Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1OC2C=CC=CC=2C=1C(=O)C1C=C(I)C(O)=C(I)C=1.[CH2:22]([C:26]1[O:27][C:28]2[CH:49]=[CH:48][CH:47]=[CH:46][C:29]=2[C:30]=1[C:31](=O)[C:32]1[CH:37]=[C:36]([I:38])[C:35]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[C:34]([I:44])[CH:33]=1)CCC>>[CH3:22][C:26]1[O:27][C:28]2[CH:49]=[CH:48][CH:47]=[CH:46][C:29]=2[C:30]=1[CH2:31][C:32]1[CH:37]=[C:36]([I:38])[C:35]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[C:34]([I:44])[CH:33]=1
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(I)c(OCC(=O)O)c(I)c1
Agent: Cc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Product: Cc1oc2ccccc2c1Cc1cc(I)c(OCC(=O)O)c(I)c1

Procedure:
Steps 3 and 4 are performed in analogy with the steps 2 and 3 of the synthesis of (011) Step 5 is performed in analogy with the step 4 of the synthesis of (005).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[C:27]2[O:32][CH2:33][O:34][C:26]=12>>[Cl:31][C:30]1[C:25]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:9][C:10]=3[O:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]=[CH:4][N:3]=2)=[C:26]2[O:34][CH2:33][O:32][C:27]2=[N:28][CH:29]=1
Reactant: ClCCCOc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Reactant: Nc1c(Cl)cnc2c1OCO2
Product: ClCCCOc1cc(OC2CCOCC2)c2c(Nc3c(Cl)cnc4c3OCO4)ncnc2c1
Yield: 78 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-7-(3-chloropropoxy)-5-tetrahydropyran-4-yloxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 78% yield; Mass Spectrum: M+H+ 493 and 495.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH2:27]([O:15][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:10]=[CH:11][C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(Br)c(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of methyl 4-bromo-3-hydroxy-2-nitrobenzoate (5.41 g, 19.6 mmol) and potassium carbonate (5.42 g, 39.2 mmol) in N,N-dimethylformamide (30 mL, 387 mmol) was treated with benzyl bromide (3.26 mL, 27.4 mmol) and stirred at 60° C. for 1 h. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude tan oil. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (6.99 g, 97%) as a yellow solid. LCMS calculated for C15H16BrN2O5 (M+NH4)+: m/z=383.0, 385.0. found: 383.0, 385.0.
Reaction SMILES: [CH3:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[NH:28][N:27]=[N:26][CH:25]=3)[CH:19]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]2=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH3:5].[CH3:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[NH:28][N:27]=[N:26][CH:25]=3)[CH:19]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]2
Reactant: CC1(c2cccc(-c3cnn[nH]3)c2)C2CN(CCCc3ccccc3)C(=O)C21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(c2cccc(-c3cnn[nH]3)c2)C2CN(CCCc3ccccc3)CC21
Product: N
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
To a solution of 6-methyl-3-(3-phenylpropyl)-6-[3-(1H-1,2,3-triazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexan-2-one (Preparation 41, 32 mg, 0.087 mmol) in tetrahydrofuran (2 ml) at room temperature was added lithium aluminium hydride (0.43 ml, 0.43 mmol, 1.0 M in THF) dropwise over a few minutes. The mixture was stirred at room temperature for 6 hours and then quenched by the cautious addition of 2N sodium hydroxide (0.5 ml) at 0° C. Excess solid sodium hydrogen carbonate and ethyl acetate (5 ml) were then added and the mixture was stirred rapidly for 30 minutes and then filtered through celite washing with ethyl acetate. The solvent was evaporated in vacuo and the crude residue was purified by silica column chromatography eluting first with hexane:ethyl acetate (1:1) and then hexane:ethyl acetate: ammonia solution (0.880) (10:90:1) to afford the title compound as a colourless oil (15.0 mg, 48%).
