Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1([CH3:13])[CH3:12].C(N(CC)CC)C.[CH3:21][C:22]1[N:26]([CH2:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[S:37][CH:38]=[C:39]([C:41](Cl)=[O:42])[N:40]=3)[CH2:32][CH2:31]2)=[O:29])[N:25]=[C:24]([C:44]([F:47])([F:46])[F:45])[CH:23]=1>ClCCl>[CH3:12][C:4]1([CH3:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]1[N:2]([CH3:1])[C:41]([C:39]1[N:40]=[C:36]([CH:33]2[CH2:34][CH2:35][N:30]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:44]([F:46])([F:47])[F:45])=[N:25]3)[CH2:31][CH2:32]2)[S:37][CH:38]=1)=[O:42]
Reactant: CNC1c2ccccc2CC1(C)C
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)C3c4ccccc4CC3(C)C)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a solution of 2,3-dihydro-N,2,2-trimethyl-1H-inden-1-amine (193 mg, 1.1 mmol) and triethylamine (0.19 mL, 1.38 mmol) in 5 mL of dichloromethane was gradually added 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (386 mg, 0.92 mmol) (i.e. the product of Example 19, Step D) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with 4 mL of dichloromethane, and washed with water, 1 N aqueous hydrochloric acid, water, saturated solution of sodium bicarbonate and brine. The filtered reaction mixture was dried over magnesium sulfate and concentrated in vacuo to give 300 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22](B5OC(C)(C)C(C)(C)O5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[N:8]1([C:14]([C:16]2[CH:28]=[C:27]3[C:19]([C:20]4[CH:21]=[C:22]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[CH:23]=[C:24]([C:29]([NH2:31])=[O:30])[C:25]=4[NH:26]3)=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)OC1(C)C
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-c2ccccn2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 100 °C

Procedure:
2-Bromopyridine (0.1 mL, 1.025 mmol), 7-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide 429A (140 mg, 0.125 mmol), Pd(Ph3P)4 (76 mg, 0.066 mmol) and Na2CO3 (2M) (0.8 mL, 1.600 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was degassed and heated at 100° C. for 12 hrs. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 401.16 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.66 (s, 1H), 9.13 (d, 1H, J=1.5), 8.73 (d, 1H, J=4.8), 8.71 (d, 1H, J=1.5), 8.40 (s, 1H), 8.33 (d, 1H, J=8.0), 8.21 (d, 1H, J=8.0), 7.95 (td, 1H, J=7.8, 1.8), 7.83 (s, 1H), 7.57 (s, 1H), 7.37 (m, 1H), 7.27(dd, 1H, J=8.1, 1.5), 3.7-3.5 (bm, 8 H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)CCC>>[S:28]1[CH:29]=[C:25]([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)[N:26]=[CH:27]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cscn2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-(tri-n-butylstannyl)thiazole. The title compound (81 mg) was obtained as a pale solid, m/z 332 (MH+).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:50][CH2:51][C:52](=[O:54])[CH3:53].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:50][CH2:51][C:52](=[O:54])[CH3:53])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: CC(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Temperature: 65 °C

