Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:26][C:27]([F:31])([F:30])[CH2:28]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:28][C:27]([F:31])([F:30])[F:26]
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Temperature: 100 °C
Yield: 569 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate (2 g, 0.57 mmol) and K2CO3 (1.58 g, 0.011 mol) in dry DMF (20 mL), slowly added trifluoroethyl iodide (7.2 g, 3.39 ml, 0.034 mol) at room temperature. Upon completion of the addition, the reaction mixture was slowly heated to 100° C. for 4 h. Upon completion, the reaction mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic layer were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1.4 g, 60% yield). 1HNMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[N:5]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH:6]=[CH:7][N:8]=1.Cl.S1C=CC=C1.[H][H]>CO.[Pd].O>[CH3:2][S:3][C:4]1[N:5]([CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:7][N:8]=1
Reactant: CSc1nccn1C(c1ccccc1)c1ccc(N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: c1ccsc1
Solvent: CO
Solvent: O
Product: CSc1nccn1C(c1ccccc1)c1ccc(N)c(N)c1
Yield: 100 %

Procedure:
(a-5) A mixture of 5.5 parts of (+)-4-[[2-(methylthio)-1H-imidazol-1-yl]-phenylmethyl]-2-nitrobenzenamine monohydrochloride, 24 parts of concentrated hydrochloric acid, 2 parts of a solution of thiophene in methanol 4%, 120 parts of methanol and 100 parts of water was hydrogenated at normal pressure and at 0° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and treated with an ammonium hydroxide solution. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated, yielding 5.6 parts (100%) of (+)-4-[[2-(methylthio)-1H-imidazol-1-yl]phenylmethyl]-1,2-benzendiamine as a residue (int. 143).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:3][CH:2]=1.Cl.O1CCOCC1.P(Cl)(Cl)([Cl:28])=O.C([O-])(O)=O.[Na+]>C(#N)C.O>[Cl:28][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:9][N:10]=1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Clc1nnc(Cc2ccncc2)c2ccccc12
Temperature: 50 °C
Reaction time: 27 h

Procedure:
Under exclusion of air, 29 g (122 mmol) 4-(4-pyridylmethyl)-1 (2H)-phthalazinone [for preparation, see German Auslegeschrift no. 1061788 (published 23.7.1959)] in 450 ml acetonitrile is mixed with 61 ml HCl/dioxane 4N and 28 ml (306 mmol) phosphoryl chloride and stirred for 27 h at 50° C. To the white suspension, 119 g NaHCO3 in 1.45 l water is then added dropwise under ice cooling, and the mixture is stirred and the title compound filtered off. Anal. calc. (C14H10N3Cl) C 65.76%, H 3.94%, N 16.43%, Cl 13.86%; found C 65.40%, H 4.12%, N 16.45%, Cl 13.66%; FAB MS (M+H)+=256.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH2:6][P:7](=O)([O:11]CC)[O:8][CH2:9][CH3:10].S(Cl)([Cl:23])=O>CN(C=O)C>[Cl:23][P:7]([CH2:6][C:5]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)c1)OCC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(Cl)Cc1ccc([N+](=O)[O-])c(OC)c1

Procedure:
A solution of diethyl (3-methoxy-4-nitrobenzyl)phosphonate (Compound 1G, 5 g, 15.5 mmol) in thionyl chloride (50 mL, 690 mmol) was treated with catalytic amount of DMF and heated to reflux under nitrogen for 6 h. The mixture was concentrated under reduced pressure and co-evaporated with dichloroethane (50 mL) to give crude (ethyl chloro[(3-methoxy-4-nitrophenyl) methyl]phosphinate). This material was taken up in DCM (20 mL) and added to a solution of 2-propanol (4 mL, 52 mmol) and DIPEA (6 mL, 34.5 mmol) in DCM (20 mL). The resulting mixture was stirred at rt for 24 hrs. The solvents were evaporated and the residue was purified by column chromatography (SiO2, 5% methanol in dichloromethane) to give 3 g of the desired product as a light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.8 2(d, J=8.4 Hz, 1H), 7.1 (s, 1H), 6.92 (d, J=8.5 Hz, 1H), 4.6-4.4.75 (m, 1H), 4.05-4.08 (m, 2H), 3.93 (s, 3H), 3.18 (d, J=20 Hz, 2H), 1.18-1.25 (m, 9H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([C:14]3[CH:23]=[CH:22][C:17]4[O:18][CH2:19][CH2:20][O:21][C:16]=4[CH:15]=3)[OH:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: Brc1ccc2c(c1)OCCO2
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: OC(c1ccc2c(c1)OCCO2)c1ccc2c(c1)OCCO2
Yield: 86.4 %