Reaction SMILES: [OH:1][C:2]12[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[C:3]1([NH:22][C:23](=[O:25])[CH3:24])[C:4]1[C:9]([O:10]2)=[CH:8][C:7]([CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[CH3:26][N:27]([CH3:29])[CH3:28].C1C[O:33]CC1>>[C:23]([NH:22][C:3]1([C:4]2[CH:5]=[CH:6][C:7]([CH:11]([CH3:12])[CH3:13])=[CH:8][C:9]=2[O:10][C:26](=[O:33])[N:27]([CH3:29])[CH3:28])[C:14](=[O:21])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]1=[O:1])(=[O:25])[CH3:24]
Reactant: CN(C)C
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Reactant: C1CCOC1
Product: CC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)N(C)C)C(=O)c2ccccc2C1=O
Yield: 43 %

Procedure:
N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-5-oxa-indeno[2,1-a]inden-9b-yl)-acetamide (0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with Dimethyl-carbamylchrolide (0.23 g, 2.22 mmol), Trimethylamine (0.17 g, 1.77 mmol). The reaction mixture was heated for 24 hrs under reflux. After concentrating in a vacuum to remove THF, and the remainder was diluted with Ethylacetate and washed with Bicarbonate sodium aqueous solution many times. After drying and filtrating, the organic layer was purified using column chromatography (ethylacetate:hexane=1:1) to afford the title compound (0.26 g, 43%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=1>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[N:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:12]=[C:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1nc(-c2cccnc2)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)Cn1nc(-c2cccnc2)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
Acetic anhydride (431 μL, 4.4 mmol) was added dropwise to a solution of methyl 2-[5-amino-3-(3-pyridyl)pyrazol-1-yl]acetate (510 mg, 2.2 mmol) in pyridine (1.7 mL) at 0° C. under an atmosphere of nitrogen. Upon complete addition, the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was filtered and the solid was washed with diethyl ether to provide the title compound as a white solid (430 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44](/[C:49](/[C:57]2[CH:62]=[CH:61][C:60]([CH:63]3[CH2:65][CH2:64]3)=[C:59]([O:66][CH3:67])[N:58]=2)=[CH:50]\[C@@H:51]2[NH:55][C:54](=[O:56])[CH2:53][CH2:52]2)[CH:45]=[CH:46][C:47]=1O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:41][C:42]1[CH:43]=[C:44](/[C:49](/[C:57]2[CH:62]=[CH:61][C:60]([CH:63]3[CH2:64][CH2:65]3)=[C:59]([O:66][CH3:67])[N:58]=2)=[CH:50]\[C@@H:51]2[NH:55][C:54](=[O:56])[CH2:53][CH2:52]2)[CH:45]=[CH:46][C:47]=1[O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(O)c(Cl)c2)ccc1C1CC1
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(OC3CCOCC3)c(Cl)c2)ccc1C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tetrahydro-4-pyranol (127 mg), a 2.2 M solution of diisopropyl azodicarboxylate in toluene (0.655 mL) and triphenylphosphine (326 mg) were added to a solution of (5R)-5-[(E)-2-(3-chloro-4-hydroxyphenyl)-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (160 mg) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for four hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give (5R)-5-[(E)-2-[3-chloro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl]-2-(5-cyclopropyl-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a colorless amorphous (120 mg, 61%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=O.O.[NH2:17][NH2:18]>>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([NH:17][NH2:18])=[O:13]
Reactant: NN
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Solvent: O
Product: NNC(=O)c1cnc2n(c1=O)CCC2
Reaction time: 1 h
Yield: 77.5 %

Procedure:
2.08 g. of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate is added to 10 ml. of 98% by weight of hydrazine hydrate and the mixture is allowed to stand for 1 hour at room temperature and the obtained crystals are filtered and washed with water. 1.5 g. (77.5%) of 4-oxo-4,6,7,8-tetrahydro-pyrrolo(1,2-a)pyrimidine-3-carbohydrazide is obtained, melting at 180°-181° C.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].[Na]>CO.O1CCCC1.C(O)(=O)C>[CH2:17]([N:24]1[C@@H:6]2[C@@H:5]([CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:7]2)[CH2:4][C:3]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC1Cc2ccccc2CC1=O
