Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>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.CC#N>[CH3:12][N:11]([CH3:13])[S:8]([C:7]1[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1cccnc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1cccnc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
The product from Example 44A (1.29 g, 5.85 mmol), 4-carboxyphenylboronic acid (0.967 g, 5.82 mmol) and Pd(PPh3)4 (0.337 g, 0.292 mmol) were combined in 1:1 0.5 M Na2CO3:MeCN (46 mL) and heated at 85° C. overnight. The mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated to 50% volume. The aqueous layer was acidified with concentrated HCl and extracted with CH2Cl2. The organics were dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound as a solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(OC)(C)C>O.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water (0.75 ml) and methanol (7.5 ml). The mixture was stirred at reflux temperature for 2 h. After this time the raw material was not observed by HPLC. MTBE (58 ml) was dripped into the solution over 2 h. The solution was cooled slowly to room temperature and was stirred overnight. The product was isolated by filtration under nitrogen, washed with MTBE (50 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 2.78 g (91.3%) of fluvastatin sodium Form B.
Reaction SMILES: C(O)(C(F)(F)F)=O.O[C:9]([C:12]1[CH:13]=[CH:14][C:15]2[C:19]([CH3:21])([CH3:20])[O:18][B:17]([OH:22])[C:16]=2[CH:23]=1)([CH3:11])[CH3:10].[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)(Cl)Cl>[N:24]([C:9]([C:12]1[CH:13]=[CH:14][C:15]2[C:19]([CH3:21])([CH3:20])[O:18][B:17]([OH:22])[C:16]=2[CH:23]=1)([CH3:11])[CH3:10])=[N+:25]=[N-:26]
Reactant: CC(C)(O)c1ccc2c(c1)B(O)OC2(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(N=[N+]=[N-])c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
A solution of TFA (200 μL, 2 mmol) in chloroform (3 mL) was added slowly to a mixture of 6-(2-hydroxypropan-2-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (88 mg, 0.4 mmol) and sodium azide (80 mg, 1.2 mmol) in chloroform (7 mL) at −5° C. to 0° C. The cooling bath was removed and the mixture was stirred at rt overnight. Concentrated ammonium hydroxide was added until pH was basic (moist PH paper). DCM (50 mL) was added and the organic layer was washed with brine:water (1:1), dried over Na2SO4, filtered and concentrated to give the crude product 6-(2-azidopropan-2-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (100 mg) as colorless oil. It was used without further purification in the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:20])[CH:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>CS(C)=O.C(OCC)(=O)C>[CH3:11][N:12]([CH3:20])[CH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: CN(C)C1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCC(Nc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (0.392 ml, 3.69 mmol) in 4 mL of dimethyl sulfoxide was added N1,N1-dimethylcyclohexane-1,4-diamine (500 mg, 3.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.449 ml, 14.06 mmol). The reaction mixture was stirred at 100° C. for 24 hours. The mixture was poured into a separatory funnel and was diluted with 50 mL of ethyl acetate. The organic mixture was then washed with 50 mL of water followed by 50 mL of saturated aqueous brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude material obtained was carried through the next step without purification. MS (ESI) m/z 264.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][N:20]3[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:22]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:21]3)=[CH:37][CH:38]=2)[N:4]=1
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyloxazole (312 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (687 mg, yield: 87%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (5:6, volume ratio).
Reaction SMILES: [CH3:1][N:2]([C:7]1[C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:11][CH:10]=[CH:9][N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:14][CH2:13][C:12]1[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(c1ncccc1CNC(=O)OC(C)(C)C)S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ncccc1CN)S(C)(=O)=O
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
To a 25 mL round bottom flask charged with tert-butyl (2-(N-methylmethylsulfonamido)pyridin-3-yl)methylcarbamate (118 mg, 0.26 mmol) was added a 40% solution of TFA in CH2Cl2 (4 mL). The resulting mixture was stirred for 20 min, then the volatiles were evaporated. Toluene (4 mL) was added to the crude followed by evaporation. This procedure was repeated once. A solution of the crude residue in CH2Cl2 (4 mL) was treated with Amberlyst A-21 (1.8 g) and stirred for 30 min. The Amberlyst A-21 resin was filtered off and washed with CH2Cl2 (20 mL). The volatiles were evaporated to yield N-(3-(aminomethyl)pyridin-2-yl)-N-methylmethanesulfonamide (50 mg, 0.23 mmol, 88%).
Reaction SMILES: C(OC1C=CC(CCNC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=CC=1)C1C=CC=CC=1.C([O:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][NH:54][CH2:55][C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=[CH:48][CH:47]=1)C1C=CC=CC=1>>[CH3:63][O:62][C:60]1[CH:59]=[CH:58][C:57]([CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=[C:56]([CH2:55][NH:54][CH2:53][CH2:52][C:49]2[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=2)[CH:61]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCCc1ccc(OCc3ccccc3)cc1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCc3ccccc3)cc1)C2
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCCc1ccc(O)cc1)C2
Yield: 106 %

