Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].C(Cl)Cl>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[C:4](/[C:8](=[N:18]\[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1cccc(Br)c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a round-bottomed flask charged with 1-(3-bromophenyl)-2-fluoroethanone (11.42 g, 52.6 mmol) in THF (100 ml), was added (R)-2-methylpropane-2-sulfinamide (12.75 g, 105 mmol). Then tetraisopropoxytitanium (31.2 ml, 105 mmol) was added into the reaction mixture. The reaction mixture was stirred at ambient temperature under inert atmosphere overnight. The material was poured slowly into a vigourously stirring solution of ice water. The resulting suspension was stirred vigourously for 20 min. Then methylene chloride was added into the mixture and the overall mixture was allowed to stir an additional 30 min. The mixture was filtered through a pad of celite and the filter cake was washed with methylene chloride. The organic layer was separated and the remaining aqueous layer was extracted with methylene chloride three times. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in-vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column, eluting with a gradient of 0-15% EtOAc/hexane to give (R,E)-N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (9.69 g, 57.5% yield).
Reaction SMILES: [F:1][CH:2]([O:7][CH2:8][CH:9]=[CH2:10])[C:3]([F:6])([F:5])[F:4].[Cl:11][SiH:12]([Cl:14])[Cl:13]>C(Cl)(Cl)Cl>[F:1][CH:2]([O:7][CH2:8][CH2:9][CH2:10][Si:12]([Cl:14])([Cl:13])[Cl:11])[C:3]([F:6])([F:5])[F:4]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOC(F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: FC(OCCC[Si](Cl)(Cl)Cl)C(F)(F)F

Procedure:
Each hour, 1.5 liters (11.3 moles) of tetrafluoroethylallylether, 1.3 liters (12.7 moles) trichlorosilane and 10 ml of a catalyst solution are added to the reactor. The catalyst solution is prepared by dissolving 19.4 g of tetrachlorodioctenediplatinum (II) in 1000 ml of chloroform.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:12]([C:13]([Cl:33])=[O:14])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)cc(C(F)(F)F)c1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc(C(F)(F)F)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoic acid (601 mg), toluene (6 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (657 mg) as a yellow oily substance.
Reaction SMILES: Cl.[F:2][C:3]1[CH:13]=[CH:12][C:11]2=[C:14]3[C:4]=1[O:5][CH2:6][C@@H:7]([CH3:33])[N:8]3[C:9]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3C1CCCCO1)[CH3:16])=[N:10]2>O1CCOCC1.CO>[F:2][C:3]1[CH:13]=[CH:12][C:11]2=[C:14]3[C:4]=1[O:5][CH2:6][C@@H:7]([CH3:33])[N:8]3[C:9]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][NH:22]3)[CH3:16])=[N:10]2
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1[C@H](C)CO3
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c3c2n1[C@H](C)CO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
HCl (260 μL of a 4M solution in dioxane) was added to a solution of [(S)-1-((R)-6-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethyl][9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (93 mg, 0.21 mmol) in MeOH (1 mL) and the reaction was stirred at RT for 30 min. The crude reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 439 (71 mg, 96%) as a white solid. LCMS (Method K): RT 2.50 min [M+H]+ 354.0. 1H NMR (CD3OD, 400 MHz): δ 8.21 (1H, s), 8.07 (1H, s), 7.07 (1H, dd, J=8.8, 3.1 Hz), 6.93 (1H, dd, J=11.9, 8.8 Hz), 5.89 (1H, br s), 4.88 (1H, qdd, J=6.6, 2.3, 1.6 Hz), 4.45 (1H, dd, J=11.8, 1.6 Hz), 4.22 (1H, dd, J=11.8, 2.3 Hz), 1.76 (3H, d, J=7.0 Hz), 1.44 (3H, d, J=6.6 Hz)
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([SH:23])([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][N:10]=1)[C:7]#[N:8])([OH:3])=[O:2]>C(O)CC(C)C>[CH3:7][CH:6]([CH3:9])[CH2:5][CH2:4][O:2][C:1]([CH2:4][CH2:5][C:6]([SH:23])([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH2:12][CH2:11][N:10]=1)[C:7]#[N:8])=[O:3]
Reactant: COc1cc2c(cc1OC)C(C(S)(C#N)CCC(=O)O)=NCC2
Solvent: CC(C)CCO
Product: COc1cc2c(cc1OC)C(C(S)(C#N)CCC(=O)OCCC(C)C)=NCC2

