflux for 2 h, with azeotropic removal of water. The solution was cooled and evaporated under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether ⅔ as eluent to give the title compound (310 mg) as a white solid; 1H-NMR (400 MHz, CDCl3) d(ppm): 8.32 (1H, s, 2-H), 5.97 (1H, s, CHO2R), 4.25 (2H, br dd, OCHeq), 4.05 (2H, br t, OCHax), 2.50 (3H, s, 6-Me), 2.25 (1H, m, CCHeqHC), 1.48 (1H, br d, CCHHaxC).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.[NH2:19][CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].N1CCCC1C(O)=O>[Cu](I)I.CS(C)=O>[Cl:14][C:12]1[CH:13]=[C:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([NH:19][CH2:20][C:21]4[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:3]=[CH:4][C:5]=3[CH:16]=[CH:15][C:9]2=[N:10][CH:11]=1
Reactant: Cc1cccnc1CN
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Agent: I[Cu]I
Agent: O=C(O)C1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cccnc1CNc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 70 °C

Procedure:
7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.100 g, 0.312 mmol), 2-aminomethyl-3-methylpyridine (0.038 g, 0.312 mmol), copper iodide (0.006 g, 0.031 mmol), potassium carbonate (0.086 g, 0.621 mmol), and dl-proline (0.007 g, 0.062 mmol) were combined in a flask. Dimethyl sulfoxide (2.0 mL) was added and argon was bubbled through the solution for several minutes. The solution was stirred and heated at 70° C. overnight. Once complete the solution was cooled to ambient temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulftate, filtered, concentrated in vacuo and purified by column chromatography (0-40% ethyl acetate/hexane gradient) to afford the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:31])[F:30])[CH2:28][CH2:27]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH:33]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([C:26]3([C:29]([F:32])([F:30])[F:31])[CH2:27][CH2:28]3)=[N:24][N:25]=[C:20]2[C@H:19]([NH2:33])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (7.5 mL, 101.3 mmol) was added to a solution of tert-butyl {(6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl}carbamate (0.38 g, 0.80 mmol) in dichloromethane (15 mL). After 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 373.1 (M+1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[O:12][N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:14]1[C:10]([CH3:9])=[N:11][O:12][C:13]=1[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
N-chlorosuccinimide (0.266 g, 2 mmol) was added, in one lot, to a stirred suspension of N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327 g, 1 mmol, Example 14nb) in chloroform (10 ml) and stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (2×50 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography using ethyl acetate as eluent to give N-(4-chloro-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzensulfonamide [210 mg, 58% yield, m.p. 260° C. (de coup)].
Reaction SMILES: C[C:2]12[C:21]3(C)[N:6]4[CH2:7][CH2:8][CH2:9][N:10]3[CH2:11][CH2:12][N:13]1[CH2:14][CH:15]([CH:16]([O:19][CH3:20])[CH:17]=[CH2:18])[N:3]2CC4.[OH-].[Na+]>O>[NH:6]1[CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH:15]([CH:16]([O:19][CH3:20])[CH:17]=[CH2:18])[NH:3][CH2:2][CH2:21]1
Reactant: C=CC(OC)C1CN2CCN3CCCN4CCN1C2(C)C34C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC(OC)C1CNCCNCCCNCCN1

Procedure:
This product is obtained according to a procedure identical to that described in example B from 0.8 g (2.61 mmol) of compound 17. Compound 18·4HCl is isolated in the form of an off-white powder. This powder is dissolved in the minimum amount of water and the solution is brought to basic pH by addition of NaOH pellets. After extraction with 3×100 ml of chloroform and drying over MgSO4, the solvents are evaporated.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH3:2].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:8]2[CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7]2=[O:9])=[CH:14][CH:13]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CCOC1CCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC1CCC(=O)N1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a mixture of 2.25 g of 5-ethoxy-pyrrolidin-2-one, 1.23 g of hydrated potassium hydroxide and 0.2 g of tetra-n-butylammonium bromide in 45 cm3 of tetrahydrofuran, there is added, without exceeding 30° C., a solution of 3.5 g of 4-methoxybenzyl bromide in 15 cm3 of tetrahydrofuran. After agitating for 1 hour at ambient temperature, filtering and evaporating the solvent under reduced pressure, the residue is taken up with water and extracted with ethyl acetate. The extracts are dried and the solvent is evaporated under reduced pressure. The residue is distilled at 245° C. under 0.2 mbar. 3.10 g of the expected product is obtained.
Reaction SMILES: O.[NH2:2][NH2:3].C1([O:10][C:11](=O)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:32]#[N:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[CH:15][CH:14]=2)C=CC=CC=1>O1CCOCC1>[C:32]([C:26]1([C:22]2[CH:21]=[C:20]([S:19][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:11]([NH:2][NH2:3])=[O:10])=[CH:18][CH:17]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)#[N:33]
Reactant: N#CC1(c2cccc(Sc3ccc(NC(=O)Oc4ccccc4)cc3)c2)CCOCC1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: N#CC1(c2cccc(Sc3ccc(NC(=O)NN)cc3)c2)CCOCC1
Temperature: 110 °C