Procedure:
Synthesized from [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Preparation Example 18, [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (367 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (320 mg).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([CH:24]4[CH2:26][CH2:25]4)[CH:23]=2)[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]3([CH3:30])[CH3:29])=[CH:8][C:7]=1[F:31])C.CO.[OH-].[Na+].O>C(#N)C>[CH:24]1([C:22]2[CH:23]=[C:14]([C:13]#[C:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([F:31])[CH:8]=3)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([CH3:27])([CH3:28])[CH2:18][C:17]3([CH3:30])[CH3:29])[CH2:25][CH2:26]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)cc(C3CC3)c2O1

Procedure:
Following general procedure L and using [4-(8-cyclopropyl-2,2,4,4-tetramethyl-chroman-6-yl-ethynyl)-2-fluoro-phenyl]acetic acid ethyl ester (Compound 37, 0.14 g, 0.323 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.110 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:12]([C:5]4[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=4)=[O:13])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cnc(Cl)nc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (35% yield). 1H NMR (300 MHz, CDCl3) δ 8.77, 8.08, 7.97, 7.01, 4.06-3.68, 3.55, 3.39, 1.50, 0.76-0.71, 0.48-0.42, 0.10-0.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:6]=[CH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1>>[C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22](/[C:6](/[C:5]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:7]/[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])=[CH:23][CH:24]=1)([OH:31])=[O:30]
Reactant: COc1ccc(C=CC(=O)N2CCOCC2)cc1OC
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: COc1ccc(/C(=C\C(=O)N2CCOCC2)c2ccc(CC(=O)O)cc2)cc1OC

Procedure:
This compound was obtained in analogy to the preceding Examples in the form of crystals, m.p. 192°-194° C., from 3,4dimethoxycinnamic acid morpholide and (4-bromophenyl)-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH3:11])=[O:4].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:13])=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[CH2:11][Br:14])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc(Cl)nc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cc(Cl)nc1Cl
Yield: 72.2 %

Procedure:
To a solution of 5.3 g (24.1 mmol) 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester in CCl4 (92 ml) were added 3.1 g (26.5 mmol) N-Bromosuccinimide, 395 mg (2.4 mmol) AIBN and 1.45 ml (25.3 mmol) acetic acid. The mixture was irradiated with a 200 W Wolfram lamp at 60° C. for 24 h. Subsequently the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 97:3) provided 5.2 g of a mixture of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid methylester and 4-(bromomethyl)-2,6-dichloro-pyridine-3-carboxylic acid methylester which was used in subsequent reactions without further purification.
Reaction SMILES: C([S:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=O)C.Cl>CO>[CH3:15][S:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([SH:4])=[CH:6][CH:7]=1)(=[O:13])=[O:14]
Reactant: CC(=O)Sc1ccc(OS(C)(=O)=O)cc1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)Oc1ccc(S)cc1
Reaction time: 2 h

