Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:30]5[CH:29]=[CH:28][N:27]=[C:26]([O:25][CH3:24])[CH:31]=5)[CH:3]=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)c1
Reactant: COc1cc(B(O)O)ccn1
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: COCCOC
Product: COc1cc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)n2)ccn1
Yield: 41.2 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (150 mg, 0.46 mmol) in 1,2-dimethoxyethane (4 mL) was added 2-methoxypyridin-4-ylboronic acid (84 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium (0) (53 mg, 0.046 mmol), and 2 M Na2CO3 (680 μL, 1.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography eluting with (0-20% ethyl acetate/hexanes) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide (76 mg, 42%). ESI-MS m/z calc. 401.2. found 402.3 (M+1)+. Retention time 1.88 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.[H-].[Na+].[C:12](=O)([O:15]C)[O:13][CH3:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([C:12]([O:13][CH3:14])=[O:15])[C:4](=[O:8])[CH2:3]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(C)(C)CC1=O
Temperature: 25 °C

Procedure:
A solution of 3,3-dimethylcyclohexanone (0.5 g, 3.97 mmol, 1 equiv) and sodium hydride in toluene was stirred at rt for half an hour. To the mixture was added dimethyl carbonate and heated at reflux for 5 h. After the reaction was cooled to rt, the reaction mixture was quenched with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give the crude product, which was directly used for the next step.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 63.5 %

Procedure:
tert-Butyl 3-hydroxypyrrolidine-1-carboxylate (3.00 g, 16.02 mmol) was dissolved in dry DCM (50 mL) and cooled in an ice-water bath. Methanesulfonyl chloride (2.38 g, 20.83 mmol) was added followed by TEA (2.43 g, 24.03 mmol) and the reaction mixture was stirred at 0° C. for 3.5 h. The reaction mixture was washed with water (250 mL) and dried with MgSO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system (40+M column, isocratic run heptane/EtOAc (50:50)) affording the title compound (2.70 g, 63.5%). 1H NMR (500 MHz, CDCl3): δ 1.38 (s, 9H), 2.07 (bs, 1H), 2.18 (bs, 1H), 2.97 (s, 3H), 3.35-3.61 (m, 4H), 5.16-5.18 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 28.59, 31.84, 32.76, 38.80, 43.61, 52.16, 80.12, 154.30.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[C:6]([Br:11])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:12])[N:3]1C(C)(C1C=CC=CC=1)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Br:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4](=[O:12])[NH:3][CH2:2]2
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(Br)cccc2C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C1NCc2cccc(Br)c21
Yield: 76.2 %

Procedure:
In a similar manner to Step 4 of Example 16, 3-hydroxy-7-bromo-2-(1-methyl-1-phenylethyl)isoindolinone (3.00 mg, 0.867 mmol) was dissolved in nitromethane (12 mL), and the solution was treated with trifluoroacetic acid (0.668 mL, 8.67 mmol) and triethylsilane (0.277 mL, 1.73 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=12/1) to obtain 7-bromoisoindolinone (140 mg, yield 76%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:29][CH2:30][CH3:31])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)#[N:2].[SH2:32].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:29][CH2:30][CH3:31])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C@H:19]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[N:7][CH:8]=1)=[S:32]
Reactant: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C#N)cn1
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C(N)=S)cn1
Temperature: 60 °C
Yield: 95 %

Procedure:
Through a solution of ethyl ((1S-5-{3-[(5-cyano-2-yridinyl)(propyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 265) (0.62 g, 1.47 mmol) in DMF (7 mL) at rt for 20 min was gently passed H2S. Diethylamine (0.23 mL, 2.21 mmol) was added in one portion, and the resultant light green solution was heated at 60° C. for 3 h. Upon completion of the reaction, the dark green solution was purged with a strong flow of argon, and then concentrated under reduced pressure. The product (0.63 g, 95%) was isolated after silica gel column chromatography (1:1 hexanes/EtOAc) as a yellow solid. 1H NMR (400 MHz, CD2Cl2) δ 8.68 (d, 1H), 8.02 (dd, 1H), 7.30 (b, 1H), 7.15-7.02 (m, 2H), 6.79 (d, 1H), 6.71 (dd, 1H), 6.49 (d, 1H), 4.16 (q, 2H), 4.00 (t, 2H), 3.75 (t, 2H), 3.56-3.45 (m, 3H), 2.96-2.78 (m, 2H), 2.75-2.68 (m, 1H), 2.48-2.34 (m, 2H), 2.11 (qt, 2H), 1.82-1.60 (m, 3H), 1.28 (t, 3H), 0.97 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH:23]=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl([O-])=[O:33].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([C:23]([OH:33])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Yield: 100 %

