Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(N(CC)CC)C.[CH:19]#[C:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])#[C:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C#CCCCC
Reactant: COc1ccc(C=O)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1cc(C=O)ccc1OC
Yield: 94.8 %

Procedure:
A mixture of 3-iodo-4-methoxybenzaldehyde (5.2 g, 20 mmol), tetrakis(triphenylphosphine)palladium (0.29 g), Cul (0.38 g, 2 mmol) and triethylamine (5 ml) in THF (25 ml) is cooled to +10° C., and 1-hexyne (3.5 ml, 30.5 mmol) is then added. The cooling bath is removed, and the temperature of the reaction mixture rises slowly to +30° C. before decreasing slowly. 3 hours after the end of the addition, the crude reaction product is concentrated to dryness, and the residue obtained is purified by flash chromatography on silica (15/85 ethyl acetate/heptane). 4.1 g (yield: 95%) of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].N1C2C(=CC=CC=2)[CH:37]=[CH:36][C:35]=1N>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]3[C:18](=[CH:35][CH:36]=[CH:37][CH:20]=3)[N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:7]2=[O:33]
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc2ccccc2n1

Procedure:
The product from Example 11, Part D (200 mg, 0.6 mmol) and quinolin-2-ylamine (131 mg, 0.91 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (220 mg, 80%). 1HNMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.87 (d, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 1H), 7.66 (m, 2H), 7.48 (t, J=7 Hz, 1H), 7.41 (m, 1H), 7.32 (m, 2H), 7.16 (t, J=9 Hz, 1H), 7.01 (t, J=7 Hz, 2H), 5.30 (d, J=15 Hz, 1H), 4.71 (m, 1H), 4.25 (d, J=15 Hz, 1H), 2.59 (m, 2H), 1.98 (m, 2H). MS: m/z (MH+) 458.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[C:18]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)=[N:19][CH:20]=[CH:21][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[C:18]([O:23][C@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]4)=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ncccc2N)C1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C

Procedure:
Prepared analogously to example 1.1. from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (S)-tert-butyl 3-(3-aminopyridin-2-yloxy)piperidine-1-carboxylate (Intermediate X)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.O.C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Cc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1cccc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a suspension of 3-benzylbenzoic acid (15 g, 70 mmol) in THF (100 ml) a solution of lithium aluminiumhydride in THF (80 ml, 80 mmol, 1M) was added dropwise. When addition was complete the mixture was stirred for 30 minutes at ambient temperature and then heated at reflux for 40 minutes. The reaction mixture was allowed to cool and water (3 ml), diethyl ether (100 ml), 4N sodium hydroxide (6 ml) and water (12 ml) were added successively. The mixture was stirred for 30 minutes, filtered and the solvent evaporated in vacuo. The residue was dissolved in toluene (200 ml) and dried (MgSO4) overnight. The solvent was evaporated in vacuo to give 11.9 g of crude 3-benzylbenzylalcohol as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([O:16]C)[C:10]([O:14]C)=[N:11]2)=[C:6]([CH2:18][N:19]([CH2:28][CH3:29])[C@H:20]([P:22](=[O:27])([O:25]C)[O:23]C)[CH3:21])[CH:5]=1)([O-:3])=[O:2]>Cl>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:16])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:18][N:19]([CH2:28][CH3:29])[C@H:20]([P:22](=[O:23])([OH:27])[OH:25])[CH3:21])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(Cc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12)[C@@H](C)P(=O)(OC)OC
Agent: Cl
Product: CCN(Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)[C@@H](C)P(=O)(O)O

Procedure:
4.24 g (9.9 mmol) of dimethyl (R)-N-(7-nitro-2,3-dimethoxyquinoxalin-5-ylmethyl)-α-ethylaminoethylphosphonate are stirred for 19 hours in 80 ml of 6N hydrochloric acid. The reaction mixture is evaporated and the residue is slurried with water. The title compound is obtained as a solid of m.p.=218° C. (dec.).
Reaction SMILES: O1CCCCC1OCC[C@@H:10]1[C@H:15]([N:16]=[N+]=[N-])[CH2:14][C@H:13]2[CH2:19][C@@H:11]1[C:12]2([CH3:21])[CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCOCC>[NH2:16][CH:15]1[CH2:10][CH:11]2[CH2:19][CH:13]([C:12]2([CH3:21])[CH3:20])[CH2:14]1
Reactant: CC1(C)[C@H]2C[C@@H](N=[N+]=[N-])[C@@H](CCOC3CCCCO3)[C@@H]1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(C)C2CC(N)CC1C2
Temperature: 0 °C
Yield: 184.4 %

