Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12]Cl.[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][OH:19]
Reactant: ClCc1ccc2ccccc2n1
Reactant: OCc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 70 °C

Procedure:
A mixture of 12.8 g (0.06 mol) of 2-quinolinylmethyl chloride HCl, 7.5 g (0.06 mol) of 3-hydroxybenzyl alcohol, and 18 g of potassium carbonate in 50 ml of DMF is heated at 70° C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 3-(2-quinolinylmethyloxy)benzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.CC(C)([O-])C.[K+].Cl[CH2:24][CH2:25][C@@H:26]1[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:24][CH2:25][C@@H:26]2[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Reactant: Oc1ccc(Cl)cc1CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(Cl)cc1CCc1ccccc1
Yield: 29 %

Procedure:
500 mg of 4-chloro-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 270 mg of potassium t-butoxide and 520 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine and extracted in the same manner as described in step (a) of Example 1. The resulting oily substance was purified by silica gel column chromatography, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 260 mg (yield 29%) of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](O)[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[N:6][CH:7]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=S(Cl)Cl
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cn1
Solvent: Cc1ccccc1
Product: Clc1ccc(C(Cl)Cn2ccnc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g of 1-(5-chloro-2-pyridyl)-2-(1H-imidazol-1-yl)ethane-1-ol is dissolved in 2 ml of toluene, 6 ml of thionyl chloride are added and the reaction mixture is stirred for 30 minutes at room temperature. The solvent and the thionyl chloride in excess are distilled off, the residue is dissolved in 2N NaOH, extracted with ethyl acetate, dried over Na2SO4 and evaporated to yield the compound as a colourless oil.
Reaction SMILES: BrC1C(F)=CC=C2C=1N=C(NC(C)(C)C)C(C)=N2.BrC1C(F)=CC=C2C=1NC(=O)C(C)=N2.Cl.CC1(N)CCC1.CC1(C)C(C)(C)OB([C:48]2[NH:56][C:55]3[CH2:54][CH2:53][NH:52][C:51](=[O:57])[C:50]=3[CH:49]=2)O1.[Br:59][C:60]1[C:61]([F:77])=[CH:62][CH:63]=[C:64]2[C:69]=1[N:68]=[C:67]([NH:70][C:71]1([CH3:75])[CH2:74][CH2:73][CH2:72]1)[C:66]([CH3:76])=[N:65]2>CS(C)=O>[Br:59][C:60]1[C:61]([F:77])=[CH:62][CH:63]=[C:64]2[C:69]=1[N:68]=[C:67]([NH:70][C:71]1([CH3:75])[CH2:74][CH2:73][CH2:72]1)[C:66]([CH3:76])=[N:65]2.[F:77][C:61]1[C:60]([C:48]2[NH:56][C:55]3[CH2:54][CH2:53][NH:52][C:51](=[O:57])[C:50]=3[CH:49]=2)=[C:69]2[C:64](=[CH:63][CH:62]=1)[N:65]=[C:66]([CH3:76])[C:67]([NH:70][C:71]1([CH3:75])[CH2:72][CH2:73][CH2:74]1)=[N:68]2
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: CC1(N)CCC1
Agent: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Agent: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Solvent: CS(C)=O
Product: Cc1nc2ccc(F)c(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C)CCC1
Yield: 42 %