Procedure:
The same operation as in Example (33c) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained by the method described in Example (28a) (400 mg, 0.85 mmol), sodium chlorite (158 mg, 1.75 mmol), sodium dihydrogenphosphate (410 mg, 2.63 mmol) and 2-methyl-2-butene (0.55 mL, 5.20 mmol), to obtain 439 mg of the title compound (100%).
Reaction SMILES: O1CCCC1.[Br-].[F:7][C:8]([F:13])([F:12])[C:9]([Zn+])=[CH2:10].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>CCCCCC>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:9]([C:8]([F:13])([F:12])[F:7])=[CH2:10])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: FC(F)(F)c1cc(I)ccc1Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(c1ccc(Cl)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
In a nitrogen atmosphere, to 53 mL of a 1M tetrahydrofuran solution of 1-trifluoromethylethenyl zinc bromide prepared according to a method described in the literatures, 7.1 g of 2-chloro-5-iodobenzotrifluoride and 0.65 g of dichlorobis(triphenylphosphine) palladium (II) were added and the resultant mixture was stirred while heating the mixture to reflux for 2.5 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and 200 mL of hexane was added to the reaction mixture, followed by filtering off the deposited insoluble substance. The resultant filtrate was washed with water (50 mL×1) and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 4.8 g of the objective substance as a colorless oily substance.
Reaction SMILES: [K].CCOCC.[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>CCO>[CH2:15]([O:14][C:7](=[O:13])[C:8](=[O:10])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:18])[CH3:19])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])[CH3:16]
Reactant: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared by adapting the procedure described by Gagliardi S., el al., in J. Med. Chem., 1998;41:1568 using potassium (1.66 g, 42.4 mmol), Et2O (200 mL), EtOH (10 mL), diethyl oxalate (7.56 g, 51.8 mmol), and 4-tert-butyl-1-methyl-2-nitrobenzene (prepared in ExampleWW; 10.0 g, 51.8 mmol). MS(APCI): 294 (M+H).
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][OH:16]>>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1
Reactant: Clc1ccc2nccn2n1
Reactant: CN(C)CCO
Agent: [Na]
Product: CN(C)CCOc1ccc2nccn2n1
Temperature: 130 °C

Procedure:
Sodium metal (0.25 g) and 6-chloroimidazo[1,2-b]pyridazine are added to 25 ml of 2-dimethylaminoethanol and the mixture is heated in a sealed tube for 3 hours at 130° C. After cooling, the solvent is evaporated and the residue is treated with water and extracted with methylene chloride. The organic layer is separated, washed with saturated sodium chloride solution and dried over MgSO4. Evaporation of the solvent gives the title compound as a viscous oil which solidified on standing. The yield is 2.5 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12](CC(O)=O)=[CH:11][CH:10]=2)[O:3]1.[CH3:20][CH:21]([CH3:24])[CH2:22][OH:23]>C(O)C>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:19])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:7][CH2:6][C:2]([O:23][CH2:22][CH:21]([CH3:24])[CH3:20])=[O:3])=[CH:13][CH:14]=2)[O:5]1
Reactant: CC(C)CO
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Solvent: CCO
Product: CC(C)COC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 67 %

Procedure:
Isobutyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (67%) was prepared according to Example 192, Step A described above, substituting 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid for 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid and 2-methylpropan-1-ol for ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].S(=O)(=O)(O)O.[BH4-].[Na+].[CH3:24][C:25]([CH3:27])=O>>[CH:25]([NH:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccc(C(=O)c2ccccc2)c(NC(C)C)c1
Temperature: 20 °C
Yield: 95 %

