Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=O)=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:34].CN(C=O)C>O=P(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([Cl:34])(=[O:31])=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1cccc(-c2ccc(S(=O)(=O)O)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1cccc(-c2ccc(S(=O)(=O)Cl)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 75 °C

Procedure:
4-(6-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-2-yl)benzenesulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl3 (30 mL) followed by the addition of SOCl2 (3 mL) and DMF (100 μl). The reaction mixture was heated at 70-80° C. for 15 min. The volatiles were evaporated and then re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and used for sulfonylation immediately. ESI-MS m/z calc. 456.0, found 457.1 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH3:16])[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-]>CCOCC>[CH3:16][C@H:4]([CH2:5][CH2:6][CH2:7][C@H:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][OH:2]
Reactant: COC(=O)[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CO
Reaction time: 0.5 h
Yield: 100 %

Procedure:
2(R),6(R),10-trimethylundecanoic acid methyl ester (172 mg., [α]D25 -11.30°) and lithium aluminum hydride (170 mg.) in absolute ether (20 ml.) were refluxed with stirring for 2 1/2 hours. The reaction mixture was cooled in an ice-bath and excess of hydride was destroyed by carefully adding water followed by 30 ml. of 1 N aqueous H2SO4. The aqueous phase was extracted with ether (3 × 40 ml.) and the combined ether extract was washed with water (3 × 30 ml.) and dried (MgSO4). The crude product (155 mg.) was purified by evaporative distillation to give 152 mg. (100% yield) of 2(R),6(R),10-trimethylundecan-1-ol as a colorless liquid, b.p. 100°-102° C./0.08 mm Hg.; [α]D25 + 6.09° C. (c 2.0366, hexane).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[C:15]([CH3:20])[N:14]=1>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:17]1[CH:18]=[C:13]([Cl:12])[N:14]=[C:15]([CH3:20])[N:16]=1)[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1cc(Cl)nc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.8 %

Procedure:
To a solution of dimethyl malonate (0.39 mL, 3.37 mmol) in THF (20 mL) was added sodium hydride (60% dispersion in oil, 138 mg, 3.37 mmol) portionwise. The reaction mixture was stirred for 10 minutes at r.t. then 4,6-dichloro-2-methylpyrimidine (500 mg, 3.07 mmol) was added and the mixture heated to reflux for 2 h. The resulting suspension was concentrated in vacuo, triturated with Et2O (3×30 mL) and the mother liquors were evaporated in vacuo to yield the title compound (300 mg, 40%) as an off-white solid. LCMS (ES+) 259.0 (M+H)+, RT 2.93 minutes (90% purity) (Method 2).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11](=[O:14])[CH2:12]Br)[CH:9]=[CH:10][C:4]=2[C:3]=1[CH3:15].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:11](=[O:14])[CH2:12][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[CH:9]=[CH:10][C:4]=2[C:3]=1[CH3:15]
Reactant: Cc1c(Br)sc2cc(C(=O)CBr)ccc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1c(Br)sc2cc(C(=O)Cn3ccnc3)ccc12
Yield: 32.9 %

Procedure:
A mixture of 2-bromo-6-bromoacetyl-3-methylbenzo[b]thiopene (1.74 g.), imidazole (0.34 g.) and sodium carbonate (1.50 g.) in acetone (20 ml.) was heated under reflux for 2 hours and then evaporated. Water (50 ml.) was added to the residue and the mixture was extracted several times with ethyl acetate. The combined extracts were dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from isopropanol/petrol (b.p. 60°-80°) to give 2-bromo-6-(1-imidazolyl)acetyl-3-methylbenzo[b]thiophene (0.55 g.), m.p. 184°-186° C.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[C:20]([NH:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cccc2c1COC(N[C@@H]1CCc3ccccc31)=N2

Procedure:
The title compound, MS (ISP) m/e=358.0 [(M+H)+], was prepared from (R)—N2-indan-1-yl-4H-benzo[d][1,3]oxazine-2,5-diamine (example 2) and methanesulfonyl chloride according to the procedure described for example 5.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:1]([C:5]1[CH:10]=[C:9]([C:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:9]2[CH:8]=[C:7]([CH3:11])[C:6]([OH:12])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)=[O:23])[CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: O=C(Cl)CCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)CCCCCCCCC(=O)c2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
18 g (110 mmol) of 2-tert-butyl-6-methylphenol are reacted with 10.7 g (50 mmol) of decanedioic acid chloride in the presence of 27.5 g (200 mmol) of aluminium chloride by the method described in Example 2 to give the corresponding 1,10-di(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)-1,10-decanedione. 19.2 g (78% of theory) of the product of melting point 165°-168° C. are obtained. The vibration band of the CO groups in the infra-red spectrum appears at 1660 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Yield: 79 %