Procedure:
8-Bromo-7-fluoro-3-methyl-N-(1-methylcyclobutyl)quinoxalin-2-amine (376a) (620 mg, 1.91 mmol, 88% yield) as a light brown viscous oil was prepared according to the procedure described for Intermediate 605a, using 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (600 mg, 2.18 mmol), TEA (0.76 mL, 5.44 mmol) and 1-methylcyclobutanamine hydrochloride (Matrix Scientific Columbia, S.C.) (500 mg, 4.11 mmol) in DMSO (5.0 mL) as the starting materials. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (1H, dd, J=9.0, 5.7 Hz), 7.13 (1H, t, J=8.6 Hz), 5.01 (1H, br. s.), 2.51 (3H, s), 2.42-2.51 (2H, m), 2.30 (2H, dddd, J=9.8, 7.3, 4.6, 2.6 Hz), 1.90-2.01 (2H, m), 1.73 (3H, s). 19F NMR (377 MHz, CDCl3) δ ppm −103.73 (1F, s). m/z (ESI, +ve ion) 324.0/326.0 (M+H)+. 2-(6-Fluoro-2-methyl-3-((1-methylcyclobutyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (269 mg, 0.71 mmol, 42% yield) as an amorphous yellow solid was prepared according to the procedure described for Example 370, using 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (800 mg, 3.05 mmol), and 8-bromo-7-fluoro-3-methyl-N-(1-methylcyclobutyl)quinoxalin-2-amine (376a) (549 mg, 1.70 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.53 (1H, br. s.), 7.61 (1H, dd, J=9.0, 5.9 Hz), 7.29 (1H, dd, J=11.5, 9.0 Hz), 7.21 (1H, s), 7.05 (1H, br. s.), 6.85 (1H, dd, J=4.1, 2.0 Hz), 3.45 (2H, td, J=6.9, 2.4 Hz), 2.93 (2H, t, J=6.8 Hz), 2.54 (3H, s), 2.38-2.47 (2H, m), 2.13-2.24 (2H, m), 1.82-1.97 (2H, m), 1.66 (3H, s). 19F NMR (377 MHz, DMSO-d6) δ ppm −109.90 (1F, s). m/z (ESI, +ve ion) 380.1 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-].Cl[Sn]Cl>CO.CCOC(C)=O>[NH2:1][CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])=[CH:14][CH:15]=2)[CH:9]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1

Procedure:
To a solution of 1-(4-(4-(azidomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one prepared above (203 mg, 0.695 mmol) in MeOH (6 mL) and EtOAc (6 mL), SnCl2 2H2O (343 mg, 1.52 mmol) was added. After the mixture was heated to reflux for 1 h, it was concentrated in vacuo. The residue was purified by HPLC to give 1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-one (145 mg). MS 267 (M+H).
Reaction SMILES: [CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]S([O-])(=O)=O.[Mg+2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([CH:8]=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=CC1CCCCCC1
Reaction time: 2.5 h
Yield: 92.3 %

Procedure:
Cycloheptanemethanol (20 mmol, 2.56 g) was combined with methylene chloride (40 ml), Celite® (2.56 g), and MgSO4 (0.5 g). Pyridinium chlorochromate (30 mmol, 6.47 g) was added. After 2.5 hours, the mixture was filtered through silica and concentrated, affording the title compound as an oil (2.33 g, 91%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]1([C:21]2[C:25]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[C:15]1([C:21]2[C:25]3[N:26]=[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:39]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:24]=3[NH:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CNc2c(-c3ccccc3)n[nH]c2-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: c1ccc(-c2nc3c(-c4ccccc4)n[nH]c3c3ccccc23)cc1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
201 mg of phosphorus pentoxide were added to a solution of 240 mg of N-(3,5-diphenyl-1H-pyrazol-4-yl)benzylamine (2) in 10 ml of xylene, after which 195 μl of phosphorus oxychloride were added dropwise at 150° C. The reaction solution was stirred at 150° C. for 4 h and then stirred at RT for 12 h; a saturated solution of sodium hydrogen carbonate was then added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The following was obtained:
Reaction SMILES: C1C2C(COC([NH:18][C:19]3([C:24]([NH:26][C@H:27]([C:31]([N:33]([C@@H:35]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:36]([O:66][CH3:67])[CH2:37][C:38]([N:40]4[CH2:44][CH2:43][CH2:42][C@H:41]4[C@H:45]([O:64][CH3:65])[C@@H:46]([CH3:63])[C:47]([NH:49][C@H:50]([C:58]4[S:59][CH:60]=[CH:61][N:62]=4)[CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[S:48])=[O:39])[CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.C(NCC)C>[NH2:18][C:19]1([C:24]([NH:26][C@H:27]([C:31]([N:33]([C@@H:35]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:36]([O:66][CH3:67])[CH2:37][C:38]([N:40]2[CH2:44][CH2:43][CH2:42][C@H:41]2[C@H:45]([O:64][CH3:65])[C@@H:46]([CH3:63])[C:47]([NH:49][C@H:50]([C:58]2[S:59][CH:60]=[CH:61][N:62]=2)[CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[S:48])=[O:39])[CH3:34])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1)C(C)C
Solvent: CCNCC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C1(N)CCCC1)C(C)C
Yield: 61.3 %

