Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:43]([NH2:46])([CH3:45])[CH3:44].[Na+].[I-]>>[CH:43]([NH:46][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][NH:33][CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1)([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CCl)cc(C(F)(F)F)c3)c2)C1
Reactant: CC(C)N
Agent: [I-]
Agent: [Na+]
Product: CC(C)NCc1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CCNC5)ccc32)cc(C(F)(F)F)c1
Temperature: 45 °C

Procedure:
To a solution of the above mixture (0.15 g, 0.227 mmol) in 3 mL of DCM, isopropyl amine (0.06 mL, 0.680 mmol) is added followed by sodium iodide (0.1 g, 0.68 mmol). After 45 min, LC-MS shows that tert-butyl 4-(1-(3-((methylsulfonyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-carboxylate is converted to desired product and the tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-carboxylate left over. To the reaction 3 mL (0.227 mmol) of isopropyl amine is added followed by NaI (0.1 g, 0.68 mmol) and the mixture is heated to 45° C. for 2 h. The solvent is then removed and the residue diluted with EtOAc, washed with H2O, brine and the organic layer dried over Na2SO4. Following concentration the residue is separated by FCC (25-100% EtOAc/heptane). This product is then treated with 60 mL of 50% TFA/DCM at rt for 1.5 h. After concentration the residue is separated by semi-prep HPLC (C-18; 10-100% I/H2O with 0.1% NH4OH) to provide the title compound. MS (ESI) m/z 525.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.95 (d, J=15.2 Hz, 2H), 7.38-7.52 (m, 2H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.78 (d, J=3.8 Hz, 1H), 3.81 (d, J=7.6 Hz, 4H), 3.03 (t, J=5.8 Hz, 2H), 2.68-2.79 (m, 3H), 1.03 (d, J=6.1 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([P:11]([CH:21](Br)[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1([Mg]Cl)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6]([NH:8][CH:9]([P:11]([CH:21]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Br)P(=O)(OCc1ccccc1)C(Br)NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NC(c1ccccc1)P(=O)(OCc1ccccc1)C(NC(=O)OC(C)(C)C)c1ccccc1
Yield: 32 %

Procedure:
In analogy to Example 11, the benzyl phosphinate 12 is prepared from the bis-substituted benzyl bromophosphinate 8 and a 2.0N phenylmagnesium chloride solution in a yield of 32%.
Reaction SMILES: [ClH:1].N1C=CC=CC=1.Cl.[C:9]([C:11]1[S:12][C:13](=[NH:28])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:26]C)=[C:19]([O:24]C)[CH:20]=3)[C:15]=12)#[N:10].Cl>O>[OH2:24].[OH2:24].[ClH:1].[C:9]([C:11]1[S:12][C:13](=[NH:28])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([OH:26])=[C:19]([OH:24])[CH:20]=3)[C:15]=12)#[N:10]
Reactant: COc1cc2c(cc1OC)-c1c(C#N)sc(=N)n1CC2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1sc(=N)n2c1-c1cc(O)c(O)cc1CC2