Procedure:
To a solution of 63.3 gms. of 2-amino-4-methylbenzophenone in 722 mls. of acetone is added 87 gms. of 49% aqueous sulfuric acid. The mixture is cooled to 20° C. With stirring, and by portionwise addition, 31.2 gms. of sodium borohydride is added to the mixture over a period of 70 minutes. After the addition, the mixture is stirred for an additional 5 hours at 25° C. The suspended solids are filtered and then washed with 300 mls. of acetone. The acetone solutions are combined and concentrated. To the concentrate is added 200 mls. of heptane and 60 mls. of 4N ammonium hydroxide. The liquid layers are separated, then the heptane phase is washed with 20 mls. of water, extracted twice with 20 mls. of 2N sulfuric acid each time, and then washed to neutrality with water. The heptane phase is then dried over magnesiun sulphate, filtered, and concentrated under vacuum to a constant weight of 74.5 gms. or crude yield of 98%, which is shown by analysis to constitute an actual yield of about 95% of the desired 2-(N-isopropylamino)-4-methylbenzophenone.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[C:37](/[CH3:41])=[CH:38]/[CH2:39]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[CH:38]=[C:37](/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:32][CH:33]=1)\[CH3:41])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: C/C(=C\CO)c1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C(\C)c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 228 mg (1 mM) of (E)-3-[4-(1-imidazolylmethyl)-phenyl]-2-buten-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 539 mg (100%).
Reaction SMILES: [CH:1]1([C:5]2[C:13](I)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:15][CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:22](=O)([O:25]C)[O:23][CH3:24]>C1COCC1>[CH:1]1([C:5]2[C:13]([C:22]([O:23][CH3:24])=[O:25])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:15][CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(C2CCC2)c(I)cc1C(=O)O
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
To a solution of 4-cyclobutyl-2-ethyl-5-iodobenzoic acid (compound 215.3, 3.30 g, 10.0 mmol, 1.00 equiv) in THF (40 mL) was added n-BuLi (2.5 M, 9.50 mL, 2.38 equiv) dropwise at −78° C. under nitrogen atmosphere. The resulting solution was stirred for another 20 min at the same temperature, followed by the addition of a solution of dimethyl carbonate (2.70 g, 30.0 mmol, 3.00 equiv) in tetrahydrofuran (2 mL) dropwise. The reaction temperature was slowly raised to 25° C. and stirred for another 1 h, then slowly quenched with 50 mL of water. The pH was adjusted to ˜4 with HCl (aq., 1 M) and the resulting mixture was extracted with 100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as eluent to furnish 1.80 g (69%) of the desired product as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[S:27][C:28]([CH2:32]O)=[C:29]([CH3:31])[N:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]#[N:17])=[C:11]3[N:10]=[CH:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:32][C:28]3[S:27][C:26]([CH3:25])=[N:30][C:29]=3[CH3:31])=[CH:22][CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1cnn2c(C3CCCCC3)c(-c3ccc(O)cc3)cnc12
Reactant: Cc1nc(C)c(CO)s1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C)c(COc2ccc(-c3cnc4c(C#N)cnn4c3C3CCCCC3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold mixture of 40 mg (0.13 mmol) of 7-cyclohexyl-6-(4-hydroxy-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 3 mL of tetrahydrofuran (THF) was added 74 mg (0.52 mmol) of (2,4-dimethyl-thiazol-5-yl)-methanol, 136 mg (0.52 mmol) of triphenylphosphine (PPh3), followed by 0.102 mL (0.52 mmol) of diisopropyl azodicarboxylate (DIAD) and the mixture was allowed to warm up to rt and stirred at rt overnight. The reaction mixture was then concentrated and the residue was chromatographed on silica gel (Biotage; 10% ethyl acetate in DCM) to give desired 7-cyclohexyl-6-[4-(2,4-dimethyl-thiazol-5-ylmethoxy)-phenyl]-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as indicated by 1H-NMR; LC-MS—calcd for C25H25N5OS [M++H]+: 444.18, found: 444.2.
Reaction SMILES: Cl.O.[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1)[C:4]#[N:5]>[Fe].C(O)C>[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([NH2:13])[CH:7]=1)[C:4]#[N:5]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#CSc1ccc(N)c(N)c1
Reaction time: 0.06 h
Yield: 79 %