Procedure:
According to general procedure A, from #29 (54 mg, 0.054 mmol) in dichloromethane (6 mL, 0.9 mM) and diethylamine (4 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give example #30 (26 mg, 61%) as a solid. HPLC (Protocol A): retention time=7.233 minutes, m/z 785.4 [M+H+], (purity >72%). 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.54 (br d, J=8 Hz) and 10.82 (br d, J=8 Hz), total 1H], 8.19-8.27 (m, 1H), [7.80 (d, J=3.2 Hz) and 7.83 (d, J=3.2 Hz), total 1H], [7.65 (d, J=3.3 Hz) and 7.69 (d, J=3.3 Hz), total 1H], 7.28-7.33 (m, 2H), 7.20-7.27 (m, 2H), 7.14-7.19 (m, 1H), [6.31 (ddd, J=11, 8, 4.5 Hz) and 6.44 (ddd, J=11, 8, 4 Hz), total 1H], [4.53 (dd, J=9, 8 Hz) and 4.60 (dd, J=9, 7.5 Hz), total 1H], 3.24 and 3.25 (2 s, total 3H), 3.17 and 3.21 (2 s, total 3H), 2.93 and 3.00 (2 br s, total 3H), [1.14 (d, J=6.5 Hz) and 1.17 (d, J=6.5 Hz), total 3H].
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[C:3]1=O.CN1C[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:31]3[CH:32]=[CH:33][C:34]4[N:35]([C:37]([CH2:40]NC(=O)OC(C)(C)C)=[N:38][N:39]=4)[N:36]=3)[CH:28]=2)C1=O.[ClH:50]>>[ClH:50].[C:27]1([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([C:37]([CH2:40][C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[CH:10]=[N:2][CH:1]=[CH:3]5)=[N:38][N:39]=3)[N:36]=2)[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=1
Reactant: CN1Cc2cc(-c3ccc4nnc(CNC(=O)OC(C)(C)C)n4n3)ccc2C1=O
Reactant: CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Agent: Cl
Product: c1ccc(-c2ccc3nnc(Cc4ccc5cnccc5c4)n3n2)cc1
Reaction time: 0.25 h

Procedure:
A 10 mL, CEM microwave vessel was charged with 3 (0.1040 g, 0.427 mmol), 1-(5-phenylpyridin-2-yl)hydrazine (4, 0.119 g, 0.641 mmol), a stirbar and 1 mL concentrated HCl. The vessel was sealed, and fitted with an 18-guage needle and an Argon inlet. The slurry was placed in a heating block at 115° C. for 15 minutes with stirring. A volatile substance evolved during this time. The vessel was briefly cooled, and the seal was replaced. The vessel was irradiated on a CEM Explorer using the following parameters: ramp time 20 s, hold time 10 min, hold temperature 150° C., powermax=on, 75 W max. The resultant turbid aqueous solution was filtered and concentrated in vacuo. The solids were suspended in 3 mL hot EtOH, and cooled. The precipitate was isolated by filtration and washed with EtOH (3×3 mL). The solids were taken up in 2 mL H2O, and filtered through a 0.1 μm PVDF Ultra-free-CL centrifugal filter (Millipore Corp, PN UFC40W00, 2000 g for 5 minutes). The aqueous filtrate was lyophilized to afford 6-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)isoquinoline hydrochloride. Anal. Calcd for C21H15N5. HCl.1.7H2O: C, 62.36; H, 4.83; N, 17.31. Found: C, 62.39±0.08; H, 4.48±0.02; N, 17.28±0.03.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[CH2:24]1[C:28]2([CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH2:27][CH2:26][NH:25]1>>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][C:28]2([CH2:24][N:25]([C:15](=[O:16])[C:14]3[CH:13]=[CH:12][C:11]([C:9]4[O:10][C:6]5[C:5]([CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=5[N:8]=4)=[CH:19][CH:18]=3)[CH2:26][CH2:27]2)[CH2:29][CH2:30]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(C(=O)OC(C)(C)C)CC5)C4)cc3)oc12