Procedure:
To a solution of 8.64 g of the above-mentioned azide compound 15 in 300 ml of ether is portionwise added 1.2 g of lithium aluminium hydride and the mixture is refluxed under heating for 1 hour. To the reaction mixture is added 10 g of ice and then added 300 ml of 10% aqueous solution of sodium hydroxide. The resulting mixture is shaken well and then the ether layer is collected. The aqueous layer is extracted with ether again. The combined layers are washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give 7.56 g of the titled compound 16, of which the physical constant is as follows.
Reaction SMILES: F[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5](F)=[C:4]([F:21])[C:3]=1[F:22].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(Cl)Cl>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:5]1[C:6]2[C:7](=[O:19])[C:8]3[C:13](=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[OH:18])[C:14](=[O:16])[C:15]=2[C:2]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[C:3]([F:22])[C:4]=1[F:21]
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CN(C)CCN
Solvent: ClCCl
Product: CN(C)CCNc1c(F)c(F)c(NCCN(C)C)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1,2,3,4-tetrafluoro-5,8-dihydroxyanthraquinone (1.0 g, 3.2 mmol) and N,N-dimethylethylenediamine (3 mL) in CH2Cl2 (30 mL) was stirred at room temperature for 12 hours. After evaporation of the solvents, the residue was purified by silica gel chromatography using isocratic solvent system of EtOAc/MeOH/Et3N (10:10:1) yielding 830 mgs of Dye 1 as dark blue product. Abs (max, PBS pH 7.4)=568 nm; Em=675 nm. The structure of Dye 1 is given below:
Reaction SMILES: [H][H].S.[C:4]1(=[O:11])[NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:12](#N)C>C1COCC1>[CH3:12][CH:4]1[CH2:5][CH2:6][CH:7]([CH3:8])[O:11]1.[C:4]1(=[O:11])[NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: CC#N
Agent: O=C1CCCCCN1
Agent: S
Solvent: C1CCOC1
Product: CC1CCC(C)O1

Procedure:
Prior to optimization of the initial H2/H2S atmosphere and the mol % catalyst of presulfided Pt (Pt—S/C) employed, a range of solvents is examined (Table 5). No formation of caprolactam is observed using acetonitrile (entry 1, Table 5) as solvent. The highest yield of caprolactam is achieved using THF (entry 2, Table 5). Use of 2,5-dimethyltetrahydrofuran (entry 3, Table 5) results in a tenfold reduction in the yield of caprolactam relative to use of THF as solvent (entry 3 vs. entry 2, Table 5).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[C:8]([C:11]#[N:12])[C:9]#[N:10])SC)[CH2:3][CH2:2]1.O.[NH2:14][NH2:15]>CCO>[NH2:10][C:9]1[NH:15][N:14]=[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:8]=1[C:11]#[N:12]
Reactant: CSC(NC1CC1)=C(C#N)C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1c(NC2CC2)n[nH]c1N
Temperature: 0 °C

Procedure:
2-((cyclopropylamino)(methylthio)methylene)malononitrile in EtOH (100 mL) and added hydrazine hydrate (1 eq), then heated to reflux until complete by TLC (absence of starting material, 18 hrs). Poured into ice water and filtered to obtain 5-amino-3-(cyclopropylamino)-1H-pyrazole-4-carbonitrile as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[C:15]1([CH:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:15]1([CH:21]([NH:23][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1ccccc1
Yield: 0 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (1.59 g, 7.57 mmol), 1-phenylethanamine (0.92 g, 7.57 mmol) and N,N-diisopropylethylamine (1.95 g, 15.1 mmol) were stirred at room temperature in dry acetonitrile (50 mL) for 20 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.28 mg, 12% yield). 1H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 7.80 (t, 1H), 7.31 (m, 5H), 6.33 (t, 1H), 6.22 (d, 1H), 4.58 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:48])[C:5]([C@@:7]1([CH3:47])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[O:37][C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O)=[O:6].I([O-])(=O)(=O)=O>>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:48])[C:5]([C@@:7]1([CH3:47])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C

Procedure:
in a polar solvent, reaction the resultant solution with a base at a temperature of 20-50° C. for a time period in the range of 20-40 hours, and isolating 7-xylosyl-10-deacetylbaccatin III, dissolving the 7-xylosyl-10-deacetylbaccatin III in a polar solvent, reacting the resultant solution with a periodate at 20-40° C. for a time period in the range of 20-40 hours to cleave the diol system of the xyloside into dialdehyde, treating the generated dialdehyde in an organic acid medium with salts of amine at 0-40° C. for 12-18 hours and isolating 10-deacetylbaccatin III of formula 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]Cl.C(OCC)(=O)C>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)Cc1ccccc1Br
Agent: Cl[Cu]
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 95.5 %