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C1C[C@@H]2Cc3ccccc3C[C@@H]2N1Cc1ccccc1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Acetic acid (12.5 ml) was added to a stirred mixture of 2-oxo-1,2,3,4-tetrahydronaphthalene-3-acetic acid methyl ester (3.62 g, 17 mmol), and benzylamine (7.2 ml, 66 mmol) in a 1:1 mixture of tetrahydrofuran and methanol (120 ml) at 0° C. under argon. After 0.5 h, sodium cyanoborohydride (2.09 g, 33 mmol) was added and the resultant mixture stirred at room temperature. After 16 h, aqueous 10% sodium hdyroxide was added and the solvent evaporated in vacuo. The residue was partitioned between water (100 ml) and dichloromethane (2×200 ml). The combined extracts were washed with water (100 ml), brine (100 ml), then dried (Na2SO4) and evaporated in vacuo to give a brown solid (4.38 g). Chromatography on silica using 0-5% methanol-ethyl acetate gradient elution afforded the title compound as a yellow solid (1.75 g, 38%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:10]=[C:11]([C:16]2([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>[Pd].C(O)C>[NH2:8][C:9]1[CH:10]=[C:11]([C:16]2([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:18]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: COC(=O)CC1(c2ccc(F)c(N(Cc3ccccc3)Cc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CC1(c2ccc(F)c(N)c2)CC1
Reaction time: 12 h

Procedure:
At room temperature, 200 mg of palladium on carbon (10%) were added to a solution of 2.1 g (5.2 mmol) of methyl {1-[3-(dibenzylamino)-4-fluorophenyl]cyclopropyl}acetate in 100 ml of ethanol, and the mixture was hydrogenated at atmospheric pressure for 12 h. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 1:1), the reaction solution was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 647 mg (2.9 mmol, 56% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].C([O-])(=O)C.[NH4+:16]>CO>[C:6]([OH:8])(=[O:7])[CH3:5].[NH2:16][CH:4]([CH2:3][CH:2]([CH3:11])[CH3:1])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)CC(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(=O)O
Product: COC(=O)CC(N)CC(C)C
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Ru(OAc)2((R)-dm-binap) (0.201 g, 0.211 mmol), methyl 5-methyl-3-oxohexanoate (10.00 g, 63.2 mmol), ammonium acetate (5.02 g, 63.2 mmol) and methanol (50 mL) were placed in a 100 mL stainless steel autoclave under nitrogen atmosphere, and then the mixture was stirred under a hydrogen pressure of 3 MPa at 80° C. for 24 hours. After completion of the reaction, the solvent was removed by evaporation to give methyl (−)-3-amino-5-methylhexanoate acetate as a crude material (12.70 g). The crude product was treated with 7N ammonia/methanol and analyzed by GLC using a capillary column TC-5HT, indicating that the yield of methyl 3-amino-5-methylhexanoate was 74.4%. The enantiomeric excess of methyl (−)-3-amino-5-methylhexanoate in the crude product was determined to be 97.7% ee by HPLC analysis using a SUMICHIRAL OA-4100R column after conversion into methyl 3-(4-nitrobenzoylamino)-5-methylhexanoate.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:9]=1[C:10]2=[O:15].[Cl:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C[O-].[Na+]>>[ClH:22].[N:25]1([CH2:24][CH2:23][O:1][C:2]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:3]=2[C:4]2[C:5]([O:20][CH3:21])=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:9]=2[C:10]3=[O:15])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ClCCN1CCCC1
Reactant: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Agent: C[O-]
Agent: [Na+]
Product: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(OCCN3CCCC3)c1-2
Product: Cl

Procedure:
