Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:40][C:41]1[CH:42]=[C:43]([N:48]2[C:52](=[O:53])[O:51][N:50]=[C:49]2[C:54]2[C:55]([NH:59]C(=O)C(F)(F)F)=[N:56][O:57][N:58]=2)[CH:44]=[CH:45][C:46]=1[F:47]>O1CCCC1>[Br:40][C:41]1[CH:42]=[C:43]([N:48]2[C:52](=[O:53])[O:51][N:50]=[C:49]2[C:54]2[C:55]([NH:59][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[N:56][O:57][N:58]=2)[CH:44]=[CH:45][C:46]=1[F:47]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)C(F)(F)F
Reactant: COCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
A solution of 3-methoxypropan-1-ol [Fluka product #38457] (3.1 mL, 32 mmol) and triphenylphosphine (8.4 g, 32 mmol) in tetrahydrofuran (93 mL) at 0° C. was treated with diisopropyl azodicarboxylate (6.7 mL, 34 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (10 g, 23 mmol) in tetrahydrofuran (47 mL), and stirred at 25° C. for 72 h. The reaction mixture was concentrated, diluted with ethyl acetate (200 mL), treated with trifluoroacetic acid (20 mL) and water (20 mL), and heated at 50° C. for 6 h. The reaction mixture was concentrated, rediluted with ethyl acetate (200 mL) and washed with water (3×80 mL), saturated sodium bicarbonate (2×80 mL) and brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a crude residue. This material was purified on silica gel to give the desired product (6.4 g, 54%) as a white solid. LCMS for C14H14BrFN5O4 (M+H)+: m/z=414.0, 416.0.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]([S:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:39][N:38]=[N:37][N:24]=3)=[CH:13][CH:12]=2)[C:8]([S:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCC2CCCCC2)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nnc(SCC2CCCCC2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 60 %

Procedure:
Reaction of 3-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-5-(cyclohexylmethylthio)-4H-1,2,4-triazole (Step A) with trimethyltin azide according to the procedure of Example 18, Step B, gave a 60% yield of the title compound as a white solid, mp 89°-91° C., homogeneous by TLC in 4:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 488 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:15])[NH:8][CH:9]=[N:10]2.[C:16]([O:22][CH2:23]Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:16]([O:22][CH2:23][N:8]1[C:7](=[O:15])[C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][CH3:3])[N:10]=[CH:9]1)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cccc2nc[nH]c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (1.24 g, 60% in oil, 31 mmol) was added portion-wise to a solution of 5-methoxyquinazolin-4(3H)-one (5 g, 28.4 mmol; obtained as described in WO-96/09294) in anhydrous DMF (50 ml) while maintaining the temperature at 25° C. The mixture was stirred at room temperature for 30 minutes. Chloromethyl pivalate (4.45 ml, 31 mmol) was added at room temperature for 3 hours. Additional sodium hydride (0.12 g, 3 mmol) and chloromethyl pivalate (0.67 ml, 4.5 mmol) were added and the mixture was stirred another hour. After evaporation of the solvents under high vacuum, the mixture was diluted with water and extracted with DCM. After drying with magnesium sulfate and evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: ethyl acetate-petroleum ether, 6:4 to 8:2) to give (5-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate as a white solid (7.4 g, 90%); HPLC tR: 2.69 min; Mass spectrum MH+ 291.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]1[O:31][N:30]=[C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:38](ON1C(=O)CCC1=O)([O:40][CH2:41][CH:42]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39]>C1COCC1>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]1[O:31][N:30]=[C:29]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][CH:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=4[C:49]4[C:54]3=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:39])[CH2:34][CH2:33]2)[N:28]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nc(C3CCNCC3)no2)N1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
DIPEA (1.6 mL, 10.0 mmol) was slowly added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(3-(piperidin-4-yl)-1,2,4-oxadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (1.1 g, 2.0 mmol) in THF (50 mL) at 0° C. The mixture was stiffed under N2 atmosphere at 0° C. for 15 minutes, then, Fmoc-OSu (2.4 g, 7.2 mmol) was added and the mixture was stirred at rt. for 8 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution 1:6 to 1:2 EtOAc/hexanes) to give (9H-fluoren-9-yl)methyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (1.0 g, 86%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)C.[Li+].[OH-]>C1COCC1.O>[Cl:13][C:10]1[N:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:14])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
(6-Chloro-pyridin-3-yloxy)-acetic acid ethyl ester (800 mg, 3.71 mmol) in THF was added to a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in H2O, then washed three times with Et2O, and neutralized with 1N HCl to pH 5˜7. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give (6-chloro-pyridin-3-yloxy)-acetic acid (300 mg, 36%).
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)#[CH:7].CN(C)[CH:27]=[O:28].Cl>CCCCCC.O1CCCC1>[CH:27]([C:7]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:28]
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#CC=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.75 ml (0.80 mmol) of 1.6 molar n-butyllithium solution in n-hexane are added dropwise at 0° C. to 2.48 g (9.80 mmol) of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene in 25 ml of tetrahydrofuran. After 1 hour, this solution is added dropwise to 0.83 ml of dimethylformamide in 20 ml of tetrahydrofuran, the mixture is stirred at room temperature for 1 hour, acidifed by means of aqueous hydrochloric acid and partitioned between ether and water, and the organic phase is dried and evaporated. Chromatography on silica gel using n-hexane/dichloromethane (1:1) gives 1.75 g of 1-(formylethynyl)-4-(trans-4-pentylcyclohexyl)benzene, ##STR39## which is stirred for 2 hours at room temperature with 1.05 g (6.49 mmol) of diethylaminosulfur trifluoride in 10 ml of dichloromethane. After partitioning between water and dichloromethane, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel using n-heptane, giving 0.89 g of product ##STR40## having the phase sequence
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[C:6]([NH2:12])[CH:5]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: COC(=O)c1ccc(CO)c(N)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)c(N)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve 3-amino-4-hydroxymethyl-benzoic acid methyl ester (step (c), 4.2 g, 23.3 mmol) in 125 mL of anhydrous CH2Cl2 and add MnO2 (20.2 g, 232.8 mmol) and stirred at RT. After 5 h, the solution was filtered through Celite and concentrated to afford the title compound as a yellow solid upon drying under vacuum. MS m/z: 180.1 (M+1).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:13].[CH2:14](N(CC)CC)[CH3:15]>CCO.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:14]([C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:13])=[CH2:15]
Reactant: CCN(CC)CC
Reactant: Cc1cc2c(c(C)c1Br)COC2=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: C=Cc1c(C)cc2c(c1C)COC2=O
Temperature: 140 °C