Procedure:
A solution of tert-butyl {3-[(3-nitrobenzyl)amino]phenyl}carbamate (100 mg, 0.3 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (110 mg, 79%) as a solid. LCMS for C13H14N3O2 (M+H)+: m/z=244.0.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[CH2:11]([NH:13][CH2:14][CH2:15][CH3:16])[CH3:12].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:11]([N:13]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)[CH2:14][CH2:15][CH3:16])[CH3:12]
Reactant: CCCNCC
Reactant: OCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CC)Cc1ccc(CO)cc1
Reaction time: 48 h
Yield: 52.9 %

Procedure:
A mixture of 5 g of [4-(chloromethyl)phenyl]methanol, 5.56 g of N-ethylpropan-1-amine, 5.29 g of potassium iodide and 4.41 g of K2CO3 in 200 ml of acetonitrile is left to stir at AT for 48 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water, the mixture is extracted with DCM, the organic phase is dried over Na2SO4, and the solvent is evaporated off under vacuum. 3.5 g of the expected compound are obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:29][CH2:30][CH3:31])[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26](Cl)=[O:27])=[O:19])=[CH:13][CH:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1>>[CH2:1]([N:3]([CH2:4][CH3:5])[C:26]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[C:18]([N:17]([C:14]1[CH:15]=[CH:16][C:11]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)=[CH:12][CH:13]=1)[CH2:29][CH2:30][CH3:31])=[O:19])=[O:27])[CH3:2]
Reactant: CCNCC
Reactant: CCCN(C(=O)C1CCCCC1C(=O)Cl)c1ccc(-n2ccnc2)cc1
Product: CCCN(C(=O)C1CCCCC1C(=O)N(CC)CC)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 16, react diethylamine with 2-[[[4-(1H-imidazol-1-yl)phenyl](propyl)amino]-carbonyl]cyclohexanecarbonyl chloride to obtain the title compound.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:18]([O:24]CC)(=O)[CH2:19][C:20]([CH3:22])=O>>[CH2:1]([N:13]1[CH2:14][CH2:15][CH2:16][N:17]=[C:20]([CH3:22])[CH2:19][C:18]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCNCCCN
Product: CCCCCCCCCCCCN1CCCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 242.1 g (1 mole) of N-dodecyl-1,3-propylenediamine and 130.1 g (1 mole) of ethyl acetoacetate. At 150° to 160° C., 18 g of water and 46 g of ethanol were distilled off to obtain 1-dodecyl-4-methyl-3,6,7,8-tetrahydro-1,5-diazocin-2-one.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[CH2:13](I)[CH2:14][CH3:15].[H-].[Na+]>>[CH2:13]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)[CH2:14][CH3:15]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1c(=O)oc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of isatoic anhydride (100 g) and propyl iodide (66 ml) in dimethylfomamide (600 ml) at 0° C., under nitrogen, was added sodium hydride (28 g of a 55% dispersion in mineral oil) portionwise. The mixture was allowed to warm to room temperature and stirred for 18 h. The solvent was then removed in vacuo and the residue partitioned between ethyl acetate (1000 ml) and water (500 ml). The organic phase was separated, washed with brine (2×500 ml), dried (MgSO4) and evaporated. The residue was triturated with anhydrous diethyl ether to give the title compound (57 g). 1H NMR (360 MHz, CDCl3) δ1.06 (3H, t, J=7.5 Hz), 1.75-1.86 (2H, m), 4.01-4.05 (2H, m), 7.17 (1H, d, J=8.5 Hz), 7.26-7.32 (1H, m), 7.73-7.78 (1H, m), 8.17 (1H, dd, J=7.9 and 1.7 Hz). MS (CI) m/e 205 [MH]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:38])[C@@H:5]([NH:10][C:11]([N:13]1[CH2:19][CH:18]([OH:20])[C@@H:17]([NH:21][C:22](=[O:36])[C@@H:23]([NH:28]C(OC(C)(C)C)=O)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:15][C@H:14]1[CH3:37])=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8]>O1CCOCC1.CO>[CH3:2][O:3][C:4](=[O:38])[C@@H:5]([NH:10][C:11]([N:13]1[CH2:19][CH:18]([OH:20])[C@@H:17]([NH:21][C:22](=[O:36])[C@@H:23]([NH2:28])[CH2:24][CH:25]([CH3:26])[CH3:27])[CH2:16][CH2:15][C@H:14]1[CH3:37])=[O:12])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC[C@H]1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC[C@H]1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4.0 M HCl in dioxane (8 ml) was added to a stirred solution (S)-2-({1-[(2R,5S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-2-methyl-6-hydroxy-azepan-1-yl]-methanoyl}-amino)-4-methyl-pentanoic acid methyl ester (490 mg, 0.93 mmol) in MeOH (8 ml). The reaction mixture was stirred for 2.5 h at RT, then was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (430 mg).
Reaction SMILES: C[O-].[Na+].[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:18]1[CH2:22][CH:21]=[CH:20][CH:19]=1>>[C:5]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:21]2[CH:20]=[CH:19][CH:18]=[CH:22]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1=CCC=C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reaction time: 2 h
Yield: 82 %