Procedure:
Following the procedure described in Example 19 but starting from 1.67 g. of α-(2-carboxyethyl)-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile and 5 ml. of isoamyl alcohol, 1.7 g. of α-[2-(3-methyl-butoxycarbonyl)-ethyl]-mercapto-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl-acetonitrile are obtained, melting at 120° C. after recrystallization from isopropanol.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[O:10]2)=[CH:5][CH:4]=1.[H-].[Na+].C(S)C.Cl>CN(C)C=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[O:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2OC3(CCN(C)CC3)c3ccccc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: CN1CCC2(CC1)OC(c1ccc(O)cc1)c1ccccc12
Temperature: 0 °C

Procedure:
A mixture of 1.0 g. of 1,3-dihydro-3-p-methoxyphenyl-1'-methylspiro[isobenzofuran-1,4'-piperidine] (Example 12), 1.0 g. of a 57% sodium hydride dispersion, and dimethylformamide is stirred under nitrogen. To the stirring mixture is rapidly added 2.0 ml. of ethanethiol. The mixture is refluxed under nitrogen for 4 hours, cooled, poured into ice-water, and acidified with 1N hydrochloric acid. The product is collected, dried, and dissolved in boiling dimethyl sulfoxide, and the solution is filtered. Upon cooling small colorless crystals, m.p. 273° dec., separate.
Reaction SMILES: [N:1]([C@@:4]12[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][C@@H:9]1[CH2:8][CH:7]=[CH:6][CH2:5]2)=C=O.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1.[ClH:40]>C1C=CC=CC=1>[ClH:40].[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]1[C@:4]2([NH2:1])[CH2:5][CH:6]=[CH:7][CH2:8]1
Reactant: COc1ccc2c(c1)[C@@]1(N=C=O)CC=CC[C@H]1CC2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [K+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)[C@@]1(N)CC=CC[C@H]1CC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 53 %

Procedure:
To a solution of the product from Example 125 (1.5 g) in benzene (10 ml) was added 50% aqueous KOH solution and a trace of 18-crown-6. The solution was stirred at room temperature for 96 hours. The reaction was treated with aqueous 3N HCl solution (300 ml) and extracted into ether (2×50 ml), dried and concentrated. The residue was converted to give the title compound as a white solid (0.83 g, 53%) mp 270° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])[CH3:3].Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:17][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:6]1[C:7](=[O:9])[CH2:8][N:4]([CH:2]([CH3:1])[CH3:3])[C:5]1=[O:18])[O:16][CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(C)N1CC(=O)N(c2ccc(O)cc2F)C1=O
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1COc1ccc(N2C(=O)CN(C(C)C)C2=O)c(F)c1