Procedure:
S-[4-(methanesulfonyloxy)phenyl] thioacetate (20.4 g., 0.083 mole) is dissolved in 150 ml. of warm (45° C.) methanol. Concentrated hydrochloric acid, 5 ml., is added and the solution is held at 45°-55° C. for 2 hours. The solution is then concentrated in vacuo to approximately 40 ml., taken up in 200 ml. of chloroform, washed with 50 ml. of water, dried over sodium sulfate and concentrated in vacuo to give 15.8 g. (93%) of the desired thiophenol as a white crystalline solid, m.p.=66°-68° C. (after recrystallization from carbon tetrachloride). Analysis calc. (found): C 41.2 (41.3); H 3.95 (4.03).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].[Mg+2].[Cl-].[Cl-].C([O-])(=O)CC([O-])=O.Cl>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([O:28][CH2:29][CH3:30])=[O:27])=[O:15])[CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCOC1
Agent: Cl
Agent: O=C([O-])CC(=O)[O-]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(Cl)cc2)CCOC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3-(4-Chlorophenyl)-tetrahydrofuran-3-carboxylic acid (375.2 mg, 1655 μmol) was mixed with thionyl chloride (1.21 mL, 16554 μmol) and heated at 70° C. for 3 hours. The solution was cooled, concentrated in vacuo, and pumped on under high vacuum for 3 hours. To a flame-dried round bottom flask containing diethyl malonate (0.25 mL, 1655 μmol) in ACN (3 mL), was added MgCl2 (158 mg, 1655 μmol). The resulting solution was cooled to 0° C. The reaction was then stirred for 15 minutes at 0° C. To the resulting mixture was slowly added TEA (0.48 mL, 3476 μmol), and the reaction was stirred at room temperature for 3 hours. The acid chloride intermediate in ACN (1.9 mL), was added to the malonate solution, and the resulting mixture was stirred at 50° C. for 13 hours. The reaction was then cooled and concentrated in vacuo to give a light yellow solid which was mixed with 1N HCl and EtOAc. The aqueous layer was extracted with EtOAc (2×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica flash chromatography (10-30% EtOAc/hexane) gave the title compound as a light yellow oil. MS m/e=369.2 (M+H)+.
Reaction SMILES: [ClH:1].FC1C(CN)=CC=CN=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][N:19]=1)[C:15]#[N:16].Cl>[Pd]>[ClH:1].[F:11][C:12]1[CH:13]=[C:14]([CH2:15][NH2:16])[CH:17]=[CH:18][N:19]=1
Reactant: N#Cc1ccnc(F)c1
Agent: [Pd]
Agent: Cl
Agent: NCc1cccnc1F
Product: NCc1ccnc(F)c1
Yield: 50 %

Procedure:
Following a method similar to C-(2-Fluoro-pyridin-3-yl)-methylamine hydrochloride, using 2-fluoro-isonicotinonitrile (0.65 g, 5.3 mmol), concentrated HCl (1.2 mL), and 5% Pd/C (1.2 g) to give the title compound (0.43 g, 50%). MS (ES) 127.1 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>[Rh].C(O)C>[CH2:9]([O:8][C:6]([C@H:5]1[CH2:11][CH2:12][C@@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](O)CC1

Procedure:
A mixture of 10 g of ethyl 4-hydroxybenzoate, 5 mL of acetic acid, 0.8 g of 5% rhodium on alumina, and 200 mL of ethanol was shaken under 55 psi of hydrogen for 48 h, filtered and concentrated under reduced pressure. The residue was taken up in 200 mL of toluene and again concentrated under reduced pressure to remove acetic acid. Drying under vacuum overnight gave 11 g of product, which was predominantly cis (83:17 cis: trans by HPLC), as a colorless oil: MS (m+1)=173.2; 1H NMR (400 MHz, CDCl3) 4.1 (dd, 2H), 3.9 (m, cis isomer, 0.85H), 3.6 (m, trans isomer, 0.15H), 2.4 and 2.2 (m, 1H), 2.0 (m, 2H), 1.62 (m, 6H), 1.2 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=2)[CH:4]=1.[Li]CCCC.[C:27](Cl)(=[O:29])[CH3:28].[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:5](=[C:6]([C:27](=[O:29])[CH3:28])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1
Reactant: COc1cc2cn(COCC[Si](C)(C)C)nc2cc1OC
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc2nn(COCC[Si](C)(C)C)c(C(C)=O)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
The title compound was prepared in a similar manner as described by G. Luo et al., J. Org. Chem. 2006, 71, 5392-5395: To a solution of 5,6-dimethoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (200 mg, 0.65 mmol) in THF (5 mL) at −78° C. was added dropwise a 2.5 M solution of n-BuLi in hexanes (0.29 mL, 0.71 mmol). The reaction mixture was stirred at −78° C. for 20 min. Acetyl chloride (0.07 mL, 0.97 mmol) was then added dropwise, and the mixture was stirred at RT for 16 h. Saturated aqueous NH4Cl solution was added to the reaction mixture, followed by stirring for 30 min. The aqueous phase was extracted twice with EtOAc and the combined organics were washed with brine, dried (Phase separator) and evaporated to give the crude title compound which was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[C:4]2[N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CC(O)C.C([O-])(O)=O.[Na+]>[Cl:17][C:13]1[CH:12]=[C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([NH:18][CH:19]4[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]4)=[N:3][C:4]=23)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnn3ccc(Cl)nc23)c1
Reactant: NC1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(Nc2ccn3ncc(-c4cccc(Cl)c4)c3n2)CC1
Yield: 23.2 %