5-Hydroxy-4-methoxy-2-propyloxy-fluoren-9-one (0.83 g, 2.9 mmole) and 2-chloroethylpyrrolidine and sodium methoxide (0.20 g, 3.5 mmole) are reacted as described in Example 9B to give a red powder, which when recrystallized from 2-butanone gives the title compound. (0.222 g, 18%). m.p. 147°-149° C. Analysis calculated for C23H27NO4.HCl; C, 66.10, H, 6.75, N, 3.35. Found: C, 65.82, H, 6.65; N, 3.09. The compound has the following structure: ##STR50##
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Na+].[CH3:22][S:23]([O-])(=[O:25])=[O:24].O>CN(C=O)C>[CH3:22][S:23]([C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)(=[O:25])=[O:24]
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(S(C)(=O)=O)c2)c1
Temperature: 140 °C
Yield: 39.3 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 1.0 g, 0.0035 mol) and methanesulfonic acid sodium salt (3.24 g, 0.021 mol) in 15 mL of DMF was heated at 140° C. for 24 hours. After the mixture was cooled, water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.45 g (40% yield) of product as a yellow solid: mp: 140-142° C.; Anal. Calc'd. for C17H17N3SO2: C, 62.36; H, 5.23; N, 12.83; S, 9.79. Found: C, 62.16; H, 5.31; N, 12.74; S, 9.86.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:19])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:19][C:20](=[O:22])[CH3:21])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CCCCC(N)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC(Cn1cncn1)(NC(C)=O)c1ccc(Cl)cc1
Yield: 32 %

Procedure:
To a stirred, cooled (0° C.) solution of 0.54 g (1.94 mmols) of [2-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-hexylamine and 0.02 g (0.15 mmols) of N,N-dimethylaminopyridine in 10 mL of methylene chloride under nitrogen was added dropwise 0.50 mL (5.28 mmols) of acetic anhydride. After 5 days the reaction was quenched with the addition of methanol and the solvents were removed to give a white solid. The solid was dissolved in toluene which was removed under reduced pressure to remove any acetic acid. The resultant solid was recrystallized from chloroform to give 0.2 g (32%) of white crystals, melting point 178.5°-179° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg]Br>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: C[Mg]Br
Reactant: COc1ccc(C(C)=O)c(F)c1
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2′-fluoro-4′-methoxyacetophenone (4.45 g, 26.5 mmol) in dry THF (50 mL) at 0° C., a solution of 2.4 M methyl magnesium bromide (11.6 mL, 27.8 mmol) was added. The mixture was stirred at 0° C. and then room temperature for 4 h. The reaction was quenched with saturated NH4Cl solution. The organic was extracted with EtOAc (3×50 mL). The combined EtOAc layers were washed with brine and dried over Na2SO4. The resulting alcohol was obtained as an oil after flash chromatography using EtOAc:hexane=2:8 as the eluant.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](Br)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:11]1([C:7]2[N:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2ccccc2)nc1
Yield: 51 %

Procedure:
5-acetyl-2-bromopyridine 38 (0.656 g, 3.28 mmol), phenylboronic acid (0.800 g, 6.56 mmol), Na2CO3 (0.243 g, 2.29 mmol), Pd(PPh3)2Cl2 (0.115 g, 0.16 mmol, 5% Pd), acetonitrile (26 mL) and H2O (26 mL) were added to 50 mL screw cap pressure vessel. The mixture was stirred, degassed by purging with argon for 15 min, sealed and placed in an 80° C. oil bath for 14 h (overnight). The dark colored mixture was cooled and extracted with ether. The organic layer was filtered through a pad of celite, rinsed with ether, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by flash column chromatography (SiO2, 20 g, 5% EtOAc/hexanes) to afford the coupled ketone 40 as a white solid (0.33 g, 52%): TLC Rf=0.4 (25% EtOAc/hexanes); mp 124.9126.2° C.; 1H NMR (500 MHz, CDCl3) δ 9.22 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.3, 2.2 Hz, 1H), 8.10-7.99 (m, 2H), 7.83 (d, J=8.3 Hz, 1H), 7.55-7.40 (m, 3H), 2.65 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.6, 161.1, 150.2, 138.2, 136.7, 130.9, 130.4, 129.2, 127.6, 120.4, 26.9; IR (neat cm−1) 3062, 2999, 2960, 2322, 1673, 1557, 1382, 1016, 736; HRMS (DART, M++H) m/z 198.0906 (calculated for C13H12NO, 198.0919).