Procedure:
By the method of Example 1, Step I, 0.60 g (0.0024 mole) of 1-(1-methylethyl)-3-(2-fluoro-4-hydroxy-phenyl)imidazolidin-2,4-dione, 1.24 g (0.0048 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step E), and 0.5 g (0.0036 mole) of potassium carbonate were reacted in 25 mL of 2-butanone. After purification, 1.04 g of methyl 2-[2-3-fluoro-4[1-(1-methylethyl)imidazolidin-2,4-dion-3-yl]phenoxymethyl]-5-chlorophenoxy]propionate was isolated as a yellow oil. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.24 (d, 6H, JHH =8 Hz); 1.64 (d, 3H, JHH =8 Hz); 3.68 (s, 3H); 3.96 (s, 1H); 4.44 (septet, 1H, JHH =8.0 Hz); 5.04 (q, 1H, JHH =8.0 Hz); 5.24 (s, 2 H); 6.80-7.34 (m, 5H) .
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1.N([O-])=O.[Na+].[I-:26].[K+].[OH-].[Na+]>C(O)(=O)C.O>[I:26][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1
Reactant: CC1(C)C=C(c2ccc(N)cn2)c2cc(C#N)ccc2O1
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C=C(c2ccc(I)cn2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
9.5 g of 4-(5-amino-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile were dissolved in 150 ml of acetic acid and 100 ml of water. 3.16 g of sodium nitrite in 10 ml of water were added at such a rate as to keep the temperature below 5° C. After 15 minutes 23 g of potassium iodide in 20 ml of water were added and the mixture was stirred at room temperature for 1 hour. The mixture was then poured into 1 l of 2M sodium hydroxide solution and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution to give 4.78 g of 4-(5-iodo-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile which was used without further purification.
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O.P(Br)(Br)[Br:18]>O>[Cl:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:18]
Reactant: OCCCCCCCCCC=CC(F)(F)Cl
Reactant: BrP(Br)Br
Solvent: O
Product: FC(F)(Cl)C=CCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 197.9 %

Procedure:
Under an argon atmosphere 4.8 grams (0.019 mole) of 12-chloro-12,12-difluoro-10-dodecen-1-ol (prepared in Example 1) was stirred, and 0.65 ml (0.007 mole) of phosphorus tribromide was added dropwise using a syringe. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. After this time the reaction mixture was poured into 100 ml of ice/water with stirring. An additional 300 ml of water was added to the gelatinous mixture, and stirring was continued for 18 hours. The mixture was extracted with pentane, and the extract was washed with aqueous sodium bicarbonate. Additional water was added to help separate the layers. The organic layer was washed with an aqueous solution saturated with sodium chloride and then was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure yielding 4.4 grams of 12-chloro-12,12-difluoro-10-dodecenyl bromide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: CC1C=[C:5](C)[N:4]([C:8](=[O:22])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N=1.[CH2:23]([C:25]1[O:29]C(N)=[N:27][N:26]=1)[CH3:24]>>[CH2:23]([C:25]1[O:29][C:5]([NH:4][C:8](=[O:22])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:27][N:26]=1)[CH3:24]
Reactant: Cc1cc(C)n(C(=O)C(c2ccccc2)c2ccccc2)n1
Reactant: CCc1nnc(N)o1
Product: CCc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 123-125° C. and MS: m/e=308.2 (M+H+) was prepared in accordance with the general method of example 48a from 1-(3,5-dimethyl-pyrazol-1-yl)-2,2-diphenyl-ethanone and 5-ethyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.Cl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([CH:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3CCNCC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 1D (100 mg, 0.23 mmol) in dichloromethane (2 mL), was added hydrogen chloride-saturated ethyl acetate (2 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified by preparative HPLC (Agilent AD/SP/C18-25/011 reversed phase column) eluting with a gradient of 0.01% trifluoroacetic acid in water to 1:1 methanol/acetonitrile to afford the title compound as the hydrochloride salt. LCMS: 327.1 (M+H)+; 1H NMR (400 MHz, DMSO-d6/D2O): δ 1.77-1.87 (m, 2H), 2.23 (d, J=12 Hz, 2H), 3.0-3.06 (m, 2H), 3.33-3.41 (m, 3H), 3.79 (s, 3H), 6.45 (s, 1H), 7.29-7.32 (m, 1H), 7.44-7.50 (m, 2H), 8.99 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]C1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cc(O)cc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Yield: 627.6 %

