Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl.[NH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>O.O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.6 %

Procedure:
87.5 g of 4-chlorobenzoyl chloride and a solution of 276 g of potassium carbonate in 552 ml of water cooled to 5° C. are added successively with stirring to a suspension of 80.6 g of powdered 4-piperidone hydrochloride hydrate in 1 l of tetrahydrofuran. The mixture is stirred at ambient temperature for a further 45 minutes. The organic phase is then separated off, the aqueous phase is extracted twice more with ethyl acetate, and the organic phases are combined, dried and evaporated down. The residue is dissolved in ethyl acetate and the solution is treated with petroleum ether. 88.6 g of the title compound of melting point 61°-63° C. are obtained.
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([OH:19])[CH2:16][NH:15]2)=O)[CH2:10][CH2:9]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.O.[OH-].[Na+]>[CH:8]1([NH:11][CH2:12][C@H:14]2[NH:15][CH2:16][C@H:17]([OH:19])[CH2:18]2)[CH2:9][CH2:10]1
Reactant: O=C(NC1CC1)[C@@H]1C[C@@H](O)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: O[C@H]1CN[C@H](CNC2CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide TFA salt (from the above reaction) and LAH (910 mg, excess) in THF was heated to reflux for 4 hours. The reaction was cooled to 0° C., diluted with water (0.9 mL), 10% NaOH (0.9 mL) and then water (0.9 mL). The mixture was stirred for 30 mins, the insolubles were filtered off, the filtrate was concentrated and dried to give 900 mg of (3R, 5S)-5-cyclopropylaminomethyl-pyrrolidin-3-ol as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:16])[N:14]=1)([O-])=O.O1CCCC1>[Pd].CN(C=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:16])[N:14]=1
Reactant: O=C(Nc1nnn[nH]1)c1csc(-c2ccccc2[N+](=O)[O-])n1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccccc1-c1nc(C(=O)Nc2nnn[nH]2)cs1
Reaction time: 22 h
Yield: 89.5 %

Procedure:
To a solution of 2-(2-nitrophenyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (200 mg) in a mixed solvent of dry tetrahydrofuran (THF, 30 ml) and dry DMF (13.7 ml) was added (10%) palladium on charcoal (200 mg) and the mixture was hydrogeneted for 22 hours. The catalyst was sucked off and the filtrate was concentrated under reduced pressure. The residue was treated with water (200 mg) to form crystals, which were filtered and dried to give colorless solids of 2-(2-aminophenyl)-N-(1H-tetrazole-5-yl)-4-thiazolecarboxamide (162 mg, 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:22][CH2:23][CH3:24])[N:20]=[CH:21][C:10]=3[C:9]2=[O:25])[CH:7]=1.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:17][C@H:16]4[N:12]([CH2:13][CH2:14][CH2:15]4)[C:11]4[N:18]=[C:19]([NH:22][CH2:23][CH3:24])[N:20]=[CH:21][C:10]=4[C:9]3=[O:25])[CH:5]=[N:4][CH:3]=2)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNCC1
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(Br)c1)C2=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cncc(N3CCN(C(C)=O)CC3)c1)C2=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 33.8 %

Procedure:
Compound 21 (90.0 mg, 0.223 mmol) obtained in Example 21 was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and tert-butyl alcohol (2 mL), and the mixture was stirred at 80° C. for 1.5 hours after adding 1-acetylpiperazine (57.0 mg, 0.446 mmol), tris(dibenzylideneacetone)dipalladium (41.0 mg, 0.0446 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (53.0 mg, 0.134 mmol), and sodium tert-butoxide (43.0 mg, 0.446 mmol). The mixture was filtered through sellite, and the residue obtained by concentrating the filtrate was purified by silica gel column chromatography to give the title compound (Compound 40) (34.0 mg, 34%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:12]2[C:7]([CH2:8][O:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=32)=[N:6]1.[I-].[K+].[O:21]=[C:22]1[N:26]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[NH:23]1.C(=O)(O)[O-].[Na+]>O.CN(C=O)C>[O:21]=[C:22]1[N:26]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:12]4[C:7]([CH2:8][O:9][C:10]5[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=54)=[N:6]3)[CH2:31][CH2:32]2)[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[NH:23]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=c1n(CCCCl)nc2n1-c1ccccc1OC2
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)nc2n1-c1ccccc1OC2