Procedure:
2,3-dihydrobenzo[1,4]dioxine-6-carbaldehyde (0.87 g, 5.28 mmol), 6-bromo-2,3-dihydrobenzo[1,4]dioxine (1.25 g, 5.81 mmol), and n-butyl lithium (2.33 ml, 5.81 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give bis-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol as an oil (1.37 g, 86%): 1HNMR (CDCl3) 6.87-6.82 (m, 6H, Ar), 5.63 (d, J=3 Hz, 1H, CHOH), 4.22 (s, 8H, 2CH2CH2), 2.19 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1=COCCC1
Reactant: N#Cc1ccc2[nH]cnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A mixture of 90 (1.63 g, 11.4 mmol), 3,4-dihydro-2H-pyran (2.87 g, 34.2 mmol), and p-TsOH.H2O (196 mg, 1.14 mmol) in THF (60 mL) was stirred under nitrogen at 80° C. for 18 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography with eluting with petroleum ether/EtOAc (1:1) to afford 2.48 g (95.9%) of 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (92) as yellow oil: MS (ESI) m/z=228.1 [M+1]+.
Reaction SMILES: [CH:1]12BC(C[CH2:7][CH2:8]1)CCC2.C(Br)C#C.[OH-].[Na+].Cl[C:17]1[N:22]=[N:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[C:19]([O:31][CH3:32])[CH:18]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O1CCCC1>[CH:7]1([C:17]2[N:22]=[N:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([O:31][CH3:32])[CH:18]=2)[CH2:8][CH2:1]1
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
Reactant: B1C2CCCC1CCC2
Agent: [Pd]
Agent: C#CCBr
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C2CC2)nnc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 70.7 %

Procedure:
To a tetrahydrofuran solution (2.94 mL) containing of 9-borabicyclo[3.3.1]nonane (0.5 mol/l, 1.47 mmol) was added 87.5 mg (0.735 mmol) of propargyl bromide, and the resulting mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, 0.74 mL (2.2 mmol) of 3 mol/L aqueous sodium hydroxide solution was added to the mixture, and the resulting mixture was stirred at room temperature for 70 minutes. To the mixture were successively added 168 mg (0.669 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1) and 38.7 mg (0.00334 mmol) of tetrakis(triphenylphosphine)-palladium, and the resulting mixture was refluxed overnight. The reaction mixture was allowed to stand for cooling, water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, and washed successively with water and brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography to obtain 121 mg (0.473 mmol, Yield: 70.1%) of 6-cyclopropyl-4-methoxy-3-(2-methylphenoxy)pyridazine.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[CH:12]=O.C([CH2:24][C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=[O:26])(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:24]/[C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: C#CCOc1ccc(C=O)cc1OC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Piperidine (158 mL, 1.59 mol) was added to a suspension of 3-methoxy-4-propargyloxybenzaldehyde (302 g, 1.59 mol) and 2-[(carboxyacetyl)amino]benzoic acid (322 g, 1.44 mol) in toluene (1.5 L). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (4 L) and water (1 L) at 50° C. and the solution was acidified with 50% aqueous AcOH. The precipitate was filtered and the crude product was recrystallised from EtOH (35 mL/g), filtered and washed with cooled EtOH to afford (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (309 g, 61%) as a yellow crystalline solid; mp 201-203° C.; δH (400 MHz, DMSO-d6) 3.59 (t, J=2.4 Hz, 1H, C≡CH), 3.84 (s, 3H, OCH3), 4.84 (d, J=2.4 Hz, 2H, OCH2), 6.81 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5,6=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.41 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.6, 55.9, 78.6, 79.1, 110.8, 113.5, 116.6, 120.4, 120.4, 122.2, 122.7, 128.2, 131.2, 134.0, 141.0, 141.5, 148.3, 149.3, 164.1, 169.5; HRMS (ESI) calculated for C20H17NO5 [M+H]+ 352.1179, found 352.1187; νmax 755, 1010, 1140, 1253, 1502, 1582, 1657, 3278, 3522 cm−1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]1=[O:19].Cl[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.C(N(CC)CC)C.CN(C)C=O>>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@:11]2([CH2:18][CH2:17][CH2:16][N:15]([C:21]3[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[CH2:14]2)[C:10]1=[O:19]
Reactant: O=C1N(c2ccccc2Cl)CC[C@]12CCCNC2
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1N(c2ccccc2Cl)CC[C@]12CCCN(c1ncc(Cl)cc1Cl)C2
Temperature: 180 °C

