Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1COCC1>[Pd].ClCCl>[CH2:1]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc2ccc(OC)cc2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCc1ccc2ccc(OC)cc2c1
Yield: 95.7 %

Procedure:
1-Decyne (1.2 g, 6.5 mmol), PdCl2(PPh3)2 (0.12 g, 0.16 mmol), CuI (13 mg, 0.065 mmol), and triethylamine (14 ml, 9.8 mmol) were added to a THF (20 ml) solution of 7-methoxy-2-naphthyltrifluoromethane sulfonate (1.0 g, 3.3 mmol). The solution was mixed at room temperature for 4 hours, and diluted with water (30 ml). The solution was made acidic with diluted hydrochloric acid (2 M), and extracted with dichloromethane (30 ml×3). The extracted solution was washed with water (100 ml×3), and dried with MgSO4. The solution was condensed, and subjected to column chromatography (silica gel, developed with dichloromethane) to obtain 7-decyn-1-yl-2-methoxynaphthalene as a light yellow oil product. The obtained 7-decyn-1-yl-2-methoxynaphthalene (2.8 mmol) and a THF (13 ml) of 10% Pd/C (0.16 g) were placed in a 50 ml round-bottomed flask. Under a hydrogen atmosphere, the solution was stirred until the reaction was completed (approximately 12 hours) while the reaction was tracked using TLC. When the reaction was completed, a catalyst was filtered out, and the filtrate was condensed. The condensed solution was refined by column chromatography (silica gel, developed with dichloromethane) to obtain 7-decyl-2-methoxynaphthalene (compound (3)-12) (0.80 g, 82%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]>CN(C=O)C>[C:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([CH:43]3[CH2:48][CH2:47][N:46]([C:11]4[CH:12]=[CH:13][C:14]5[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=5)[N:16]=4)[CH2:45][CH2:44]3)=[CH:41][CH:42]=2)[CH2:29][CH2:28]1)(=[O:26])[CH3:25]
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCNCC3)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
DIPEA (5.21 mL, 29.93 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (6.06 g, 27.21 mmol) and 4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidine (9.40 g, 27.21 mmol) in DMF (200 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature then evaporated to dryness. Water (600 mL) was then added and the mixture extracted with DCM (2×600 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (13.80 g, 95%) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH: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].Cl[C:18]1[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=1.[H-].[Na+]>CN(C)C=O>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][C:18]2[CH:19]=[CH:20][C:21]([N+:33]([O-:35])=[O:34])=[C:22]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:23]=2)=[CH:15][C:2]=1[OH:1])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C(=O)c3ccccc3)c(O)c2)ccc1[N+](=O)[O-]
Yield: 22.6 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2,4-dihydroxybenzophenone (4.5 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.0 g), sodium hydride (55 wt. %, 1.75 g) and anhydrous N,N-dimethylformamide (130 ml) and the reaction mixture was purified to give the title compound (2.2 g).
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][CH2:5]Br.[Na].[CH2:8]1[O:18][C:17]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=2[O:9]1>COCCOC>[Br:1][CH2:2][CH:3]=[CH:4][CH2:5][O:14][CH2:13][C:12]1[CH:15]=[CH:16][C:17]2[O:18][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: BrCC=CCBr
Reactant: OCc1ccc2c(c1)OCO2
Agent: [Na]
Solvent: COCCOC
Product: BrCC=CCOCc1ccc2c(c1)OCO2
Reaction time: 0.25 h

Procedure:
11.8 g (0.055 mol) of 1,4-dibromo-2-butene and 8.7 g (0.05 mol) of sodium salt of 3,4-methylendioxy-benzylalcohol are covered with a layer of 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 20°-25° for 16 hours and at 50° for 15 minutes. The solvent is subsequently distilled off at reduced pressure, the residue is taken up in ether and the ether solution is extracted with water. The organic phase is dried with sodium sulphate and the ether is then distilled off and the residue is chromatographed on silica gel with hexane/ethyl acetate 9 : 1. The chromatographically uniform 5-[(4-bromo-2-butenyloxy)-methyl]-1,3-benzodioxol is obtained as slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=C(C#N)[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1.S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:27]([C:26]([OH:29])=[O:28])[CH:16]=[CH:17][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2