Procedure:
A mixture of 3-bromo-5-hydroxybenzoic acid (3.8 g, 18 mmol) and p-TsOH (350 mg, 2.0 mmol) in MeOH (100 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature. Saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with dichloromethane (100 mL×3). The combined organic layers were washed with brine and water, dried over anhydrous Na2SO4, and concentrated under vacuum to afford methyl 3-bromo-5-hydroxybenzoate (2.9 g, 73%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.74 (t, J=1.5 Hz, 1H), 7.50 (dd, J=1.2, 2.4 Hz, 1H), 7.23 (t, J=2.1, 1H), 5.68 (brs, 1H), 3.92 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[N:12]([CH3:22])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=4)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:71][O:72][C:73]1[CH:74]=[C:75]([CH:77]=[CH:78][C:79]=1[O:80][CH3:81])[NH2:76]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:21][O:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:22])[C:11]([C:8]1[N:6]3[N:7]=[C:2]([NH:76][C:75]4[CH:77]=[CH:78][C:79]([O:80][CH3:81])=[C:73]([O:72][CH3:71])[CH:74]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=1)=[CH:19]2
Reactant: COc1ccc2c(c1)cc(-c1cnc3ccc(Cl)nn13)n2C
Reactant: COc1ccc(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc2c(c1)cc(-c1cnc3ccc(Nc4ccc(OC)c(OC)c4)nn13)n2C
Temperature: 110 °C
Yield: 96.8 %

Procedure:
To a solution of 6-chloro-3-(5-methoxy-1-methyl-1H-indol-2-yl)imidazo[1,2-b]pyridazine (49 mg, 0.157 mmol, 1.0 equiv), xantphos (18 mg, 0.0313 mmol, 0.2 equiv), palladium acetate (4 mg, 0.0156 mmol, 0.1 equiv), and potassium carbonate (433 mg, 3.13 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (26 mg, 0.172 mmol, 1.1 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 40 mg, 0.152 mmol of the yellow solid, 59%.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]([NH:21][C@@H:22]([CH2:28][OH:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:15]([O:14][C:12](=[O:13])[CH2:11][C@H:10]([C:19]1[O:29][CH2:28][C@@H:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:21]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H](CO)NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.7 %

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-({[(1S)-2-ethoxy-1-(hydroxymethyl)-2-oxoethyl]amino}carbonyl)hexanoate (preparation 151) (10.0 g, 24.2 mmol) in THF (80 ml) was treated with Burgess reagent (6.34 g, 26.6 mmol) and heated at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and stored in a fridge for 3 days. The solvent was removed under reduced pressure. The crude material was ourififed on a silica column eluting with a solvent gradient of pentane:EtOAc (100:0) gradually changing to (80:20) to afford the title compound as a colourless oil (9.26 g, 97%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH:11]([CH2:12][CH2:13]3)[CH:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1.C(O)(C)C>Cl>[Cl:19][C:5]1[C:6]([NH:8][C@H:9]2[CH:14]3[CH2:15][CH:11]([CH2:12][CH2:13]3)[C@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: NC(=O)C1C2CCC(C2)C1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4C5CCC(C5)[C@H]4C(N)=O)n3)cc2CC1
Reaction time: 2.5 h