Procedure:
78.0 g (0.24 mol) of sodium methylate solution were initially introduced into a 500 ml four-necked flask at 50° C. and 45.6 g (0.25 mol) of benzophenone were then added. After complete dissolution, 20 g (0.30 mol) of freshly distilled cyclopentadiene were added dropwise in the course of 30 min at 45-50° C. After the end of the addition, stirring was effected for a further 2 h at room temperature, a dark red suspension forming. This was filtered over a G3 frit and the solid was washed four times with 25 ml of ethanol each time. After drying in a vacuum from an oil pump, 47.1 g (0.20 mol; 82% yield) of red 6,6-diphenylfulvene were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Ni](Cl)Cl.[Zn].N1C=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccccc1Cl
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100 ml flask, 50 ml of dry pyridine, 4.28 g (0.025 mol) of 4-bromotoluene, 4.26 g (0.025 mol) of methyl 2-chlorobenzoate, 0.32 g (0.0025 mol) of anhydrous nickel chloride, 1.31 g (0.005 mol) of triphenylphosphine and 4.90 g (0.075 mol) of zinc powder were charged under a nitrogen atmosphere and stirred at room temperature for 30 minutes. The mixture was heated by an oil bath and reacted at 85° C. for 3 hours. The reaction solution was analyzed by gas chromatography. The results are shown in Table 1. The data confirming the structure are shown below.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:6].C([O-])(=O)C.[K+].Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH:8]1[NH:7][C:5](=[O:6])[C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:3]=1
Reactant: O=C(NC1Cc2ccccc2C1)c1cccc(Br)c1
Reactant: Brc1cccnc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1Cc2ccccc2C1)c1cccc(-c2cccnc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
100 mg of 3-bromo-N-indan-2-yl-benzamide, 88 mg bis-(pinacolato)-dibor, 93 mg potassium acetate and 48 mg PdCl(dppf) were dissolved in 6 ml DMF and stirred at 80° C. for 2 h. The solution was cooled to ambient temperature and 100 mg of 3-bromo-pyridine added. Then, further 24 mg of PdCl(dppf) were added and the mixture stirred at 80° C. for 3.5 h. The mixture was cooled to ambient temperature and diluted with 20 ml ethyl acetate. The crude mixture was washed three times with 5 ml of a saturated aqueous solution of Na2CO3 each and dried over MgSO4. The solvents were removed under reduced pressure and the residue purified by chromatography on silica gel using MTB. Yield 60 mg of a viscous oil. Rf(MTB)=0.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]2[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-].[K+].Cl[CH2:29][C:30]1[C:31]([CH3:36])=[N:32][O:33][C:34]=1[CH3:35]>C(#N)C>[CH3:36][C:31]1[C:30]([CH2:29][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=3)(=[O:9])=[O:10])=[CH:4][CH:3]=2)=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CC(C)CN(c1nccc(C(F)(F)F)n1)S(=O)(=O)c1ccc(O)cc1
Reactant: Cc1noc(C)c1CCl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)N(CC(C)C)c2nccc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 121.9 %

Procedure:
To a suspension of 4-hydroxy-N-(2-methylpropyl)-N-[4-(trifluoromethyl)-2-pyrimidinyl]benzenesulfonamide (31 mg, 0.083 mmol) and potassium fluoride on alumina (30 mg, 0.207 mmol) in acetonitrile (0.5 mL) stirred under nitrogen at room temperature was added a solution of 4-(chloromethyl)-3,5-dimethylisoxazole (12 mg, 0.083 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at 20° C. for 16 hours. The reaction mixture was filtered to remove the potassium fluoride on alumina and the filtrate evaporated. The sample was purified by mass directed autoprep (TFA modifier). The solvent was evaporated under a stream of nitrogen and then freeze-dried from water/dioxane to give the title compound (49 mg). LCMS (2 min, formic) Rt 1.35 min, m/z (ES+) 485 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25]/[CH:26]=[CH:27]/[CH2:28]Cl)[N:9]=2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH:31]([F:32])[F:33])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(C/C=C/CCl)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=C(Nc1cn(C/C=C/CN2CCOCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12

Procedure:
A solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-chlorobut-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (160 mg, 0.324 mmol) and morpholine (0.5 mL) in DMF (4 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, CH3CN/H2O=20% increasing to CH3CN/H2O=50% within 20 min; Detector, UV 254 nm. 35.4 mg product was obtained. This resulted in 35.4 mg (20%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a off-white solid. LCMS (Method 23) [M+H]+=544.0, RT=2.37 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.58 (d, 1H, J=2.8 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.94-5.84 (m, 1H), 5.79-5.69 (m, 1H), 4.82 (d, 2H, J=6.0 Hz), 3.56 (t, 4H, J=4.6 Hz), 2.96 (d, 2H, J=6.4 Hz), 2.40-2.30 (m, 4H).
Reaction SMILES: F[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH:13]([F:24])[CH2:14][CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.F[C:28](F)(F)N1CCN(C(F)CCC(C2C=CC=CC=2)=O)CC1>>[CH3:28][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH:13]([F:24])[CH2:14][CH2:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(CCC(F)N1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Reactant: O=C(CCC(F)N1CCN(C(F)(F)F)CC1)c1ccccc1
Product: Cc1ccc(CN2CCN(C(F)CCC(=O)c3ccccc3)CC2)cc1

Procedure:
γ-[4-(p-Fluorobenzyl)piperazino]-4-fluorobutyrophenone γ-[4-(p-Trifluoromethylpiperazino]-4-fluorobutyrophenone
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[C:23]1([C:33](O)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:33]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][N:24]=3)=[O:34])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)c1nccc2ccccc12
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3nccc4ccccc34)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and isoquinoline-1-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.33 (m, 1H), 1.47 (m, 1H), 1.56-1.74 (m, 2H), 1.81 (m, 1H), 1.93 (m, 1H), 3.00 (m, 1H), 3.21 (m, 1H), 4.26 (dd, 1H, J=10.1, 3.7 Hz), 4.82 (t, 1H, J=10.1 Hz,), 5.45 (m, 1H), 6.66 (d, 1H, J=8.0 Hz,), 6.95 (d, 1H, J=8.5 Hz), 7.50 (t, 1H, J=8.5 Hz,), 7.61 (m, 1H), 7.74-7.90 (m, 3H), 7.97 (br s, 1H), 8.02 (d, 1H, J=8.0 Hz), 8.28 (br s, 1H), 8.49 (d, 1H, J=5.8 Hz,), 10.94 (s, 1H). MS 466 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][C:15](=N)[CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH2:20][CH2:19]1)[CH2:6]2.[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[OH-].[Na+].ClCCl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH2:20][CH2:19]1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC(=N)NC[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNC[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
1 g of the product obtained in Step 1 (containing 47% amidine) is dissolved in 15 mL of methanol; the resulting solution is then cooled to 0° C. and 100 mg (2.61 mmol, 1.2 equivalents) of sodium tetraborohydride are added. Stirring is carried out overnight at ambient temperature, and then 5.3 mL of 20% aqueous sodium hydroxide solution and 20 mL of dichloromethane are added. Vigorous stirring is carried out for 15 minutes. The organic phase is then extracted, washed with water, dried over MgSO4, filtered and then evaporated to dryness. There is obtained 1 g of an oil which is purified by flash chromatography on 100 g of silica (eluant=dichloromethane/ethanol/NH4OH: 90/10/1) to yield 300 mg of expected product in the form of an oil.