Procedure:
A mixture of 5-chloro-3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.379 mmol), 4-aminocyclohexanone (43 mg, 0.379 mmol), and DIEA (0.158 ml, 1.515 mmol) in 2-propanol (3 ml) was irradiated to 150° C. for 14 h in a Biotage microwave. After cooling, the mixture was diluted with saturated aqueous NaHCO3, and extracted three times with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. After absorbing on celite, the compound was purified by chromatography (12 g silica, 0-15% methanol/DCM) to give 4-((3-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)cyclohexanone (30 mg, 24% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[C:19]1[CH:20]=C(C(=O)CCC(O)=O)C=[CH:23][C:24]=1OC.C([O-])([O-])=O.[K+].[K+].BrC1CCCC1.Cl>Br.O.CN(C=O)C.CCOC(C)=O>[CH:1]1([O:2][C:3]2[CH:4]=[C:5]([C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])[CH2:23][CH2:24][CH2:19][CH2:20]1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1OC
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1O
Agent: Br
Agent: BrC1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)CCC(=O)O)cc1OC1CCCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 14.4 %

Procedure:
4.7 g (0.019 mol) of 4-(3,4-dimethoxyphenyl)-4-oxo-butanoic acid (FN 549) are dissolved in 50 ml of 47% HBr in water, heating to reflux for one hour until the reaction compound disappears. The reaction solution is concentrated to dryness, adding acetonitrile several times, and then the dark pitch is extracted hot several times with ethyl ether. On concentrating the organic solution to dryness, 3.3 g of crude product are obtained, which can be used as such in the next reaction. 3.3 g (0.015 mol) of crude 4-(3-hydroxy-4-methoxyphenyl)-4-oxo-butanoic acid (FN 551) are suspended in 30 ml of anhydrous DMF with 6.2 g (0.045 mol) of K2CO3, left under stirring for 30 minutes, and then added with 2.4 ml (0.0225 mol) of bromocyclopentane and heated at 70° C. for 4 hours under a nitrogen atmosphere. After one night at room temperature, the reaction mixture is dried under reduced pressure and the residue obtained is divided between HCl 2N and EtOAc, washing the organic phase with water. The reaction mixture is anhydrified on anhydrous sodium sulphate and evaporated to dryness, obtaining a dark oil which is chromatographed on a silica gel column, eluting with n-hexane/EtOAc. After crystallisation, the same mixture of solvents yields fractions containing the dried product. 0.63 g of product are obtained. Yield 14%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)C.[C].[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: C(=C1CCNCC1)c1ccc2ccccc2n1
Agent: [Pd]
Solvent: CCO
Product: c1ccc2nc(CC3CCNCC3)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(2-Quinolylmethylene)piperidine (9.62 g) was dissolved in ethanol (500 ml), and 10% palladium-carbon (1.9 g) was added to the solution. The mixture was stirred under a hydrogen stream at room temperature for 90 minutes. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure, to thereby obtain the title compound as a colorless solid.