Procedure:
320 Mg. 8-chloro-3-cyanodibenzo[b,f]thiepin-5,5-dioxide is refluxed for 24 hours in a mixture of 10 cc. acetic acid and 10 cc. 50% aqueous sulfuric acid. The mixture is cooled down and the crystalline product filtered, washed with water and dried at 70° C., 0.5 mm./Hg., to yield 289 mg. (82%) of pure acid, m.p. 276°-278° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[Br:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)c(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-4-fluoro-5-nitro-phenol (3.5 g, 14.83 mmol) and Cs2CO3 (5.80 g, 17.80 mmol) in DMF (26 mL) was added benzyl bromide (2.80 g, 1.94 mL, 16.31 mmol) dropwise. The reaction was stirred at room temperature under an inert atmosphere for 2 h. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using 40% DCM/hexane gradient to yield 1-(benzyloxy)-2-bromo-4-fluoro-5-nitrobenzene. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=6.4 Hz, 1H), 7.59 (d, J=9.9 Hz, 1H), 7.52-7.34 (m, 5H), 5.23 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CC(C)=O>[CH:20]1([CH2:19][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=2[C:9](=[O:11])[CH3:10])[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1c(O)cccc1OCC1CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a stirred solution of 1-(2,6-dihydroxyphenyl)ethanone (50.0 g, 328 mmol) in acetone (1000 mL) was added potassium carbonate (227 g, 1643 mmol) and (bromomethyl)cyclopropane (35.1 mL, 361 mmol). The mixture was stirred at 50° C. for 2 days. The reaction mixture was filtrated on Celite®, and then the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was suspended in hexane. Then the suspension was stirred at 80° C. for 30 min. The solution was filtered and the filtrate was allowed to cool to room temperature. The resulting white solid was collected by filtration, washed with hexane, and dried under reduced pressure to give 1-{2-[(cyclopropylmethyl)oxy]-6-hydroxyphenyl}ethanone as a pale yellow solid (56.3 g, yield; 83%).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH:9]12[CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH:13]1[CH2:14][CH2:15][NH:8]2
Reactant: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2CCNC2C1

Procedure:
21.2 g (77.3 mmol) of ethyl 2-benzyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate (Example Ae) in 400 ml of ethanol are hydrogenated on 3 g of palladium/active carbon (10% Pd) at 100° C. and 100 bar. The catalyst is filtered off, the filtrate is concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:25]([NH:24][CH2:22][CH3:23])=[O:26])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Reactant: CCN=C=O
Product: CCNC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)aniline 1 (102 mg, 0.35 mmol) in 1 mL of dry CH2Cl2was added ethyl isocyanate (95%, 35 μL, 1.2 eq.) at room temperature. After being shaken at room temperature for overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of the CH2Cl2 afforded N-(1-Boc-piperidin-3-yl-methyl)-N-phenyl-N′-ethylurea (2) (120 mg, 95%). LRMS 285 (M-100)+ 261.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=[N:5][OH:6])[NH2:4].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>>[NH2:4][C:3](=[N:5][O:6][CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])[C:2]([F:8])([F:7])[F:1]
Reactant: C#CC(=O)OCC
Reactant: NC(=NO)C(F)(F)F
Product: CCOC(=O)C=CON=C(N)C(F)(F)F

Procedure:
The title compound was prepared using the procedure described in Example 65(b) starting from 2,2,2-trifluoro-N′-hydroxyacetimidamide (218.7 mmol, 28 g) and ethyl propiolate (262.5 mmol, 25.7 g). Yield 45.2 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.32 (t, 3H), 4.31 (q, 2H), 7.03 (d, 1H), 7.60 (bs, 2H), 8.29 (d, 1H). LC-MS: [M−1]=225.34.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21](Cl)(Cl)=[S:22]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([N:18]=[C:21]=[S:22])[CH:17]=1)=[CH:5]2
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N=C=S