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (100 mg, 0.156 mmol) in DMF (4 mL) was added 4-chlorobutan-2-one (20 mg, 0.187 mmol) followed by K2CO3 (65 mg, 0.468 mmol). The mixture was heated at 65° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxobutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide. The crude product was used in the next step without purification. MS: (M+H)+=713.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:50][CH2:51][CH2:52][CH3:53])[CH2:48][CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:48][CH3:49])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CCCNCCC
Product: CCCN(CCC)C(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with dipropylamine (Pennwalt) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=C(F)C=C(N)C=4C)C=3C=2)CC1)=O.Cl[C:31]1[C:32]2[CH:39]=[C:38]([C:40]3[CH2:41][CH2:42][O:43][CH2:44][CH:45]=3)[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(N5CCC6C(=CC=C(C(O)(C)C)C=6)C5=O)C=4CO)C=3C=2)CC1)=O.[C:89]([C:93]1[CH:118]=[CH:117][C:96]([C:97]([NH:99][C:100]2[CH:105]=[C:104]([F:106])[CH:103]=[C:102](B3OC(C)(C)C(C)(C)O3)[C:101]=2[CH3:116])=[O:98])=[CH:95][CH:94]=1)([CH3:92])([CH3:91])[CH3:90]>>[C:89]([C:93]1[CH:118]=[CH:117][C:96]([C:97]([NH:99][C:100]2[CH:105]=[C:104]([F:106])[CH:103]=[C:102]([C:31]3[C:32]4[CH:39]=[C:38]([C:40]5[CH2:41][CH2:42][O:43][CH2:44][CH:45]=5)[NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[C:101]=2[CH3:116])=[O:98])=[CH:95][CH:94]=1)([CH3:92])([CH3:90])[CH3:91]
Reactant: Clc1ncnc2[nH]c(C3=CCOCC3)cc12
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1B1OC(C)(C)C(C)(C)O1
Agent: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(N5CCc6cc(C(C)(C)O)ccc6C5=O)c4CO)ncnc3[nH]2)CC1
Agent: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCOCC3)cc12

Procedure:
Example 49 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with Intermediate 11 and Intermediate 5 with Intermediate 38.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15].C(N(CC)CC)C>CN1C(=O)CCC1>[F:8][C:7]1[C:2]([NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: NCc1cccc(F)c1
Reactant: Fc1ccc(F)c(F)n1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Fc1cccc(CNc2nc(F)ccc2F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2,3,6-trifluoropyridine (1.07 mL, 1.5 g, 11.27 mmol), 3-fluorobenzylamine (3.18 mL, 3.53 g, 28.2 mmol), and triethylamine (4.71 mL, 3.42 g, 33.8 mmol) were dissolved in NMP (39 mL) to form a mixture This mixture reaction mixture was stirred at 100° C. for 1 hr. The reaction mixture was then extracted with EtOAc (3×75 mL). The combined extracts were washed with H2O (4×75 mL) followed by brine (1×75 mL). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 100 hexanes to 30 EtOAc/70 hexanes yielded 2.63 g (98%) of 3,6-difluoro-N-(3-fluorobenzyl)pyridine-2-amine. LCMS (m/z): 239.1 (MH+), retention time=1.01 min.
Reaction SMILES: [O-:1]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18](NCC(C)C)=[O:19]>>[C:18]([OH:19])(=[O:1])[CH:17]=[CH:16][CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=[CH:10][CH3:9]
Reactant: O=P([O-])([O-])[O-]
Reactant: C/C=C/C=C\CC/C=C/C(=O)NCC(C)C
Agent: [K+]
Product: CC=CC=CCCC=CC(=O)O

Procedure:
0.05 g (10% wt) of K3PO4 and 0.05 g (10% wt) of polyethylene glycol (PEG 400) were added to 0.5 g of the spilanthol mixture (αβ unsaturated form:βγ unsaturated form=43:57) obtained in the above-mentioned (7), followed by stirring at 80° C. for 16 hours. When verified by GC, the ratio of αβ unsaturated form to βγ unsaturated form was converted to αβ unsaturated form:βγ unsaturated form=99:1. After cooling of the reaction liquid and subsequent separation of liquid by adding 5 ml of toluene and 5 ml of water, the organic layer was subjected to solvent evaporation under a reduced pressure to obtain 0.5 g of the target spilanthol (yield 99%, αβ unsaturated form:βγ unsaturated form=99:1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:20]=[N:19][C:18]=2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][C:12]=1[O:34][CH3:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.C(O)(=O)C.O.CCOC(C)=O.C([O-])(O)=O.[Na+].CCOCC>[ClH:1].[ClH:1].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([CH3:39])[CH2:26][CH2:25]3)[N:20]=[N:19][C:18]=2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][C:12]=1[O:34][CH3:35])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OCc2ccccc2)c(OC)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 166.1 %