Procedure:
A mixture of (5S)-2-(2-chlorophenyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (18.2 mg, 0.0000604 mol), 2,3,5-trichloropyridine (16 mg, 0.000091 mol) and triethylamine (0.025 mL, 0.00018 mol) in N,N-dimethylformamide (0.4 mL, 0.005 mol) was irradiated with microwaves to heat the mixture to 180° C. for 20 min. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 410.1/412.1/414.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](C2C=CN=CC=2)=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=1.[CH2:29]([O:36]/[N:37]=[C:38]1\[CH2:39][CH2:40][C:41]2[C:46]\1=[CH:45][CH:44]=[C:43](B(O)O)[CH:42]=2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:29]([O:36]/[N:37]=[C:38]1\[CH2:39][CH2:40][C:41]2[C:46]\1=[CH:45][CH:44]=[C:43]([C:2]1[CH:3]=[N:4][N:5]([CH:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:14])[CH2:11][CH2:12]3)[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH:42]=2)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(OCc1ccccc1)N1CCC(n2cc(Br)c(-c3ccncc3)n2)CC1
Reactant: OB(O)c1ccc2c(c1)CC/C2=N\OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(n2ncc(-c3ccc4c(c3)CC/C4=N\OCc3ccccc3)c2-c2ccncc2)CC1
Temperature: 80 °C
Yield: 166.1 %

Procedure:
To benzyl 4-(4-bromo-3-(pyridin-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.32 g; Example 5, Step 1) in 10 mL acetonitrile and 3 mL water was added 0.315 g (E)-1-(benzyloxyimino)-2,3-dihydro-1H-inden-5-ylboronic acid (prepared as described in example 2, step 4) and 0.30 g potassium carbonate. The reaction mixture was purged with nitrogen and 84 mg tetrakis(triphenyphosphine)palladium(0) catalyst was added. The reaction mixture heated to 80° C. for 2 hours, filtered through celite, and the filter cake was washed with acetonitrile. The filtrate was evaporated under vacuum to yield crude product. The residue was purified by chromatography, eluting with ethyl acetate to afford 0.36 g (83% yield) product as a colorless oil. 1H NMR (CDCl3) was consistent with the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 598.3 by positive ESI.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1.COC.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC/C=C/CCC(=O)O)cc1
Agent: BrB(Br)Br
Agent: COC
Solvent: ClCCl
Product: O=C(O)CC/C=C/CCc1ccc(O)cc1
Reaction time: 4 h

Procedure:
E-7-(4-hydroxyphenyl)hept-4-enoic acid was prepared from E-7-(4-methoxyphenyl)hept-4-enoic acid by removal of the methyl ether with boron tribromide. Boron tribromide was added to a solution of E-7-(4-methoxyphenyl)hept-4-enoic acid in methylene chloride at −78° C. and stirred for four hours. The product, E-7-(4-hydroxyphenyl)hept-4-enoic acid, was obtained by aqueous work-up of the reaction mixture followed by chromatography on silica gel, and was fully characterized by spectroscopic methods (infrared and nuclear magnetic resonance) and combustion analysis.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[O:24][CH2:25][CH2:26][N:27]=2)[CH:19]=[CH:20][C:21]=1[OH:22].CC1ON=C(CCC(OC)=O)C=1>>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[O:24][CH2:25][CH2:26][N:27]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1
Reactant: Oc1ccc(C2=NCCO2)cc1Cl
Reactant: Cc1cc(CCCCCCCBr)on1
Agent: COC(=O)CCc1cc(C)on1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2Cl)on1