Procedure:
The title compound was synthesized from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate following the procedure described in EXAMPLE 120. Mass spectrum (ESI) 529.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]([F:24])([F:37])[F:36])=[CH:10][C:9]=1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)cc1NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared from (4-bromo-2-tert-butoxycarbonylamino-phenyl)-carbamic acid tert-butyl ester (as prepared in the previous step) and 2-trifluoromethoxyphenylboronic acid according to the procedure described in Example 1, step D. 1H-NMR (400 MHz, CDCl3) δ: 7.59 (br. s., 2H), 7.37-7.42 (m, 1H), 7.26-7.34 (m, 3H), 7.24 (dd, J=8.3, 2.0 Hz, 1H), 7.00 (br. s., 1H), 6.94 (br. s., 1H), 1.52 (s, 9H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH:26]=[O:27])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.BrN1[C:34](=[O:35])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CO>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([C:26]([O:35][CH3:34])=[O:27])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Cl)c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)s1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1cc(Cl)c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 14 h
Yield: 80.9 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((5-formyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.31 g, 0.69 mmol) in CCl4 (10 mL) and benzene (15 mL) was added N-bromosuccinimide (NBS) (0.18 g, 1.03 mmol) and 2,2′-azobisisobutyronitrile (AIBN) (0.011 g, 0.068 mmol). The reaction mixture was heated to reflux for 1 hour, and the resulting clear yellow solution was cooled to 0° C. Methanol (0.1 mL) was added and the reaction mixture was stirred for 14 hours at ambient temperature. Water was added and the reaction mixture was extracted with methylene chloride. The combined extracts were dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography on silica to afford 0.27 g of N-(4-chlorophenyl)-2-[((5-methoxycarbonyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide. as a pale yellow solid; NMR (DMSO-d6/TFA) 11.3 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (m, 3), 7.6 (d, 1), 7.4 (d, 2), 3.8 (s, 3) ppm.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][N:17]([CH3:32])[C:18]1[CH:31]=[CH:30][C:21]([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=O)=[CH:20][CH:19]=1.O>O1CCCC1.CCCCCC.ClCCl>[CH3:32][N:17]([CH3:16])[C:18]1[CH:31]=[CH:30][C:21]([C:22](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(=C2SCCCS2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
There is added to a solution of 2-trimethylsilyl-1,3-dithiane (16.2 g ) in dry tetrahydrofuran (170 ml) at -65° a 1.9M solution of n-butyllithium in hexane (45 ml). The reaction mixture is progressively warmed to 0° in the course of 31/2 hours and cooled to -65°. A solution of 4-dimethylamino-benzophenone (19.2 g) in dry tetrahydrofuran (100 ml) is than slowly added. The reaction mixture is progressively warmed to room temperature overnight and poured into a mixture of water (1000 ml ) and dichloromethane (200 ml). After separation of the layers, the aqueous solution is extracted with dichloromethane (3×200 ml). The combined organic solutions are washed with water (100 ml) and dried over magnesium sulphate. The solvents are evaporated in vacuo and the residue is recrystallised from ethyl acetate. The product is dried in vacuo to constant weight to yield (4-dimethylaminophenyl)(1,3-dithian-2-ylidene)-phenylmethane, m.p. 172°-174°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH2:16])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[CH2:18][C:19]([NH2:21])=[O:20].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][CH2:18][C:19]([NH2:21])=[O:20])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccccc2CN)cc1C
Reactant: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccccc2CNCC(N)=O)cc1C

Procedure:
A reaction vessel was charged with 11.5 g (54.5 mmole) of [(3,4-dimethylphenyl)phenyl]methylamine dissolved in 200 ml of absolute ethanol. A mixture of 5.05 g (54 mmole) of chloracetamide and 4.62 g (55 mmole) of sodium bicarbonate was added to the reaction vessel and the solution was brought to refulux and held at reflux for 42 hours. Solvent was evaporated under reduced pressure and the residue was diluted with water. The aqueous phase was extracted with dichloromethane and the organic solution dried over potassium carbonate. After evaporation of solvent under reduced pressure, the solid residue was crystallized in ethyl acetate.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[CH:9]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1>C1(C)C=CC=CC=1.CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:9][C:10]=1[O:15][CH3:16]
Reactant: COc1cc(Br)ccc1Cl
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 56.5 %