Procedure:
Methyl 2-bromophenylacetate (47.0 grams 216.3 mmol) and 4-chloro-phenol (27.8 grams, 215.8 mmol) were dissolved in dioxane (790 ml) while warming to 50° C. To the resulting solution were added, under stirring in an inert nitrogen atmosphere, cesium carbonate (141 grams, 432.2 mmol) and copper(I) chloride (18.56 g, 86.2 mmol). Finally, N,N-dimethylglycine (4.46 grams, 43.2 mmol) was added to the green suspension. The reaction mixture was heated at 110° C. (reflux temperature) for 4 days while stirring. The reaction mixture was filtered over dicalite, which was washed with dioxane (40 ml). The dioxane was removed in vacuo to leave a brownish oil. Ethyl acetate (100 ml) was added to the oil and the pH of the resulting mixture was adjusted to 1 by addition of 1 M HCl (300 ml). The organic phase was washed with saturated brine (300 ml), dried on magnesium sulphate and then concentrated under vacuum to yield 57.2 grams (206 mmol; 95%) of [2-(4-chloro-phenoxy)-phenyl]-acetic acid methyl ester as a brown oil. The oil was dissolved in methanol (250 ml), whereupon KOH (16.2 grams; 1.4 eq) was added. The resulting solution was heated for 3 h at 60° C. The reaction mixture was cooled and the methanol (200 ml) was removed under vacuum. To the residue water (100 ml) was added and the pH was adjusted to 1 by addition of 1M HCl (25 ml). The resulting crystals were filtered off and dried in vacuum at 40° C. to yield 47.3 grams (180 mmol; 87%) of [2-(4-chloro-phenoxy)-phenyl]-acetic acid (IX).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>CC(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(C)=O
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
4-Aminobenzoic acid (17.24 g, 0.1257 mol) was added to a stirred solution of maleic anhydride (12.33 g, 0.1257 mol) in propanone (300 ml). Stirring was continued at room temperature for 3 hours. The product, which separated as a yellow solid, was collected by suction filtration and dried on the filter: mp 217°-219° C. (Ref: K C Liu, J. Chin. Chem. Soc., 1973, 20, 163).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNCc1ccc(F)cc1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
(2-Amino-ethyl)-carbamic acid tert-butyl ester (5.95 g, 37.1 mmol), 4-fluorobenzaldehyde (5.07 g, 40.9 mmol, 4.4 mL), triethylamine (1.50 g, 14.9 mmol, 2.1 mL) and magnesium sulfate (6.71 g, 55.7 mmol) were stirred in methanol (50 mL). After 1.5 h the solution was cooled to 0° C. and sodium borohydride (8.4 g, 223 mmol) was added in portions. After 2 h the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed three times with water and the desired product extracted into the aqueous layer with 0.5 M hydrochloric acid (4×50 mL). The combined acid wash was cooled to 0° C. and basified with saturated aqueous ammonium hydroxide. The aqueous layer was extracted three times with chloroform and the combined chloroform layer washed three times with water, dried over sodium sulfate and concentrated to yield the title compound as a colorless oil (7.49 g).
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[N:9]=[N:10][CH:11]=[C:12](Cl)[N:13]=1.Cl.[CH3:16][CH:17]1[NH:22][CH2:21][CH2:20][N:19]2[C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][CH:25]=[C:18]12.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:7][C:8]1[N:9]=[N:10][CH:11]=[C:12]([N:22]2[CH2:21][CH2:20][N:19]3[C:23]([C:26]([F:29])([F:27])[F:28])=[N:24][CH:25]=[C:18]3[CH:17]2[CH3:16])[N:13]=1
Reactant: CC1NCCn2c1cnc2C(F)(F)F
Reactant: Clc1cnnc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1c2cnc(C(F)(F)F)n2CCN1c1cnnc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Dioxane (12.0 ml) solution of 3,5 dichloro-1,2,4-triazine (780 mg, 5.20 mmol) was added 8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine hydrochloride (CA, 1257 mg, 5.20 mmol) followed by diisopropylethylamine (2.73 ml, 15.60 mmol). Dichloromethane (2 mL) was added to solubilize the reaction. The reaction was stirred for 2 hrs at RT and then diluted with DCM. The reaction was washed with saturated sodium bicarbonate then brine, dried with sodium sulfate and concentrated to anoil. Purification of the oil on Biotage Normal Phase system (DCM:MeOH, 0-9% B) to afford the product as a solid, 1-17, (1.2 g, 71.7%). LRMS (ESI) m/z 319.1 [(M+H)+; calcd for C11H10ClF3N6: 319.1].
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[NH:19]CCO.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[NH2:19][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([Cl:11])[C:2]=1[Cl:1])[C:8](=[O:12])[C:7]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)([CH3:13])[CH2:6]2
Reactant: CC1(C2CCCC2)Cc2cc(NCCO)c(Cl)c(Cl)c2C1=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(N)c(Cl)c(Cl)c2C1=O