Procedure:
Hydrazine hydrate (99%, 0.44 g, 8.72 mmol) was added to a solution of phenyl(4-{[3-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl]thio}phenyl)carbamate (1.50 g, 3.49 mmol) (example 5) in 1,4-dioxane (10 mL). The reaction mixture was refluxed at 110° C. for about 4 hours. The solvent was evaporated under vacuum and water was added. The white solid so obtained was filtered under vacuum and dried to obtain the title compound. Yield: 1.0 g
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])(C)C.C([Li])CCC.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[O:25].[Cl-].[NH4+]>CCOCC.CCCCCC.C(OCC)(=O)C>[OH:9][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH3:1])[C:6]=1[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[OH:25]
Reactant: O=Cc1ccccn1
Reactant: CC(C)Oc1cccc(CO)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: -20 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a mixture of 30 g (0.18 mol) of 3-isopropoxybenzyl alcohol in 600 ml of ether cooled to -20° C. was added in portions 38.7 ml (0.387 mol) of n-butyllithium (10M) in hexane over a 20 min period, and the reaction mixture was allowed to warm to room temperature and stirred for 2 hr. The above reaction mixture was cooled to -20° C., 23.1 g (0.216 mol) of pyridine-2-carboxaldehyde was added in one portion to the mixture, and the resulting reaction mixture was allowed to warm to room temperature and stirred for 1 hr. Ammonium chloride solution (200 ml) and 100 ml of ethyl acetate were added to the mixture. The resulting mixture was separated, the aqueous layer was extracted with methylene chloride (2×200 ml), the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The diol was purified by chromatography on silica gel eluting with ethyl acetate/hexane (9:1; and 0.05 % TEA). The solvent was concentrated in vacuo, the brown oil was dissolved in methylene chloride/hexane, and removal of methylene chloride in vacuo to 1/2 of its volume afforded 11.1 g (22.6%) of 2-[1-hydroxy-(6'-hydroxymethyl-2'-isopropoxy) -benzyl]pyridine (Formula XIII: R1 =R7 =H; R2 =2'--OCH (CH3)2), as a tan solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C1(P(=[CH:40][CH:41]=[O:42])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:40][CH:41]=[O:42])[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)#[N:2]
Reactant: COc1ccc(COc2ccc(C#N)cc2C=O)cc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C#N)cc2C=CC=O)cc1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A mixture of 3-cyano-6-((4-methoxybenzyl)oxy)benzaldehyde (2.8 g) and (triphenylphosphoranylidene)acetaldehyde (3.5 g) in 40 mL CH2Cl2 was stirred at reflux for 16 hours. The solution was cooled to ambient temperature, concentrated and purified on silica gel column (ethyl acetate/hexane/CH2Cl2, 1:8:3) to give 3-cyano-6-((4-methoxybenzyl)oxy)-1-(2-formylethenyl)benzene (2.8 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C@H:12]([C:16]([O:18][CH3:19])=[O:17])[N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][CH2:9]2.CN(C)N>CO>[NH2:31][C:28]1[CH:29]=[CH:30][C:2]([Cl:1])=[C:3]([CH:27]=1)[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C@H:12]([C:16]([O:18][CH3:19])=[O:17])[N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:10][CH2:9]2
Reactant: COC(=O)[C@H]1c2ccc(OCc3cc([N+](=O)[O-])ccc3Cl)cc2CCN1C(=O)OC(C)(C)C
Agent: CN(C)N
Solvent: CO
Product: COC(=O)[C@H]1c2ccc(OCc3cc(N)ccc3Cl)cc2CCN1C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 32 %