Procedure:
A 10-mL round bottom flask containing a magnetic stir bar and fitted with a condenser and a inert gas inlet was charged successively with sodium tert-butoxide (304 mg, 3.16 mmol), acetato (2′-di-t-butylphosphino-1,1′-biphenyl-2-yl) palladium (II) (20.90 mg, 0.045 mmol) and a solution of 4-bromo-1-chloro-2-methoxybenzene (500 mg, 2.258 mmol) and ethyl piperidine-4-carboxylate (426 mg, 2.71 mmol) in anhydrous toluene (2.5 mL). The flask was purged with argon and the mixture heated at 80° C. After 45 min, the reaction was cooled to RT, diluted with Et2O (50 mL) and washed with water (2×15 mL) and brine (15 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator to give the crude product, which was purified by flash chromatography using a 12 g silica gel cartridge and 20:1 Hex/EtOAc to 10:1 Hex/EtOAc to elute the product. The fractions containing the product were pooled and concentrated on a rotary evaporator to give ethyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (380 mg, 1.276 mmol, 56% yield) as a colorless oil. LC/MS [M+H]+=298.28. 1H-NMR (400 MHz, CDCl3) δ 7.18 (1 H, d, J=8.57 Hz), 6.50 (1 H, s), 6.44 (1 H, s), 4.15 (2H, q, J=7.10 Hz), 3.87 (3 H, s), 3.58 (2 H, dt, J=12.47, 3.65 Hz), 2.79 (2 H, s), 2.38-2.47 (1 H, m), 2.02 (2 H, d, J=11.42 Hz), 1.88 (2 H, s), 1.26 (3 H, t, J=7.14 Hz).
Reaction SMILES: BrCCCC[N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH:7]1[CH3:16].[N:17]1([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[Br-]>C(OCC)(=O)C.C(#N)C>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([N:17]2[CH2:22][CH2:21][N:20]([CH2:10][CH2:9][CH2:12][CH2:13][C:7]3([CH3:16])[NH:6][C:10](=[O:11])[C:9]4([CH2:12][CH2:13][CH2:14][CH2:15]4)[S:8]3)[CH2:19][CH2:18]2)=[N:24]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC1SC2(CCCC2)C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(CCCCN2CCN(c3n[nH]c4ccccc34)CC2)NC(=O)C2(CCCC2)S1
Temperature: 25 °C
Reaction time: 18 h
Yield: 171.9 %

Procedure:
A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one (4.20 g), 3-(1-piperazinyl)-1H-indazole (3.0 g), K2CO3 (5.68 g), NaI (310 mg), and acetonitrile (220 ml) was heated between 60° and 80° C. under nitrogen. After 18 hours, TLC analysis showed only a trace of the starting bromide. The mixture was cooled to ambient temperature, ethyl acetate (150 ml) was added, the inorganics filtered, and the filtrate concentrated under reduced pressure. The residue was taken up in dichloromethane (230 ml), washed with H2O (130 ml), brine (130 ml), dried (Na2SO4), and concentrated to a foam. The foam was chromatographed on silica gel, diluting with 8% methanol in dichloromethane, to furnish 5.04 g of a foam which solidified upon addition of ether/hexanes. The solid was recrystallized from ethyl acetate/hexanes to give 3.72 g of 3-(4-(1-[1 H-indazol-3-yl]-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]non-4-one, m.p. 113°-115° C.
Reaction SMILES: BrCCCC[N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]1[CH3:14].[ClH:15].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:17]1.S1[C:35]2[CH:36]=CC=C[C:34]=2[C:33](N2CCNCC2)=N1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[ClH:15].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([N:25]2[CH2:26][CH2:27][N:28]([CH2:33][CH2:34][CH2:35][CH2:36][C:7]3([CH3:14])[NH:6][C:10](=[O:11])[C:9]([CH3:12])([CH3:13])[S:8]3)[CH2:29][CH2:30]2)=[N:17]1
Reactant: CC1SC(C)(C)C(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CC1(CCCCN2CCN(c3nsc4ccccc34)CC2)NC(=O)C(C)(C)S1
Temperature: 65 °C
Yield: 61.3 %

Procedure:
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (4.70 g), 1-(1,2-benzisothiazol-3-yl)piperazine 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.72 g), K2CO3 (8.13 g) and NaI (300 mg) in acetonitrile (200 ml) was heated at 65° C. for 16 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.77 g of crystals, m.p. 209°-214° C.