Procedure:
The starting material 2,3-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one is alkylated with ethylene bromide in the presence of potassium carbonate to form 5(2-bromoethoxy)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1H-inden-1-one (Step 1). This material is then reacted with liquid ammonia to accomplish the substitution of bromine by ammonia and to form 6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-(2-aminoethoxy)-2-methyl-1H-inden-1-one (Step 2). Following the formation of the compound of Step 2, an intramolecular Smiles rearrangement takes place (Step 3). The 6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-(2-hydroxyethylamino)2-methyl-1H-inden-1-one formed in Step 3 is then oxidized with Jones Reagent (CrO3, H2SO4, H2O) to form 5-amino-6,7-dichloro-2-cyclopentyl2,3-dihydro-2-methyl-1H-inden-1-one (Step 4). When n is 1, 3 or 4, alkylation of the amino group (Step 5) with a haloalkanoic acid ester, such as ethyl bromoacetate, followed by acid or base hydrolysis of the alkyl ester (Step 6) gives a compound of the present invention, such as [6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)amino]acetic acid. When n is 3, alkylation with 4-bromo-1-butene followed by oxidation with potassium permanganate gives the compound of the present invention, without the need for hydrolysis. The starting material used in these examples is obtained as shown in Woltersdorf, O. W. et al., J. Med. Chem., 20, 1400 (1977). This synthetic route is illustrated ##STR3##
Reaction SMILES: [BH4-].[Li+].[F:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([C:11](OC)=[O:12])[S:10][C:6]=2[CH:5]=1.O>CO>[F:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([CH2:11][OH:12])[S:10][C:6]=2[CH:5]=1
Reactant: COC(=O)c1nc2ccc(F)cc2s1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: OCc1nc2ccc(F)cc2s1
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
16.5 mg of lithium borohydride were added to a solution of 106.1 mg of methyl (6-fluorobenzothiazol-2-yl)formate [prepared as described in step (a) above] in 2.1 ml of methanol cooled in an ice-water bath, and the resulting mixture was stirred at the same temperature for 10 minutes. At the end of this time a further 10 mg of lithium borohydride were added to the reaction mixture which was then stirred at the same temperature for a further 10 minutes. Water was then added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and an aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give 93.1 mg of the title compound as a crude white crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10](Br)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:49])[C@H:20]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][CH:31]=1)[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C.ClCCl.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>[CH3:17][O:18][C:19](=[O:49])[C@H:20]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:10]2[C:9](=[O:16])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:13]=[C:12]([Cl:14])[CH:11]=2)=[CH:34][CH:35]=1)[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: O=c1c(Br)cc(Cl)cn1Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(Cc3ccccc3)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
A solution of 1-benzyl-3-bromo-5-chloro-2-pyridone (296 mg, 0.98 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (560 mg, 0.99 mmol) in DMF (15 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3×). Bis(triphenylphosphine)palladium dichloride (80 mg, 0.11 mmol) was added and the mixture was heated to 90° C. for 4 hr as the mixture turned dark. An additional 60 mg of the catalyst was added and heating continued for 2 hr. The mixture was allowed to cool, was diluted with dichloromethane, and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was chromatographed over 150 g of silica gel eluting with 1:2 ethyl acetate:hexane to give 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (255 mg, 52%). LMS-Electrospray: m/z 1015 (2M+Na) (4 Cl) 519 (M+Na) 514 (M+NH4) 497 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:19])=[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.O.C(O)(=O)C(O)=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:19])=[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]3[CH2:31][CH2:30][CH:29]([C:26]4[C:25]5[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=5[O:28][N:27]=4)[CH2:34][CH2:33]3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2sc(C)c(C(=O)CCCCl)c2C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: O
Product: CC(=O)N1CCc2sc(C)c(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)c2C1
Yield: 23.2 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.6 g of 5-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine and 1.4 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.6 g of 5-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil, m.p. 116°-118° C. as an oxalate monohydrate thereof.