Procedure:
20.0 g. of pyridine hydrochloride are added to 6.0 g. of 1-cyano-3-imino-8,9-dimethoxy-3,4,5,6 -tetrahydro-1,3-thiazolo[4,3-a]isoquinoline hydrochloride, and the mixture is kept for 2 hours in an oil bath of 210°-220°C. The mixture is cooled and a mixture of 6 ml. of concentrated hydrochloric acid and 14 ml. of water is added. 5.2 g. of crystalline 1-cyano-3-imino-8,9-dihydroxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline hydrochloride dihydrate are obtained; m.p.: graduallly decomposes from 280°C (after recrystallization from hot water).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].Cl[C:10]1[CH:19]=[C:18]([O:20]CC2C=CC(OC)=CC=2)[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([O:30][CH3:31])=[CH:15][CH:16]=2)[N:11]=1.O>CN1CCCC1=O>[OH:20][C:18]1[C:17]2[C:12](=[C:13]([CH3:32])[C:14]([O:30][CH3:31])=[CH:15][CH:16]=2)[N:11]=[C:10]([N:6]2[CH:7]=[CH:8][C:4]([CH:1]([CH3:3])[CH3:2])=[N:5]2)[CH:19]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(C)c(OC)ccc23)cc1
Reactant: CC(C)c1cc[nH]n1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of compound 233b (350 mg, 1 eq.) and compound 221b (480 mg, 6 eq.) in N-methylpyrrolidone (5 mL) was heated at 200° C. for 30 min. After the reaction mixture was cooled to room temperature, water was added. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (EtOAc/DCM). Recrystallisation in diethylether gave compound 236b as a white solid in 49% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 1.35 (s, 3H), 1.36 (s, 3H), 2.85 (s, 3H), 3.97 (s, 3H), 6.40 (d, J=2.65 Hz, 2H), 7.01 (d, J=9.00 Hz, 1H), 8.00 (brs, 1H), 8.23 (d, J=9.00 Hz, 1H), 9.81 (brs, 1H); MS (ESI, EI+): m/z=298 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[OH:17][CH2:18][CH2:19][NH:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][NH:20][CH2:19][CH2:18][OH:17])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NNCCO
Solvent: CCN(CC)CC
Product: OCCNNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[2-hydroxyethylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-hydroxyethylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Na].[CH3:2][OH:3].[CH3:4][C:5]1[CH:10]=[C:9]([N+]([O-])=O)[C:8]([CH3:14])=[CH:7][N+:6]=1[O-:15].Cl>C(OCC)(=O)C>[CH3:2][O:3][C:9]1[C:8]([CH3:14])=[CH:7][N+:6]([O-:15])=[C:5]([CH3:4])[CH:10]=1
Reactant: CO
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1cc(C)[n+]([O-])cc1C

Procedure:
12.2 g of sodium were dissolved 2 1 of methanol under argon, whereupon 60 g of 2,5-dimethyl-4-nitropyridine 1-oxide were added portionwise and the solution was left to boil under reflux overnight. The pH was adjusted to 7 with 5N hydrogen chloride in ethyl acetate while cooling and the mixture was evaporated in vacuo. The residue was taken up in 1 1 of methylene chloride, the solution was filtered through silica gel, which was rinsed with 0.4 1 of methylene chloride, and the combined filtrates were evaporated in vacuo The residue crystallized from methylene chloride/petroleum ether and there was obtained 4-methoxy-2,5-dimethylpyridine 1-oxide of melting point 99-101° .
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)=[O:21]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To an ice-cooled solution of 1-(4-nitro-phenyl)-piperazine (prepared as described in Reference Example 29; 5 g, 24 mmol) in DCM (40 mL) was added pivaloyl chloride (4.36 g, 36.2 mmol) and triethylamine (8.73 mL, 60 mmol) at 0-5° C. The mixture was warmed to room temperature and stirred for 1 hour then diluted with DCM (150 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate and concentrated to dryness to afford 2,2-dimethyl-1-[4-(4-nitro-phenyl)-piperazin-1-yl]-propan-1-one (6 g, 85.7%) as a yellow solid.
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.[ClH:12].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H]([N:43]5[CH:48]=[C:47]([C:49]([NH2:51])=O)[CH2:46][CH:45]=[CH:44]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[ClH:12].[ClH:12].[NH2:5][CH2:44][CH2:45][CH2:46][C:47]1[CH:48]=[N:43][NH:51][CH:49]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: Cl
Product: NCCCc1cn[nH]c1
Temperature: 4 °C