Procedure:
To a solution of 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (1.0 mmol, 520 mg) in dichloromethane (5.0 mL) was added formaldehyde solution in water (37%, 10 mmol, 1.0 mL), and 2 drops of acetic acid. Then sodium triacetoxyborohydride (4.0 mmol, 848 mg) was added. And the mixture was stirred at room temperature for 0.5 hour then condensed. It was then diluted with water/EtOAc and neutralized with NaHCO3 powder. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (5.0 mL), 2N HCl in ether (5.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to afford 4-(4-benzyloxy-3-methoxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine dihydrochloride (444 mg).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:17][C@@H:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[NH:24]C(=O)OC(C)(C)C)=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C@@H:19]1[C@H:18]([NH:17][C:6]2[N:7]=[C:8]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:3]([C:1]#[N:2])=[N:4][CH:5]=2)[CH2:23][CH2:22][O:21][CH2:20]1
Reactant: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Nc2nc(N[C@@H]3CCOC[C@@H]3N)cnc2C#N)cc1

Procedure:
To a suspension of tert-butyl (3R,4R)-4-(5-cyano-6-(p-tolylamino)pyrazin-2-ylamino)tetrahydro-2H-pyran-3-ylcarbamate in DCM (1 mL) was added TFA (1 ml), after completion, the solution was concentrated to give 5-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-3-(p-tolylamino)pyrazine-2-carbonitrile as crude residue.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[S:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]([NH:17][C:8]3[S:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[N:7]=3)=[O:19])[CH2:21][CH2:22]2)=[N:28][CH:29]=1)#[N:34]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc(N2CCC(C(=O)Nc3nc(-c4ccco4)c(N4CCOCC4)s3)CC2)nc1
Reaction time: 8 h
Yield: 68 %

Procedure:
Compound 44 (181 mg, 0.50 mmol), 2-chloro-5-cyanopyridine (104 mg, 0.75 mmol) and potassium carbonate (207 mg, 1.50 mmol) were suspended in 1,4-dioxane (4 mL), followed by stirring overnight under heating and reflux. The insoluble was removed through filtration, the filtrate was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=20:1) to afford the entitled Compound 45 (158 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[S:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][C:25]([CH3:28])=[CH:26][CH:27]=4)[S:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: Cc1ccc(-c2nc(CCl)cs2)s1
Product: Cc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)cs2)s1
Yield: 88 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 4-chloromethyl-2-(5-methyl-2-thienyl)thiazole to obtain 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)thiazole. The yield was 88%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 78-79° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: OCc1ccc(B(O)O)cc1
Agent: OBO
Product: OCc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(hydroxymethyl)phenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[N:18]=[C:17]([C:19]([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[CH2:38][OH:39])[CH:15]=2)[N:10]=1.C(OCC)(=O)C.O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:39][CH2:38][C:31]1[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:30]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH2:8])[N:18]=[C:17]2[C:19]([N:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29]1)=[O:20])=[O:6]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
47 μl of pivaloyl chloride are added to a solution of 200 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 4 ml of dimethylformamide, and the mixture is stirred at 80° C. for 16 h. 8 ml of ethyl acetate and 8 ml of water are added, the organic phase is separated off and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:5][NH:6][C:7]([CH:9]1[CH2:11][CH2:10]1)=[O:8].[N:16]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[Cl:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][NH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[O:8])=[CH:3][C:2]=1[NH:1][NH2:16]
Reactant: O=N[O-]
Reactant: Nc1cc(CNC(=O)C2CC2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1cc(CNC(=O)C2CC2)ccc1Cl
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a cold solution of N-(3-amino-4-chlorobenzyl)cyclopropanecarboxamide (2.00 g, 8.90 mmol) in conc. HCl (25 mL) was added aqueous solution of sodium nitrite (0.676 g, 9.7 mmol) at −20° C. to −25° C. The reaction mass was stirred at −20° C. to −25° C. for 30 min, followed by addition of stannous chloride solution (5.0 g, 22.2 mmol) in conc. HCl slowly. The reaction mass was stirred at −20° C. to −25° C. for 1 h. The reaction mass was basified with aqueous NaOH at below 0° C. The reaction mass was diluted with water, extracted with 10% MeOH:DCM and concentrated to afford 1.6 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.66 (m, 4H), 1.58 (m, 1H), 4.10 (s, 2H), 4.18 (d, J=5.4 Hz, 2H), 6.47 (m, 2H), 7.11 (m, 2H), 8.51 (br s, 1H); MS (m/z): 240.05 (M+FI)+.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(I)C>C1COCC1.[Cl-].[Na+].O>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH2:1][CH3:2])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCI
Solvent: O
Solvent: C1CCOC1
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1CC
Reaction time: 1 h
Yield: 95.6 %