Procedure:
63 g. of iron powder are activated by heating with a mixture of 12 ml of 5N hydrochloric acid and 30 ml. of water on a water bath for half an hour, addition of 270 ml. of water and cooling the suspension to 45° C. follows. A hot solution of 58.5 g. of 4-thiocyanato-2-nitro-aniline and 180 ml. of 96% ethanol is added under stirring to the suspension formed. The temperature of the reaction mixture rises slowly. When the temperature reaches 75° C. the reaction mixture is cooled with ice in order to maintain the internal temperature below 85° C. The exothermic stage of the reaction lasts for 3-4 minutes. The reaction mixture is then heated to boiling until no more starting material can be detected by means of thin layer chromatography (about 15 minutes). The warm reaction mixture is filtered, 225 ml. of hot water are added to the filtrate, the solution is clarified with activated charcoal, filtered until warm and the filtrate is allowed to crystallize slowly under stirring. The mixture containing crystals is stirred at 0° C. for 5-6 hours, the crystals are filtered off, washed with cold 25% ethanol and dried in vacuo. Thus 41.6 g. of 4-thiocyanato-1,2-diamino-benzene are obtained, yield: 79%, M.p.: 108°-110° C.
Reaction SMILES: C[O-].[Na+].[CH3:4][CH:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[C:12]([O:14]C)=O)[CH3:6].[CH3:16][NH:17][CH3:18]>CO>[CH3:16][N:17]([CH3:18])[C:12]([C:8]1[O:9][CH:10]=[CH:11][C:7]=1[CH:5]([CH3:6])[CH3:4])=[O:14]
Reactant: COC(=O)c1occc1C(C)C
Reactant: CNC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1ccoc1C(=O)N(C)C

Procedure:
A solution of sodium methoxide (3.3 g) and 3-(1-methylethyl)-2-furancarboxylic acid, methyl ester (14 g) in dry methanol (50 ml) was treated with dimethylamine gas during 2 hours. The solvent was removed in vacuo and the residue was dissolved in diethyl ether (150 ml) and washed with water (100 ml). The ethereal extract was dried over anhydrous sodium sulphate and evaporation of the solvent gave the title compound (12 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:31]3[C:26](=[O:25])[CH:27]=[CH:28][C:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: CCOC(=O)c1ccc(O)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(=O)n(-c2ccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)cc2)c1
Reaction time: 8 h

Procedure:
A mixture of {4-[(4-{[(tert-butoxy)carbonyl]amino}piperidin-1-yl)methyl]phenyl}boronic acid (800 mg; 2.39 mmol; prepared as described for the synthesis of intermediate X.7 without BOC deprotection step), ethyl 6-hydroxypyridine-3-carboxylate (420 mg; 2.51 mmol), copper(II) acetate (250 mg; 1.38 mmol) and pyridine (210 μl; 2.60 mmol) in DCM (10 ml) is stirred overnight. The mixture is filtered and extracted with water. The organic layer is dried with sodium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient DCM/methanol 98:2→94:4) to yield ethyl 1-{4-[(4-{[(tertbutoxy)carbonyl]amino}piperidin-1-yl)methyl]phenyl}-6-oxo-1,6-dihydropyridine-3-carboxylate
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[CH2:26][CH2:25][CH2:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)CCC2)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 5-aminoindan (Aldrich) according to the method described in Example 1c. Melting Point: 150-152° C. (diethylether)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[NH:16])[NH:14][OH:15])(=[O:3])[CH3:2].[C:17](Cl)(=O)[CH2:18][CH2:19][CH3:20]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:16]=[C:17]([CH2:18][CH2:19][CH3:20])[O:15][N:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C(=N)NO
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCc1nc(C2Cc3ccccc3N2C(C)=O)no1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of intermediate (14) (0.00898 mole) and butanoyl chloride (0.0094 mole) in pyridine (140 ml) was stirred at room temperature for 40 hours and then heated to reflux. After 21 hours the reaction was cooled and concentrated in vacuo. The residue was extracted between DCM and saturated aqueous NaHCO3 and the organic fraction was dried over Na2SO4, filtered, and concentrated. The residue was subjected to silica gel flash column chromatography (eluent 100% CH2Cl2 to 95/5 CH2Cl2/ether), yielding 1-acetyl-2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indole (compound 89, mp. 93-94° C.).