Procedure:
This phthalimide intermediate (8.0 l gram, 0.03 mole) was refluxed in 100 ml. of 6 normal hydrochloric acid overnight. The clear solution was cooled to 4° C., phthalic acid removed by filtration, and the filtrate evaporated to dryness to give a product which, after recrystallization from a mixture of ethanol and ethyl ether, amounted to 4.4 grams of a white solid identified as 4-(3-aminopropyl)-pyrazole dihydrochloride, melting point 189°-190° C. This pyrazole compound could be coupled to the activated dextran by reaction of the terminal amino group, but the resulting affinity resin, in which the coupling arm had a length of only 6 Angstrom units, had poor binding capacity for the binary complex of alcohol dehydrogenase and NAD.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.N1CCCCC1>C(O)C>[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cc(-c3cccnc3)ccc2C1=Cc1ccccc1O
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of 6-pyridin-3-yl-1,3-dihydroindol-2-one (100 mg, 0.5 mmol), 2-hydroxybenzaldehyde (60 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was heated to reflux and stirred overnight. The reaction mixture was concentrated and column chromatographed (eluant—isopropanol/dichloromethane) to give 100 mg (64%) of 3-(2-hydroxybenzylidene)-6-pyridin-3-yl-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.P(Br)(Br)[Br:20].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CCCCCC>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCCCCC
Product: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate was dissolved in 7.9 g of pyridine and n-hexane (100 ml). 8.3 g (31 mmol) of phosphorus tribromide was dropwise added thereto under cooling with ice, followed by stirring for 2 hours as such. The reaction liquid was added to an aqueous solution of sodium hydrogencarbonate, followed by the extraction with n-hexane. The organic phase was washed with water, dried and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 9.5 g of the title compound (yield 75%). m.p.; 50°-51° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:21][C:22]([CH3:41])([CH2:27][C:28](=O)[CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]([CH3:39])[CH3:38])[C:23]([O:25]C)=[O:24]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:29]([S:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH:37]([CH3:39])[CH3:38])=[C:28]2[CH2:27][C:22]([CH3:41])([CH3:21])[C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)(C)CC(=O)CSc1ccccc1C(C)C
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CC(C)c1ccc2c(c1)c(Sc1ccccc1C(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 104, but using 1-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-(2-isopropylphenylthio)pentanoate as starting materials followed by hydrolysis at reflux gave the title compound, m.p. 142°-143°.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:6])[CH2:4]Cl.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+]>CO.O.O>[Cl:1][CH2:2][C:3](=[O:6])[CH2:4][S:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=1
Reactant: O=C(CCl)CCl
Reactant: COc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(SCC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 1,3-dichloro-2-propanone (12.70 g, 0.1 mol) in methanol/water (100 ml, 1:3) at 0° C. is added a suspension of 3-methoxybenzenethiol (14.02 g, 0.1 mol) and sodium hydroxide (4.00 g, 0.10 g) in water (100 ml). The mixture is stirred at 0° C. for 7 h and at mom temperature for 10 h. The precipitated product is extracted with dichloromethane (100 ml), washed with water (80 ml), and dried with sodium sulfate. After removal of the solvent, we obtained the good product (oil, 18.70 g).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Br)cc1
Reactant: O=Cc1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Cc1ccc(Br)cc1
Yield: 82 %

Procedure:
A solution of 4-bromobenzyl sulfonylacetic acid (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 82% yield.
Reaction SMILES: S(=O)(=O)(O)O.O.[NH2:7][NH2:8].[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10].[Na]>>[C:12]1([C:9]2[CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:8][N:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
490 parts (3 mol) of 60% strength by weight sulfuric acid were initially introduced into the stirring flask. 46.9 parts (0.75 mol) of 80% strength by weight hydrazine hydrate, 90 parts (0.75 mol) of acetophenone, 79.5 parts (0.75 mol) of benzladehyde and 1.5 parts (0.01 mol) of sodium iodidewere metered in in succession at room temperature. The reaction mixture wasbrought to 120° C. by distilling off water and kept at 120° C. for 2.5 hours. 110 parts of water were distilled off. The mixture was diluted with the distilled-off water and neutralized with 717 parts (4.5 mol) of 25% strength by weight sodium hydroxide solution. The precipitate was filtered off at room temperature, and the filter residue was washed with water and dried. 160.6 parts of 3,5-diphenylpyrazole having a purity of 94.4% (HPLC) were obtained, which corresponds to a yield of 91.9% of theory. M.p.: 194° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:18])([F:19])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Nc1ccccc1
Temperature: 35 °C