Procedure:
Potassium t-butoxide (2 . 3 g, 20.5 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1, 1-dioxide (5 g, 18.6 mmol) in 100 ml of THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added ethyl iodide (11.64 g, 74.6 mmol) and the resulting mixture was allowed to stir at room temperature for 40 hours. The resulting mixture was diluted with brine, extracted with ethyl acetate (150 ml) and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 5.27 g of 2-phenylmethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[S:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][C:21]=2[C:22]([NH2:24])=[O:23])[N:11]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:19]2[S:18][C:17]([NH:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:7][CH3:6])[N:11]=3)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=2)=[CH:26][CH:27]=1
Reactant: CN(Cc1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl[(6-{[3-(aminocarbonyl)-5-(4-fluorophenyl)-2-thienyl]amino}pyridin-2-yl)methyl]methylcarbamate (90 mg, 0.197 mmol) in dichloromethane (0.4 mL) was added trifluoroacetic acid (0.4 mL) and the reaction was maintained at room temperature for 1 hour. The volatiles were removed in vacuo and the crude product was purified by reverse phase HPLC (20-90% acetonitrile/water with 0.05% trifluoroacetic acid). The appropriate fractions were diluted with ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (40 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (40 mL) and water (2×40 mL), dried over sodium sulfate, filtered and concentrated to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[OH:21])[CH2:33][CH2:32]2)=[O:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Oc1ccccc1N1CCNCC1
Product: COc1cc(C)c(C)cc1NC(=O)N1CCN(c2ccccc2O)CC1
Yield: 87 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)carbamate and 1-(2-hydroxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])#[N:6].[C:27]1(=O)[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH2:28]1.C(N(CC)CC)C>ClCCl>[C:5]([CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:9][C:10]([O:12][C:27]1[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH:28]=1)=[O:11])#[N:6]
Reactant: N#CC(c1cccc(F)c1)C(CC(=O)O)c1ccc(F)cc1
Reactant: O=C1CCCC(=O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: N#CC(c1cccc(F)c1)C(CC(=O)OC1=CC(=O)CCC1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
1.79 g (15 mmol) of thionyl chloride were added to 0.452 g (1.5 mmol) of 4-cyano-3-(4-fluorophenyl)-4-(3-fluorophenyl)butanoic acid, and the mixture was stirred at 80° C. for 1.5 h. Excess thionyl chloride was removed under reduced pressure. The reaction mixture concentrated in this manner (which contains acid chloride) was dissolved in 3 ml of dichloromethane and, at 0° C., added dropwise (about 30 min) to a mixture of 0.252 g (2.25 mmol) of 1,3-cyclohexanedione and 0.304 g (3 mmol) of triethylamine in dichloromethane (10 ml). After 3 h of stirring at 25° C., the solvent was removed under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure.