Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.OC=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4N(CC)N=C(C)C=4)=[O:26])=[CH:20][CH:19]=3)=[O:17])[CH:14]=2)[NH:9][C:8]1=[O:35]>C1COCC1>[O:35]=[C:8]1[CH2:7][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[CH3:27])=[CH:20][CH:19]=3)=[O:17])[CH:14]=2)[NH:9]1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)CC(=O)N3)cc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
A dry 25 mL flask was charged with acetyl chloride (0.209 g, 2.67 mmol) and THF (10 mL). 5-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 7, 0.512 g, 2.06 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The precipitate that formed was filtered and washed with THF affording N-[4-(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.503 g, 1.56 mmol, 83%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:29][CH3:30]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:29][CH3:30])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:14][CH3:15]
Reactant: CCI
Reactant: CCN1CCc2occ(C(=O)O)c2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc2c1C(=O)N(CC)CC2
Temperature: 85 °C
Yield: 80.4 %

Procedure:
To a stirred solution of potassium hydroxide (3.79 g, 67.6 mmol) in methyl alcohol (15 mL) under Nitrogen at 0° C. was added dropwise a solution of N-ethyl-2,4-piperidione (9.54 g, 67.6 mmol) in methyl alcohol (20 mL). The mixture was stirred at 0° C. for 1 hour, then a solution of ethyl bromopyruvate (8.9 mL, 71 mmol) in methyl alcohol(50 mL) was added dropwise. After allowing the mixture to stir at ambient temperature for 2.5 hours, a 50% aqueous sodium hydroxide solution (10 mL) was added dropwise and stirring continued an additional 17 hours. After cooling in an ice water bath, the solution was acididfied and the methanol removed in vacuo. Ice water was added and the precipitate filtered and dried in vacuo to afford 4-oxo-5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-3-carboxylic acid (3.91 g). More acid (1.15 g) was obtained via extraction of the aqueous filtrate 2X wtih ethyl acetate, drying over magnesium sulfate, filtration, concentrating in vacuo, and purification on Silica gel (5% methyl alcohol/dichloromethane). A stirring mixture of 4-oxo-5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-3-carboxylic acid (4.94 g, 23.6 mmol), potassium carbonate (9.79 g, 70.8 mmol), cesium carbonate (770 mg, 2.4 mmol), and iodoethane (9.4 mL, 118 mmol) in N,N-dimethylformamide was heated at 85° C. for 15.5 hours. The reaction mixture was cooled and concentrated in vacuo. Ethyl acetate was added, the mixture filtered, the filtrate washed with water, and the organic layer dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (4.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCc2ccc(O)cc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)C(=O)CC3)nc1
Yield: 38.1 %

Procedure:
Using a method similar to Intermediate 1, using 6-hydroxy-1-indanone (J. Med. Chem. (1998), 41(7), 1068-1083) (2.07 g, 13.9 mmol), 6-chloronicotinamide (2.08 g, 13.3 mmol) and K2CO3 (2.75 g, 19.9 mmol) gives the title compound (1.36 g) as a yellow solid. Mass spectrum (ion spray): m/z=269 (M+1); 1HNMR (DMSO-d6): 8.57 (s, 1H), 8.26 (d, 1H), 8.02 (s, 1H), 7.63 (d, 1H), 7.46 (m, 2H), 7.33 (s, 1H), 7.14 (d, 1H), 3.10 (t, 2H), 2.68 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[S:19][CH:18]=[N:17][C:16]=2[CH3:20])=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1>>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[S:19][CH:18]=[N:17][C:16]=2[CH3:20])=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH2:5][NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1
Reactant: CSc1cc(Br)c(OCCc2scnc2C)c(C=O)c1
Reactant: NCCCNc1cc(=O)c2sccc2[nH]1
Agent: Cl
Product: CSc1cc(Br)c(OCCc2scnc2C)c(CNCCCNc2cc(=O)c3sccc3[nH]2)c1

Procedure:
5-(3-{3-bromo-5-methylsulfanyl-2-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzylamino}-propylamino)-4H-thieno[3,2-b]pyridine-7-one was prepared by reductive amination of the aldehyde prepared in Example 4 with amine XVIII following method C, Scheme 1. 1H NMR (400 MHz, CD3OD) δ 8.75 (1H, s), 7.70 (1H, d), 7.41 (1H, s), 7.29 (1H, s), 6.98 (1H, d), 5.59 (1H, s), 4.13 (2H, t), 3.72 (2H, s), 3.33 (4H, m), 2.65 (2H, t), 2.46 (3H, s), 2.40 (3H, s), 1.73 (2H, d).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:29])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:31](N)[CH2:32][NH2:33]>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([CH2:17][NH:16][CH2:15][CH2:14][CH2:13][C:12]([NH:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:33][CH2:32][CH2:31][N:2]=2)=[CH:8][CH:7]=1)=[O:29])(=[O:20])=[O:19]
Reactant: NCCN
Reactant: N#Cc1ccc(CCNC(=O)CCCNCS(=O)(=O)c2cccc(Cl)c2Cl)cc1
Agent: [S]
Product: O=C(CCCNCS(=O)(=O)c1cccc(Cl)c1Cl)NCCc1ccc(C2=NCCN2)cc1

Procedure:
Analogously to 13b), 4-[(2,3-dichlorobenzenesulphonyl)methylamino]-N-{2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl}butyramide was prepared from 0.297 g (0.654 mmol) of N-[2-(4-cyanophenyl)ethyl]4-[(2,3-dichloro-benzenesulphonyl)methylamino]butyramide, 42 mg (1.31 mmol) of sulphur and 1.8 ml of ethylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1(C(O)=O)[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1.CCN(CC)CC>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:8]#[N:9]
Reactant: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N#Cc1ccc(C2CCc3cncn32)c(Cl)c1

Procedure:
The 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (0.02 g, 70 pmol) is dissolved in DMSO (2 mL) and Et3N (0.2 mL) and heated at 100° C. for 2 h. The solution is evaporated to dryness and residue purified via reverse phase HPLC (5-100% MeCN/water w/0.1% TFA) to give 3-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile as a white solid. MS (ESI) m/z 244.2, 246.2 (M+H); 1H NMR (400 MHz, CDCl3) (TFA salt) δ ppm 2.60-2.73 (m, 1 H), 3.08-3.20 (m, 2 H), 3.22-3.36 (m, 1 H), 6.04 (dd, J=7.6, 5.8 Hz, 1 H), 6.91 (d, J=8.1 Hz, 1 H), 7.24 (s, 1 H), 7.61 (d, J=8.1 Hz, 1 H), 7.81 (d, J=1.5 Hz, 1 H), 8.53 (s, 1 H).
Reaction SMILES: [C:1](=[S:20])([S-:19])[S:2][CH2:3][CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7].[K+].C(O[C@@H:26]1[NH:29][C:28](=[O:30])[C@H:27]1[O:31][CH3:32])(=O)C.O1CCOCC1>O.P([O-])([O-])([O-])=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:6]([NH:5][CH2:4][CH2:3][S:2][C:1]([S:19][C@H:26]2[NH:29][C:28](=[O:30])[C@@H:27]2[O:31][CH3:32])=[S:20])=[O:7])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=C(NCCSC(=S)[S-])OCc1ccc([N+](=O)[O-])cc1
Reactant: CO[C@@H]1C(=O)N[C@H]1OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@H]1C(=O)N[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of 422 mg of potassium 2-p-nitrobenzyloxycarbonylaminoethyl trithiocarbonate in 1 ml of water is added dropwise at room temperature under, a nitrogen atmosphere to a solution of 159 mg (1 mmole) of (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine in 3 ml of phosphate buffer of a pH of 7 and 0.2 ml of dioxan, and the mixture is stirred at the same temperature for 30 minutes. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel and yields the title compound with the following
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([CH3:18])=[CH:10][C:9]2[NH:19][C:20](=[O:43])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:17]
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(ethyl-methyl-amino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M81) (0.39 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a off-white solid (159 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1O[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:4][N:3]=1.[NH2:15][NH2:16]>O>[NH2:15][N:16]1[C:2]([NH2:1])=[N:3][N:4]=[C:5]1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: NN
Reactant: Nc1nnc(Cc2ccc(O)cc2)o1
Solvent: O
Product: Nc1nnc(Cc2ccc(O)cc2)n1N
Temperature: 190 °C

Procedure:
A mixture of 4-(5-amino-[1,3,4]oxadiazol-2-ylmethyl)-phenol 4.902 g (25.64 mmol), water 40 mL and anhydrous hydrazine 13 mL was refluxed on an oil bath (190° C.) for 18 hours. The mixture was cooled, allowed to crystallize at room temperature for 2 hours, then placed into a freezer (−20° C.) overnight (16 hrs). The precipitated product was collected by filtration, washed with chilled MeOH (−15° C.) and dried on high vacuum. The crude product was re-crystallized from water (80 mL, reflux to +4° C. overnight). Filtered, washed with ice-cold water and dried on high vacuum.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[I-:15].[Na+]>C(#N)CC>[I:15][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: N#Cc1cccc(Cl)n1
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1cccc(I)n1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
6-Chloro-pyridine-2-carbonitrile (5.0 g, 36 mmol) was taken up in propionitrile (35 mL). To this was added TMSCl (4.6 mL, 36 mmol) and sodium iodide (16.0 g, 108 mmol) and the solution was heated to 90° C. for 16 h. The solution was cooled and quenched by the addition of 2M sodium hydroxide (35 mL) The mixture was extracted with ethyl acetate (3×30 mL) and washed with water (1×50 mL) and saturated aqueous sodium bisulfate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica-gel) using 0-100% ethyl acetate in hexanes to afford 4.6 g of the title compound.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30]([CH3:32])C)[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:36][C:37](=O)C>>[CH:32]1([CH2:30][N:25]2[CH2:24][C:23]3[C:27](=[CH:28][CH:29]=[C:21]([C:18]4[CH:19]=[C:20]5[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=4)[NH:14][CH:13]=[C:12]5[CH:9]4[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]4)[CH:22]=3)[CH2:26]2)[CH2:37][CH2:36]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(C)C)C5)cc23)CC1
Reactant: CC(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(CC4CC4)C5)cc23)CC1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide, substituting cyclopropanecarbaldehyde (14 mg, 0.198 mmol) for 2-propanone to afford 10.8 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][C:3]=1I.C([O:31][B:32](OC(C)C)[O:33]C(C)C)(C)C>C1COCC1.C([Li])CCC>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH:5]=[CH:4][C:3]=1[B:32]([OH:33])[OH:31]
Reactant: Fc1c(I)ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Reaction time: 2 h

Procedure:
To a solution 2,3-difluoro-1-iodo-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-benzene (10A) (1 equi.) in THF (5 mL/mmole), butyllithium (1.3 equi.) was added at −78 C. The reaction mixture was stirred at that temperature for 2 hr,. Then triisopropylborate (1 equi.) was added at that temperature. The reaction mixture was stirred at that temperature for 1 h and at room temperature for 10 h, quenched with water, extracted with ethyl acetate washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by recrystallization from hexane afforded 2,3-difluoro-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-phenylboronic acid (11A), as a white solid (75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH3:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CSc1cc(C(C)=O)c(O)cc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(SC)cc3C(C)=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
1-(2-Hydroxy-4-methyl-5-methylsulfanyl-phenyl)ethanone (29 mg), 4-chloro-6,7-dimethoxyquinoline (66 mg), and 4-dimethylaminopyridine (54 mg) were suspended in o-dichlorobenzene (2 ml) to prepare a suspension which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (17 mg, yield 30%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc(Oc5ccc(Cl)cc5)c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(4-chlorophenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(4-chlorophenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[CH3:11][NH:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:12]([CH3:11])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CNCCC(=O)OC(C)(C)C
Product: CN(CCC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyanobenzyl bromide (1.5 g, 7.7 mmol) and tert-butyl N-methyl-beta-alaninate (1.5 g, 9.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a yellow oil (1.9 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 7.78 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 3.55 (s, 2H), 2.60 (t, J=6.9 Hz, 2H), 2.38 (t, J=6.9 Hz, 2H), 2.11 (s, 3H), 1.39 (s, 9H). LC/MS (Method B): 275.0 (M+H)+. HPLC (Method A) Rt 2.40 min (Purity: 82.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8].CCN(CC)CC.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1sc(CO)cc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1sc(CO[Si](C)(C)C(C)(C)C)cc1Br
Reaction time: 14 h

Procedure:
A solution of (4-bromo-5-isopropyl-thiophen-2-yl)-methanol (Example Q; 3.4 g, 14 mmol) in CH2Cl2 (4.0 mL) was treated with NEt3 (2.8 mL, 20 mmol), p-dimethylaminopyridine (0.050 g), and t-butyldimethylsilylchloride (2.41 g, 16.0 mmol). The mixture was stirred for 14 hours, then diluted with Et9O and washed with H2O. The organic layer was dried (MgSO4) and the solvent evaporated to provide the crude product, which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[N:15]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[S:16]([CH3:19])(=[O:18])=[O:17])[C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1.[Li+].C(Cl)CCl.O[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[N:15]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)[S:16]([CH3:19])(=[O:17])=[O:18])[C:9]([O:11][CH2:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CN1CCN(CCN(c2ccc(C(=O)[O-])cc2OCC2CC2)S(C)(=O)=O)CC1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(CCN(c2ccc(C(=O)OCC(=O)OCc3ccccc3)cc2OCC2CC2)S(C)(=O)=O)CC1
Yield: 76 %

Procedure:
To a solution of lithium 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)benzoate (theoric 0.869 mmol) and EDC (349 mg, 1.821 mmol) in dry DCM (3 ml), benzyl 2-hydroxyacetate (151 mg, 0.910 mmol) and DMAP (111 mg, 0.910 mmol) were added at RT. The final mixture was stirred for 2 days, then the solvent was evaporated, the residue was portioned between water and EtOAc, the organic layer was washed with NaHCO3 sat. sol. and brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography on silica gel (eluent: DCM/MeOH/32% NH4OH 95/5/0.5) to give 2-(benzyloxy)-2-oxoethyl 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)-methylsulfonamido)benzoate as a colorless oil (370 mg, 0.661 mmol, 76% yield over 2 steps, MS/ESI+ 560.1 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:23][O:24][CH3:25])[CH:10]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O.NN>C(O)C>[CH3:25][O:24][N:23]=[C:9]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH:10]([NH2:12])[CH3:11]
Reactant: CON=C(c1ncc(Cl)cc1Cl)C(C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CON=C(c1ncc(Cl)cc1Cl)C(C)N
Yield: 80.9 %

Procedure:
To 810 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-methoxyinnino-1-methylethyl]phthalimide in 30 ml of ethanol, 161 mg of hydrazine monohydrate was added and refluxed with heating for 1 hour with stirring. After completion of the reaction, the solvent was evaporated under reduced pressure, and the resulting residue was mixed with 20 ml of water and extracted with ethyl acetate (30 ml×1). The resulting organic layer was washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 430 mg of the desired crude product as a pale yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [C:1]1([OH:14])[C:2]([C:7]2[C:8]([OH:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[K+].CS(C)=O.[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH2:21]([O:14][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: CCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccccc1-c1ccccc1OCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A 100 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser with nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with 3.74 grams (0.02 moles) of 2,2′-biphenol, 2.8 grams (0.04 moles, 85 wt. %) of potassium hydroxide, and with 25 mL of dimethylsulfoxide. The mixture was stirred under nitrogen while heating to 100° C. After about 2½ hours, the potassium hydroxide had dissolved, and the mixture was cooled to about 70° C. Dodecyl bromide (9.60 mL; d 1.038; 9.97 grams; 0.04 moles) was added in one portion. An exotherm to about 86° C. was observed. After the exotherm subsided, the reaction mixture was stirred at 70° C. After about 5 hours, the reaction mixture was poured into about 400 mL of water. The white solids that separated were collected by filtration, and were washed on the filter with several portions of water. The solids were first air-dried, and then were dried in a vacuum oven at 50° C. for about 2 hours. The yield of product was 9.49 grams (91%), having a melting point of 33-35° C. The structure was confirmed by IR, 1H- and 13C-NMR, and GC/MS analyses.