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (5.48 g, 20 mmol) was reacted with thiophosgene (1.9 mL, 25 mmol) according to the procedure for Example 26, Step A to give the product as a greenish tan solid (5.40 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:7]#[N:8])([O-:3])=[O:2].[ClH:15].[CH2:16]([OH:18])[CH3:17]>>[ClH:15].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:7](=[NH:8])[O:18][CH2:16][CH3:17])([O-:3])=[O:2]
Reactant: CCO
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Product: CCOC(=N)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
Ethyl 3,5-dinitrobenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, 3,5-dinitrobenzonitrile (25.2 g, 0.130 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 34.5 g (96%) of the target compound as pale-brown crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)[C:8](=[O:13])[CH:9]=[C:10]([OH:12])[CH:11]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:31]=1[CH2:32]Br>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[CH:15]=2)[C:8](=[O:13])[CH:9]=[C:10]([O:12][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:30]=2[F:29])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(O)cc(=O)n1-c1cccc(C(N)=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
{1-[3-(aminocarbonyl)phenyl]-4-hydroxy-6-oxo-1,6-dihydropyridin-2-yl}methyl acetate (crude from step 1) (3.61 g, 11.94 mmol) was dissolved in N,N-dimethylformamide (40 mL). K2CO3 (3.80 g, 27.46 mmol) was added followed by 2,4-difluorobenzyl bromide (5.44 g, 26.27 mmol). The reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was then partially concentrated and the residue taken up in dichloromethane/tetrahydrofuran 1:1 and filtered. The filtrate was collected, concentrated and the residue tritrated with dichloromethane to afford a tan solid (1.64 g, 32%). 1H NMR (400 MHz, DMF-d6) δ 8.19 (br s, 1H), 8.07 (app dt, J=1.35, 7.66 Hz, 1H), 7.91 (app t, J=1.81 Hz, 1H), 7.76 (app dt, J=6.58, 8.59 Hz, 1H) 7.62 (t, J=7.79 Hz, 1H), 7.55 (ddd, J=1.21, 2.01, 7.79 Hz, 1H), 7.46 (br s, 1H), 7.34 (ddd, J=2.55, 9.40, 10.47 Hz, 1H), 7.23-7.18 (m, 1H), 6.26 (d, J=2.55 Hz, 1H), 6.11 (d, J=2.69 Hz, 1H), 5.23 (s, 2H), 4.62 (AB q, JAB=14.97 Hz, 2H), 1.96 (s, 3H). ES-HRMS m/z 429.1280 (M+H calcd for C22H18F2N2O5 requires 429.1257).
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>>[NH:1]1[C:9](=[O:10])[C:8]2[N:7]=[CH:6][N:5]([CH2:11][CH:12]([OH:13])[CH2:14][OH:15])[C:4]=2[N:3]=[CH:2]1
Reactant: O=c1[nH]cnc2nc[nH]c12
Reactant: OCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1[nH]cnc2c1ncn2CC(O)CO

Procedure:
Hypoxanthine is treated as in the procedure of Example 1 with glycidol in the presence of potassium carbonate to give 1-(hypoxanthine-9-yl)-2,3-propandiol. The resulting 1-(9-hypoxanthine)-2,3-propandiol is treated with dimethoxytrityl chloride in pyridine as in Example 2 to give 1-(9-hypoxanthine)-3-O-dimethoxytrityl-2-propanol. The resulting 1-(9-hypoxanthine)-3-O-dimethoxytrityl-2-propanol is phosphitylated with chloro-β-cyanoethoxy-N,N-diisopropylaminophosphine as per Example 3 to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=2)=[O:20])=[CH:14][C:13]=1[O:29][CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1.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:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)=[O:20])=[CH:14][C:13]=1[O:29][CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(CC(=O)Nc2cccc(I)c2)ccc1OCCNC(=O)OC(C)(C)C
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: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CC(=O)Nc2cccc(-c3ccccc3)c2)ccc1OCCNC(=O)OC(C)(C)C
Yield: 77.3 %