Procedure:
Into a microwave vial was placed 3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid amide (90.0 mg, 0.000299 mol) and 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (60 mg, 0.0003 mol) in isopropyl alcohol (6 mL, 0.08 mol). Several drops of 4M HCl were added to the reaction mixture and the contents subjected to microwave conditions (120° C., 20 min). Total reaction time was 150 min at 120° C. A solid had precipitated out of the reaction mixture overnight and was collected by filtration to give (2R,3S)-3-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]heptane-2-carboxylic acid amide; hydrochloride. 1HNMR (400 MHz, DMSO-d6) δ 10.62 (broad s, 1H), 10.15 (broad s, 1H), 9.19 (broad s, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.62 (dd, 1H, J=8.6, 18.7 Hz), 7.36 (d, 1H, J=6.6 Hz), 7.29 (s, 1H), 7.17 (d, 1H, J=8.6 Hz), 4.07 (q, 1H, J=8.6 Hz), 3.74 (m, 4H), 3.36 (m, 4H), 3.31 (s, 3H), 2.93-3.09 (m, 4H), 1.87 (d, 9.8 Hz), 1.55 (m, 2H), 1.28 (m, 2H), 1.18 (d, 1H, J=9.8 Hz); MS (m/e) 485 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:29])[CH2:18][O:19][C:20]1[C:21]([CH3:28])=[CH:22][C:23]([CH2:26][NH2:27])=[N:24][CH:25]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:27]([CH2:26][C:23]3[CH:22]=[C:21]([CH3:28])[C:20]([O:19][CH2:18][CH:17]([F:29])[F:16])=[CH:25][N:24]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)ncc1OCC(F)F
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)F
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (360 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.3 mmol, Step-1 of Intermediate-1) and (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride (410 mg, 1.3 mmol, Amine-52) in a similar manner to Intermediate-2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH:19]=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[C:28]([Cl:31])[CH:27]=[CH:26][C:25]=2[F:32].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOC(C)=O>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([F:32])=[C:24]2[C:29]=1[CH:30]=[C:21]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[CH:9]=[N:10][N:11]([CH:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)[CH:12]=3)[CH:4]=1)[N:22]=[CH:23]2
Reactant: Nc1ncc(-c2cnn(C3CCN(C=O)CC3)c2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carbaldehyde (50.0 mg, 0.111 mmol) in THF (5 mL, 60 mmol), cooled to ≈0° C., LiAlH4 (1.0M solution in THF; 0.27 mL, 0.27 mmol) was added, and the reaction mixture was stirred at 0° C.→rt for 30 min. Sodium sulfate decahydrate (0.1 g, 0.4 mmol) and EtOAc were added and the reaction mixture was stirred for 10 min at rt. The solids were filtered off, and the filtrate was concentrated and purified on prep-TLC eluting with 5% 7M NH3 (MeOH)/DCM to give the title compound as pale yellow oil. MS (ES+): m/z=436.79/438.74 [MH+]. HPLC: tR=2.24 min (ZQ2, polar—5 min).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[N:14]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[N:14]1([CH2:19][CH2:20][CH2:21][NH:22][C:11]([C:8]2[CH:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:10][N:9]=2)=[O:13])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: O=C(O)c1cc(-c2ccco2)on1
Reactant: NCCCn1ccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCCn1ccnc1)c1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
To a solution of 5-furan-2-yl-isoxazole-3-carboxylic acid (7 mg) and 3-imidazol-1-yl-propylamine (0.005 mL) in DMF were added HOBt (8 mg), EDC (9 mg) and TEA (0.014 mL). The resulting solution was stirred at a room temperature for 18 hours, and then concentrated under reduced pressure. The resulting concentrate was purified with preparative HPLC to give 4 mg of 5-furan-2-yl-isoxazole-3-carboxylic acid (3-imidazol-1-yl-propyl)-amide (yield: 35%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([NH:12][NH2:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH2:14](O)C>C([O-])([O-])OCC>[Cl:1][CH2:2][C:3]1[N:4]2[CH:14]=[N:13][N:12]=[C:5]2[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CCO
Reactant: NNc1nc(CCl)nc2ccsc12
Agent: CCOC([O-])[O-]
Product: ClCc1nc2ccsc2c2nncn12
Temperature: 125 °C
Reaction time: 3 h

Procedure:
4. 15.7 g of 2-(chloromethyl)-4-hydrazinothieno[3,2-d]pyrimidine are suspended in 280ml of ethyl orthoformate. The suspension is heated (bath temp. 125° C.) while stirring and the ethanol which results is distilled off. After 3 h., the mixture is cooled to 0° C., the precipitate is filtered off and washed with ethanol. The product is dried in a vacuum. There are obtained 15.2 g of 5-(chloromethyl)thieno[2,3-e][1,2,4]triazolo[4,3-c]-pyrimidine. m.p. above 400° C. (dec.).