Procedure:
5-{7-[2-Chloro-4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole [IX; R=CH3, R2, R3, R4, R5 and R6 =H, R1 =2-Cl, Y=(CH2)7, oxazole at 4-position] was prepared from 5-(7-bromoheptyl)-3-methylisoxazole (Example 9, part c) and 4,5-dihydro-2-(3-chloro-4-hydroxyphenyl)oxazole according to the procedure of Example 9, part (d), and was obtained in the form of a colorless solid, m.p. 120°-120.5° C. when recrystallized from methanol and further purified by chromatography.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][C:32]=2[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:35][CH:34]=2)[N:29](COCC[Si](C)(C)C)[N:28]=[C:27]3[NH:55][C:56](=[O:60])[CH2:57][CH2:58][CH3:59])=[CH:20]1.C(OCC)(=O)C>O1CCCC1>[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][C:32]=2[C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:37][CH:38]=2)[NH:29][N:28]=[C:27]3[NH:55][C:56](=[O:60])[CH2:57][CH2:58][CH3:59])=[CH:20]1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccoc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccoc3)cc12
Yield: 68.3 %

Procedure:
10.3 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[5-(3-furyl)-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 75 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 100 cm3 of saturated sodium hydrogen carbonate solution and with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.4 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is dried (90 Pa; 45° C.) to give 530 mg of N-[5-(3-furyl)-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:25]([CH3:26])=[CH:24][S:23][C:14]=2[N:15]=[C:16]([C:18]2[O:22][N:21]=[CH:20][CH:19]=2)[N:17]=1>>[O:22]1[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:25]([CH3:26])=[CH:24][S:23][C:14]=3[N:15]=2)=[CH:19][CH:20]=[N:21]1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1csc2nc(-c3ccno3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C@H:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH3:11])=[O:8])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[O:8])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2csc(Br)c2Cc2cccc(Cl)c2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@H](NC(=O)c1csc(Br)c1Cc1cccc(Cl)c1)c1ccc(C(=O)O)cc1

Procedure:
Methyl 4-[(S)-1-({[5-bromo-4-(3-chlorobenzyl)-3-thienyl]carbonyl}amino)ethyl]benzoate from Example 4, Step 1 (25.0 mg, 0.0507 mmol) was reacted under conditions similar to Example 1, Step 11. After trituration of the crude product in 1:1 EtOAc/hexane, the desired product was obtained as an off-white solid. MS (−APCI): m/z 476 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:27][CH2:28]3)[N:21]=[CH:22][C:15]=12
Reactant: CC(C)c1noc(N2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Temperature: 180 °C
Yield: 13.3 %

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 20 mg, 0.1 mmol), 4-chloro-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 22; 31 mg, 0.09 mmol) and potassium carbonate (14 mg, 0.1 mmol) in DMF (2 mL) was heated in a Biotage Optimizer microwave at 180° C. for 10 min. The mixture was cooled and filtered through Celite, concentrated and held under vacuum. The residue was purified on a silica column (ISCO 4 g) eluting with 0-3% methanol/dichloromethane to give 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (6 mg, 14%). Mass spectrum (ES) MH+=502.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(CC)CC)C.Cl>C(Cl)Cl.O.N1(C2C=CN=CC=2)CCCC1>[C:30]([O:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 95.1 %

Procedure:
A solution of methyl 3α-hydroxy-7-keto-5β-cholanoate (10 g, 24.72 mmoles) in methylene chloride (40 ml) was added with acetic anhydride (3.79 g, 37.1 mmoles), triethylamine (3.63 g, 36 mmoles) and 4-pyrrolidino-pyridine (0.11 g, 0.74 mmoles) and the reaction mixture was left to react for 3 hours under strong magnetic stirring, then it was diluted with methylene chloride (50 ml) and water (50 ml) and acidified with 10% hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic phases were washed with brine (1×30 ml), dried over sodium sulfate and concentrated under vacuum. The residue (11.0 g) was subjected to flash chromatography on silica, eluting with methylene chloride/methanol 99:1, to obtain 10.5 g of a pure product (95%).