Procedure:
A stirred solution of 1.33 g. (0.005 mole) of 2-(3-chloropropyl)2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-one, from Example 1, hereinabove, 0.83 g. (0.005 mole) of potassium iodide, and 2.39 g. (0.011 mole) of 4-(2-keto-1-benzimidazolinyl)piperadine in 25 ml. of DMF under a nitrogen atmosphere, was warmed to 105° C. for 4.75 hours. The solution was cooled, poured into cold sodium bicarbonate in water solution, and extracted with methylene chloride. The methylene chloride extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on 175 g. of silica gel and eluted with a 2% diethylamine/15% methanol/ethyl acetate, v/v/ mixture. The eluted product thus obtained was crystallized in the manner described in example 1, hereinabove, from a methylene chloride/methanol mixture to give in two crops 1.76 g., m.p. 176°-178° C. and 0.058 g., m.p. 175.5°-178° C. of the titled compound. The analytical sample had a melting point of 176.5°-177.5° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:39]=[CH:38][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]2[S:28][CH:29]([CH2:32][C:33](OCC)=[O:34])[CH2:30][N:31]=2)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[BH4-].[Li+].O>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:39]=[CH:38][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]2[S:28][CH:29]([CH2:32][CH2:33][OH:34])[CH2:30][N:31]=2)=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCC4CCOCC4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.8 %

Procedure:
Ethyl (2-{5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (310 mg) was dissolved in tetrahydrofuran (15 mL), lithium borohydride (24 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 2.5 hr, and then at 50° C. for 2.5 hr. Lithium borohydride (24 mg) was added to the reaction mixture, and the mixture was stirred at 50° C. for 30 hr. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80 to 100:0, volume ratio), and the obtained amorphous solid was washed with diethyl ether to give the title compound (123 mg, yield 55%) as a pale-yellow solid. melting point 104-105° C. MS 531 (MH+).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([N:22]2[C:26]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[CH:25][C:24]([CH:32]=O)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:26]1[N:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]=[C:24]([CH2:32][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:25]=1
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Product: c1ccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)cc1
Yield: 69.2 %

Procedure:
Compound 8 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.CN(C)C=O.[CH2:34]1[C@H:38]2[CH2:39][NH:40][C:41]3[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=3[C:43](=[O:44])[N:37]2[CH2:36][CH2:35]1>O1CCCC1.C(Cl)(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]1([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:40]3[C:41]4[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=4[C:43](=[O:44])[N:37]4[CH2:36][CH2:35][CH2:34][C@H:38]4[CH2:39]3)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2NC[C@@H]2CCCN12
Reactant: O=C(O)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2C[C@@H]3CCCN3C(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a solution of 4-[(2-phenylbenzoyl)amino]benzoic acid (1.44 g) in tetrahydrofuran (10 ml), there were added, with ice-cooling, 0.62 g of thionyl chloride and a catalytic amount of N,N-dimethylformamide and the mixture was stirred at room temperature for one hour. After concentration of the reaction solution, the resulting acid chloride was dissolved in 10 ml of tetrahydrofuran and the resulting solution was dropwise added to a solution of (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one (4 g) prepared in Reference Example 24 and triethylamine (0.5 g) in tetrahydrofuran (10 ml) with ice-cooling. The reaction solution was stirred for 2 hours under ice-cooling and it was concentrated and dissolved in ethyl acetate. The resulting organic phase was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained after concentration of the reaction solution was subjected to silica gel column chromatography and then eluted with chloroform/ethyl acetate (100/1) to thus give 0.89 g (yield 44.4%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1N