Procedure:
Intermediate 4 (500 mg) is dissolved in tetrahydrofuran (10 ml), and thereto are added tetrakis(triphenylphosphine)palladium (0) (110 mg), phenylboronic acid (230 mg), cesium carbonate (1.2 g) and water (2 ml), and the mixture is heated under reflux for 18 hours under argon atmosphere. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-[2-(tert-butoxycarbonylamino)ethoxy]-3-methoxy-N-(3-phenylphenyl)phenylacetamide (350 mg). This product is treated with 10% hydrogen chloride-methanol to give the desired compound (210 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:18]1(O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:18]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a solution of methyl 4-(4-hydroxyphenyl)benzoate (3.00 g) and cyclohexanol (1.58 g) in tetrahydrofuran (60 ml) was added dropwise diethyl azodicarboxylate (2.48 ml) at 0-10° C. under nitrogen atmosphere, and the mixture was stirred at ambient temperature for 4 hours. After concentration, to the residue was added ethyl acetate (50 ml) and n-hexane (10 ml), and the resulting precipitate was removed by filtration and discarded. To the filtrate was added silica gel (12 g) and the mixture was evaporated. The residue was purified by column chromatography on silica gel (80 g) eluting with a mixed solvent of 5% ethyl acetate in n-hexane to give methyl 4-(4-cyclohexyloxyphenyl)benzoate (1.79 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][NH2:34])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](C1C=CC([O:44][C:45](=O)[NH:46][C:47]2[O:51][N:50]=[C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=2)=CC=1)([O-])=O>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[CH2:33][NH:34][C:45]([NH:46][C:47]4[O:51][N:50]=[C:49]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=4)=[O:44])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4CN)ccc32)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCn2ncc3cc(Oc4ccc(F)cc4CNC(=O)Nc4cc(C(C)(C)C)no4)ccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
A solution of 4-{2-[5-(2-aminomethyl-4-fluorophenoxy)-indazol-1-yl]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (0.050 g, 0.107 mmol) dissolved in dichloromethane (2 mL) was treated with (3-tert-butyl-isoxazol-5-yl)-carbamic acid 4-nitrophenyl ester (0.081 g, 0.266 mmol) and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (60 mL), washed with 1N NaOH (5 mL), water (2×10 mL), brine, dried over MgSO4, and concentrated under reduced pressure. The residue was chromatographed eluting with acetone/hexanes (2:3, then 1:1) to afford 0.056 g of product (83% yield).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH2:7][C:6]1=NCCC2.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[C:11]([N:1]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)Cl
Reactant: C1CN=C2CCCN2C1
Solvent: ClCCl
Product: CCOC(=O)n1cccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of compound ◯3 (10.43 g, 20 mmol.) in dichloromethane (100 ml) at 0° C. was added DBN (1,5-diazabicyclo[4,3,0]non-5-ene) (4.96 g, 40 mmol.) followed by a solution of ethyl chloroformate (3.42 g, 32 mmol.) in dichloromethane (20 ml). After completion of the transformation to the N-carboethoxy derivative 4 (approximately 1 hour), an additional equivalent of DBN (2.48 g, 20 mmol.) was added and the reaction mixture was stirred at 25° C. for 20 hours and evaporated to dryness. Chromatographic purification of the residue on silica gel (chloroform/ethyl acetate; 9/1) afforded the N-carboethoxy pyrrole ◯5 (α, β-anomeric mixture) as a white foam (10 g, 84% from ◯3 ). The structure was confirmed by CHN elemental analysis and NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[C:19]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH2:22][CH2:23][NH:24][CH:25]3[CH3:30])=[C:18]([CH3:31])[O:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[C:26](=[CH:27][CH:28]=[CH:29][C:20]=4[C:19]4[C:15]([CH3:14])=[N:16][O:17][C:18]=4[CH3:31])[CH:25]3[CH3:30])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1noc(C)c1-c1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1noc(C)c1-c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(3,5-Dimethyl-isoxazol-4-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:7][C:8]3[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:9]=3)[CH:24]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Product: Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (10 mg, 0.029 mmol) and 4-chlorobenzoyl chloride (6 mg, 0.035 mmol) similar to Example 139 and isolated as a white solid (7 mg, 50%). 1H NMR (CDCl3): 8.77 (d, J=6.0 Hz, 2H), 8.29 (d, J=6.0 Hz, 2H), 8.00 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.81 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.35 (s, 2H), 7.01 (s, 1H), 6.75 (s, 1H), 2.30 (2, 3H).