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 3.6 ml (0.039 mol) of aniline, 1.3 g (0.013 mol) of triethylamine in 30 ml of DMF were reacted at room temperature for 16 hours and heated to 35° C. for 20 minutes. The residue was recrystallized in hot hexane affording 4.0 g (68.0%) of product as a beige solid; mp 91°-92° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[C@:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=[O:7])(C)(C)C.[CH2:31]([O:38][CH2:39][CH:40]([NH:44][C:45](=[O:57])[C:46]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])([CH3:48])[CH3:47])C(O)=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[C:53]([O:52][C:50](=[O:51])[NH:49][C:46]([C:45](=[O:57])[NH:44][C@H:40]([CH2:39][O:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:16](=[O:17])[C@:10]2([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:9]1)=[O:7])([CH3:48])[CH3:47])([CH3:54])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(COCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)[C@]2(Cc2ccccn2)C1

Procedure:
reacting said 1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester with 3-benyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propionic acid in the presence of a tertiary amine and 1-propanephosphonic acid cyclic anhydride in a reaction inert solvent to form (1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1-methyl-ethyl)-carbamic acid tert-butyl ester, and
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[F:1][C:2]1[CH:24]=[C:23]([CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=3)[S:13][C:6]=12)[NH2:25]
Reactant: CN1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reaction time: 0.67 h
Yield: 66.7 %

Procedure:
To a mixture of 4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1,2,3,6-tetrahydropyridine 259 (279 mg, 0.72 mmol) and NH4Cl (33 mg, 0.612 mmol) in EtOH (7.2 mL)/water (3.6 mL) at 100° C. Fe (342 mg, 6.2 mmol) was added in one portion and the mixture heated to reflux with vigorous stirring for 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was dissolved in MeOH and purified by flash chromatography (DCM/MeOH 5:1) giving 260 (171.3 mg, 0.48 mmol, 67% yield) as a yellow solid. MS (m/z): (M+1) 356.0 (100%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][CH:10]=1
Reactant: Oc1ccc(CCCCCCCBr)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: BrCCCCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a stirred solution of 9.1 (0.9 g, 3.32 mmol) in anhydrous acetone (40 mL), was added anhydrous K2CO3 (1.38 g, 10 mmol) and benzyl bromide (0.624 g, 3.65 mmol) and the mixture was refluxed for 6 h. The reaction mixture was cooled to room temperature, diluted with acetone and solid materials were filtered off. The filtrate was evaporated under reduced pressure and the residue obtained was dissolved in diethyl ether (50 mL). The ethereal solution was washed with water and brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (5% Et2O-hexane) afforded 10.1 (0.938 g, 78% yield) as a white solid (m p 32-34° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:23])([CH3:22])[C@H:16]23)=[O:11])=[CH:4][C:3]=1[CH3:24].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(O)(=O)C>[CH3:24][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:22])([CH3:23])[C@H:16]23)=[O:11])[CH:6]=[CH:7][C:2]=1[O:1][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: ClCC1CO1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)ccc1OCC1CO1
Reaction time: 1.5 h
Yield: 32.7 %

Procedure:
A solution of 3-(4-hydroxy-3-methyl-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (179 mg, 0.525 mmol, Intermediate 4) in isopropanol (10 mL) and 3 N aq. NaOH (4 mL) is treated with epichlorohydrine (197 mg, 1.58 mmol). The reaction mixture is stirred at 70 for 1.5 h. The mixture is diluted with acetic acid (0.3 mL) and the solvent is removed under reduced pressure. The residue is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm ID, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-(3-methyl-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (68 mg) as a pale brown oil; LC-MS: tR=1.15 min, [M+1]+=397.27.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-phenylpiperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=448.