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (Aldrich; 2.4 g, 14.36 mmol) in DMF (100 mL) was added 4-amino-1-bocpiperidine (Aldrich; 3.15 g, 15.72 mmol) and DIPEA (7.5 mL, 43.06 mmol). The resultant solution was carefully treated portionwise (2-3 portions) with HATU (6.88 g, 18.09 mmol) and the resultant mixture was stirred, under nitrogen, at ambient temperature overnight.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([NH:14][C:15](OC(C)(C)C)=O)[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.C=O.S([O-])([O-])(=O)=O.[Mg+2].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][NH:14]1)=[O:22]
Reactant: COC(=O)C(CNCc1ccccc1)NC(=O)OC(C)(C)C
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(Cc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Benzylamino-2-tert-butoxycarbonylamino-propionic acid methyl ester (4.01 g, 13.02 mmol) was dissolved in dichloromethane (20 mL) and HCl (4M Dioxane, 40 mL) was added. The resultant suspension was stirred at room temperature for 30 minutes, after which all volatiles were removed in vacuo. The crude material was mixed with para-formaldehyde (390 mg, 13.02 mmol), magnesium sulfate (2.6 g), potassium carbonate (2.6 g) and suspended in chloroform (40 mL). Triethylamine (5.07 mL) was added and the reaction was stirred at room temperature for 48 hours. The suspension was filtered and the volatiles were removed in vacuo. The crude material 1-Benzyl-imidazolidine-4-carboxylic acid methyl ester (3.5 g) was used in the next step without further analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=1>>[F:28][CH:27]([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[CH:21][CH:22]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)Oc1ccc(CBr)cc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-4-(difluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.76 min.; [M+H]+: 392.16 g/mol.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:12]([C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21](=[CH:26]N(C)C)[C:22](OC)=[O:23])=[C:16]([CH3:30])[CH:15]=1)#[N:13].Cl.C(N(C(C)C)C(C)C)C>O.CC(O)C>[C:12]([C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[N:2][N:1]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=3)[C:22]=2[OH:23])=[C:16]([CH3:30])[CH:15]=1)#[N:13]
Reactant: NNc1ccc(C(=O)O)cn1
Reactant: COC(=O)C(=CN(C)C)c1cc(F)c(C#N)cc1C
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reaction time: 2 h
Yield: 74.4 %

Procedure:
Combined 6-hydrazinylnicotinic acid (0.73 g, 4.77 mmol), methyl 2-(4-cyano-5-fluoro-2-methylphenyl)-3-(dimethylamino)acrylate (1.375 g, 5.24 mmol), 2-propanol (18 mL), and 0.5M aqueous hydrochloric acid (11.44 mL, 5.72 mmol). After 2 hours, N-ethyl-N-isopropylpropan-2-amine (4.15 mL, 23.83 mmol). After an hour the reaction mixture was diluted with water and washed with IPAc twice. The aqueous phase was acidified to ˜pH=3.5 and stirred for 30 minutes to give a solid which was collected by filtration, washed with water, ethanol, and heptanes, and dried overnight under vacuum to give the title compound (1.20 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.41 (s, 3H) 7.74 (d, J=7.07 Hz, 1H) 7.91 (d, J=11.62 Hz, 1H) 8.26 (s, 1H) 8.37-8.47 (m, 1H) 8.47-8.56 (m, 1H) 8.96 (dd, J=2.15, 0.88 Hz, 1H). ESI-MS m/z [M+H]+ 339.2.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=[O:15])[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[C:8]1(=[O:15])[C:9]2[CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]3[O:14][C:10]=2[CH2:11][CH2:12][CH2:13]1
Reactant: O=C1CCCCC1
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CCCC2=C1C1CCCCC1O2

Procedure:
A solution of cyclohexanone (5.28 mL, 50.9 mmol), cyclohexane-1,3-dione (5.89 g, 50.9 mmol), and p-toluenesulfonic acid monohydrate (0.485 g, 2.55 mmol) in xylene (600 mL) was heated at reflux under a Dean Stark trap for 16 hours. The mixture was filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-30% ethyl acetate in hexanes to provide the title compound: 1H NMR (CDCl3) δ 1.21-1.31 (m, 2H), 1.43-1.57 (m, 3H), 1.72-1.83 (m, 1H), 1.96-2.08 (m, 4H), 2.33 (t, 2H), 2.41 (t, 2H), 2.96-3.06 (m, 1H), 4.61-4.69 (m, 1H); MS (DCl/NH3) m/z 193 (M+H)30.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:34])=[N:13][C:14]2[N:15]([N:29]=[C:30]([CH3:33])[C:31]=2[Cl:32])[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>O1CCOCC1>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:34])=[N:13][C:14]2[N:15]([N:29]=[C:30]([CH3:33])[C:31]=2[Cl:32])[C:16]=1[C:17]1[C:18]([CH3:28])=[C:19]2[C:24](=[C:25]([F:27])[CH:26]=1)[O:23][CH2:22][CH2:21][CH2:20]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(Cl)c(C)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2c(Cl)c(C)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1C(OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of methyl 2-tert-butoxy-2-(3-chloro-7-(8-fluoro-5-methylchroman-6-yl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)acetate, (5 mg, 10 umol) in dioxane (0.5 mL) was added 1.0 N LiOH aqueous solution (0.5 mL, 0.5 mmol). The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC to afford (3 mg, 60%) of the title compound. Preparative HPLC condition: Phenomenex Luna C18 30×100 mm S10, 50 to 100% B over 22 min gradient, 6 min hold time, A=10% methanol 90% water 0.1% TFA, B=90% methanol 10% water 0.1% TFA. Flow rate: 40 mL/min. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.03 (9H, br. s.), 1.8 (2H, s), 2.28 (2H, br. s.), 2.52 (3H, s), 2.74 (3H, br. s.), 2.96 (3H, s), 4.29 (2H, br. s.), 4.7 (1H, s), 6.98 (1H, s), 7.96 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:25])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC/C=C/c1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CC/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-5-phenyl-pent-4-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30]Br>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: NC1CCC(CNC(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCC1CCC(N2CCCC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.8 %