Procedure:
To a solution of (R)-2-tert-butyl 1-methyl 6-(2-chloro-5-nitrobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate prepared following procedure 2 (56 mg, 0.12 mmol) in MeOH (5 mL) was added FeCl3.6H2O (10 mg, 0.04 mmol) followed by the addition of 1,1-dimethylhydrazine (0.5 g, 7 mmol). The reaction was refluxed at 85° C. for 16 h and filtered. The filtrate was concentrated and purified by preparative HPLC (Phenomenex 20×100 mm eluting with 0-100% MeOH/H2O (90% in H2O, 0.1% TFA) gradient over 8 min with flow rate 25 mL/min) to yield (R)-2-tert-butyl 1-methyl 6-(5-amino-2-chlorobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a yellow oil (17 mg, 32%). HPLC retention time (Method C)=3.35 min. LC/MS (ESI) (M+Na)+=469. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 5H), 1.48 (s, 4H), 2.69-3.00 (m, 2H), 3.57-3.85 (m, 5H), 5.04 (s, 2H), 5.36 (s, 0.5H), 5.52 (s, 0.5H), 6.71 (s, 1H), 6.80 (m, 1H), 6.98 (d, J=7.47 Hz, 1H), 7.27-7.40 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1.[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C(OC(=O)C)C>[Cl:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:13]=1[C:14]([NH:16][C:17]([NH:8][C:5]1[S:6][CH:7]=[C:3]([C:2]([F:10])([F:9])[F:1])[N:4]=1)=[O:18])=[O:15]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1nc(C(F)(F)F)cs1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1nc(C(F)(F)F)cs1
Reaction time: 4 h

Procedure:
To a solution of 1.7 g (0.01 mole) of 4-trifluoromethyl-2-aminothiazole in 50 ml of dry ethylacetate was added all at once to a solution of 2.16 g (0.01 mole) of freshly prepared 2,6-dichlorobenzoylisocyanate dissolved in 10 ml of dry ethylacetate. The mixture was allowed to stir at 25° for 4 hours. The solvent was evaporated in vacuo, ether was added to the residue, and the solid was removed by filtration to give 3.7 g of product, m.p. 210°-213°. The infrared and nuclear magnetic resonance spectra were consistent with the proposed structure.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][C@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[C@H:6]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5]1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[CH2:19]([O:18][CH2:17][C@H:6]1[C@@H:7]([O:9][Si:10]([C:13]([CH3:15])([CH3:14])[CH3:16])([CH3:12])[CH3:11])[CH2:8][C@H:4]([NH2:1])[CH2:5]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N=[N+]=[N-])C[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N)C[C@H]1COCc1ccccc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A suspension of ({(1S,2S,4R)-4-azido-2-[(benzyloxy)methyl]cyclopentyl}-oxy)(tert-butyl)dimethylsilane (2.20 g, 0.00608 mol) and 10% Pd/C (0.16 g, 0.00015 mol) in EtOAc (23.9 mL) was stirred under an atmosphere of hydrogen overnight. The reaction was purged with nitrogen and the mixture filtered through celite with EtOAc. The filtrate was concentrated to obtain 2.01 g (98%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH:35][C:32]2=[N:33][CH:34]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:28][C:29]1[CH:30]=[C:31]2[CH:37]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:35]([CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:32]2=[N:33][CH:34]=1
Reactant: CCOC(=O)c1cc2cc(F)cnc2[nH]1
Reactant: OCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(F)cnc2n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.4 %

Procedure:
0.19 g (1.8 mmol) of 4-pyridylmethanol and then 0.48 g (1.8 mmol) of triphenylphosphine are successively added with stirring to a solution of 0.25 g (1.2 mmol) of ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, obtained according to the protocol described in step 1.3, in 10 mL of dry tetrahydrofuran maintained under an inert atmosphere. 0.32 g (1.8 mmol) of diethyl azodicarboxylate is then added dropwise at 0° C. The reaction mixture is then stirred for 72 hours at room temperature and then concentrated under reduced pressure. The resulting oil is purified by chromatography on a column of silica gel, eluting with a mixture of heptane and ethyl acetate. 0.26 g of the expected product is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][CH2:6][C@@H:7]([N:11]1[CH:15]=[C:14]([C:16](OCC)=[O:17])[N:13]=[CH:12]1)[C@@H:8]([OH:10])[CH3:9].[OH-].[NH4+:26]>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][CH2:6][C@@H:7]([N:11]1[CH:15]=[C:14]([C:16]([NH2:26])=[O:17])[N:13]=[CH:12]1)[C@@H:8]([OH:10])[CH3:9]
Reactant: CCOC(=O)c1cn([C@H](COc2ccc(Cl)c(Cl)c2)[C@H](C)O)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: COCCOC
Product: C[C@H](O)[C@@H](COc1ccc(Cl)c(Cl)c1)n1cnc(C(N)=O)c1

Procedure:
A mixture of ethyl 1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxylate (0.23 g), 28% ammonium hydroxide (12 mL) and 1,2-dimethoxyethane (6 mL) was heated at 100° C. in the stainless steel bottle for 24 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (gradient elution; 20:1 to 10:1 chloroform-methanol) to give the product, which was recrystallized from 1:5 n-hexane-ethyl acetate (12 mL) to give 1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxamide (81) (0.13 g).