Reaction SMILES: [N:1]([C:4]([F:8])([F:7])[CH2:5][OH:6])=[N+:2]=[N-:3].Br[C:10](F)(F)[C:11](OCC)=[O:12].[N-]=[N+]=[N-].[Na+]>CS(C)=O>[N:1]([C:4]([C:5]([O:12][CH2:11][CH3:10])=[O:6])([F:8])[F:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(F)(F)CO
Reactant: CCOC(=O)C(F)(F)Br
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)N=[N+]=[N-]

Procedure:
The preparation of 2-azido-2,2-difluorethanol can be summarized as follow: ##STR1## The ethyl 2-bromo-2,2-difluoroacetate, CBrF2COOCH2CH3, starting material is available from chemical laboratory supply houses. The ethyl 2-bromo-2,2-difluoroacetate used in example 1 was obtained from PCR, Inc., P.0. Box 1466, Gainesville, Fla. 32602. The ethyl 2-bromo-2,2-difluoroacetate reacts with sodium azide, NaN3, in dry dimethyl sulfoxide at room temperature (20° C.) to produce ethyl 2-azido-2,2-difluoroacetate, N3CF2COOCH2CH3. The reaction conditions are illustrated in example 1. Next, the ethyl 2-azido-2,2-difluoroacetate reacted with sodium borohydride, NaBH4, in water to produce the desired 2-azido-2,2-difluoroethanol, N3CF2CH2OH. The reaction conditions are illustrated in example 2. The reactivity of 2-azido-2,2-difluoroethanol is demonstrated by example 3 in which the alcohol reacts with phenylisocyanate.
Reaction SMILES: [OH:1][C:2]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:4]([O:5][C:6]3=[O:13])[CH2:3]1)[CH2:10]2.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]([O:1][C:2]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:4]([O:5][C:6]3=[O:13])[CH2:3]1)[CH2:10]2)(=[O:17])[CH:15]=[CH2:16].[OH:1][C:2]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:4]([O:5][C:6]3=[O:13])[CH2:3]1)[CH2:10]2
Reactant: C=CC(=O)Cl
Agent: O=C1OC2CC3CC1CC(O)(C3)C2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)OC12CC3CC(C1)OC(=O)C(C3)C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 50 mmol of 1-hydroxy-4-oxatricyclo[4.3.1.13,8]undecan-5-one, 150 mmol of acryloyl chloride, 150 mmol of triethylamine, and 250 ml of toluene was stirred at 60° C. for 4 hours. The resulting reaction mixture was concentrated and was then subjected to column chromatography on a silica gel to yield 1-acryloyloxy-4-oxatricyclo[4.3.1.13,8]undecan-5-one of the following formula in a yield of 50% with a conversion rate from 1-hydroxy-4-oxatricyclo[4.3.1.13,8]undecan-5-one of 73%.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:25])[N:7]([C@@H:8]2[C:14](=[O:15])[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10][CH2:9]2)[C:6](=[O:20])[C:5]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:4]12.Cl[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C)C=O>[O:15]=[C:14]1[N:13]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][CH2:9][C@@H:8]1[N:7]1[C:6](=[O:20])[C:5]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:4]2[C:3]1=[O:25]
Reactant: O=C1Nc2ccccc2SC[C@@H]1N1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)CSc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To a stirred mixture of 50 ml of N,N-dimethylformamide and 0.5 g of sodium hydride (60% in oil) is added 4 g of 3(R)-phthalimido-2,3-dihydro-1,5(5H)-benzothiazepin-4-one obtained in Reference Example 2 at ice bath temperature. After 5 minutes, 2 g of tert-butyl chloroacetate is added at ice bath temperature. The resulting mixture is stirred in an ice bath for b 15 minutes and diluted with ice water (200 ml). The deposited crystals are collected by filtration, dried and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 4 g of tert-butyl 4-oxo-3(R)-phthalimido-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as colorless crystals. Recrystallization of a part of the crystals from ethyl ether yields colorless prisms, m.p. 181°-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Product: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.