Procedure:
To a solution of (4-amino-cyclohexylmethyl)-carbamic acid benzyl ester (350 mg, 1.34 mmol) in DMF (5 mL) was added K2CO3 (924 mg, 6.70 mmol) and 1,4-dibromobutane (160 mL, 1.34 mmol). The reaction mixture was stirred at room temperature for 14 h before diluting with EtOAc (100 mL). The reaction solution was washed with water (2×100 mL) and brine before concentrating in vacuo. The residue was purified by chromatography using a 12 g ISCO combi-flash cartridge (silica gel, 95:4.75:0.25 DCM/MeOH/NH4OH) to afford (4-pyrrolidin-1-yl-cyclohexylmethyl)-carbamic acid benzyl ester (351 mg, 83%) as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](O)=[N:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([O:13][CH2:12][C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][O:9][C:10]=2[C:14]([F:16])([F:17])[F:15])=[N:23][CH:22]=1
Reactant: OCc1c(-c2ccccc2)noc1C(F)(F)F
Reactant: COC(=O)c1ccc(O)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Temperature: 50 °C
Yield: 42.6 %

Procedure:
To a solution of (3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-methanol (100 mg, 0.41 mmol) in THF (5 mL) was added 6-hydroxy-nicotinic acid methyl ester (69.3 mg, 0.45 mmol) and triphenylphosphine (162 mg, 0.62 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (96 μL, 0.62 mmol) was added and the reaction mixture was heated at 50° C. for 2 h. After cooling to room temperature the mixture was evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (66 mg, 42%) as an off-whit solid. MS: m/e=379.5 [M+H]+.
Reaction SMILES: ClC1C(C2C=C3C(=CC=2)NN=C3)=CC=CN=1.[Cl:17][C:18]1[C:23]([C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[CH:29][N:30]=[CH:31]3)=[CH:26][CH:25]=2)=[CH:22][CH:21]=[CH:20][N:19]=1.BrC1C=C2C(C=CN=C2)=CC=1.ClC1C(B2OC(C)(C)C(C)(C)O2)=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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(Cl)Cl>[Cl:17][C:18]1[C:23]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Clc1ncccc1-c1ccc2ccncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1ccc2ccncc2c1
Agent: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ncccc1-c1ccc2ncccc2c1

Procedure:
Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole, 7-(2-chloropyridin-3-yl)isoquinoline was prepared by heating the mixture of 7-bromoisoquinoline (1.0 g, 4.8 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.5 g, 6.20 mmol), Pd(PPh3)4 (330 mg, 0.28 mmol) and 2M aq.Na2CO3 (7 mL, 14 mmol) in 1,4-dioxane (40 mL). 6-(2-Chloropyridin-3-yl)quinoline was isolated as a white solid (820 mg, 70%) after the CH2Cl2 work-up and silica gel flash column purification. 1H NMR (DMSO-d6): δ 9.37 (s, 1H), 8.55 (d, 1H, J=5.8 Hz), 8.49 (dd, 1H, J=1.7 and 4.7 Hz), 8.23 (s, 1H), 8.07 (d, 1H, J=7.5 Hz), 8.02 (dd, 1H, J=1.7 and 7.6 Hz), 7.91-7.88 (m, 2H), 7.58 (dd, 1H, J=4.7 and 7.6 Hz).LCMS: rt 3.96 min (A), purity 95%, MS (m/e) 241 (MH+).