Procedure:
5-Bromo-4,6-dimethyl-2-benzofuran-1(3H)-one (375 mg, 1.56 mmol), potassium vinyl trifluoroborate (417 mg, 3.11 mmol), Pd(dppf)Cl2 (127 mg, 0.156 mmol), and triethylamine (409 μL, 3.11 mmol) were combined together in EtOH (10 mL) and heated at 140° C. for 30 min. Analysis by LC as well as TLC (hexanes/EtOAc=1/0.3) indicated that reaction had gone to completion. The reaction mixture was then diluted with EtOAc, washed with NaCl, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was then re-dissolved in dichloromethane, absorbed to silica gel, concentrated, and loaded onto a silica MPLC column for separation to afford of 5-ethenyl-4,6-dimethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[NH:15][CH3:16])[CH:9]=1)[CH3:6])[CH3:2].Cl[CH2:21][C:22]1[C:23]([CH2:39][CH2:40][O:41][CH3:42])=[N:24][C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[N:26][C:27]=1[CH3:28]>>[CH2:1]([O:3][C:4](=[O:19])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[N:15]([CH2:21][C:22]2[C:23]([CH2:39][CH2:40][O:41][CH3:42])=[N:24][C:25]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=3)=[N:26][C:27]=2[CH3:28])[CH3:16])[CH:9]=1)([CH3:18])[CH3:6])[CH3:2]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC)c1
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)N(C)Cc2c(C)nc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)c1

Procedure:
In analogy to the procedures described in examples 59C] and 26C], 2-methyl-2-(3-methylcarbamoyl-phenoxy)-propionic acid ethyl ester (example 59B]) was reacted 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 118G]) to give 2-(3-{[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-carbamoyl}-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light brown solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cccnc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2cccnc2)cc1F
Yield: 90.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-pyridin-3-ylcyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.11 g, 0.19 mmol) prepared in Example 39c, triethylsilane (0.15 mL), trifluoroacetic acid (0.19 g) and dichloromethane (1.9 mL), to yield the title compound (77 mg, 92%) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:14]1[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 474 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.00-6.55 (m, 10H), 4.75-2.75 (m, 5H), 1.75-0.65 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:21][C:13]1[NH:12][C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-2-oxindole (167 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-chloro-3-(1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[N:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[CH:26]1([B-](F)(F)F)[CH2:28][CH2:27]1.[K+]>>[NH2:2][C:1](=[O:3])[C@@H:4]([NH:9][C:10](=[O:11])[C:12]1[CH:17]=[CH:16][C:15]([CH:26]2[CH2:28][CH2:27]2)=[C:14]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][O:22]2)[N:13]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: F[B-](F)(F)C1CC1
Reactant: CC(C)C[C@H](NC(=O)c1ccc(Br)c(OCC2CCCO2)n1)C(N)=O
Agent: [K+]
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 166 b, using 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide (Example 186 a) and potassium cyclopropyltrifluoroborate as starting materials, MS (EI): m/e=376.2 [M+H]+.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([C:24]([O:30][CH2:31][CH3:32])=[C:25]([CH:27](O)[CH3:28])[CH:26]=1)[C:19]([NH:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([C:24]([O:30][CH2:31][CH3:32])=[C:25]([CH:27]([Cl:3])[CH3:28])[CH:26]=1)[C:19]([NH:21][CH2:22][CH3:23])=[O:20]
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1OCC
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)Cl)c1OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
A mixture of cyanuric chloride (0.15 g, 0.84 mmol) and N,N-dimethylformamide (0.065 mL, 0.84 mmol) was stirred at room temperature for 10 min and then a solution of 3-chloro-6-ethoxy-N-ethyl-5-(1-hydroxyethyl)-2-methylbenzamide (0.16 g, 0.56 mmol) in methylene chloride (3.1 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with water, concentrated and purified on silica gel (eluting with 0 to 40% EtOAc in hexanes) to give the desired product (0.13 g, 76%). LCMS calculated for C14H20Cl2NO2 (M+H)+: m/z=304.1; Found: 304.1.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][CH:31]([CH2:33]Br)[CH2:30][C:29]=2[CH:35]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][N:8]([CH2:33][CH:31]2[CH2:30][C:29]3[CH:35]=[C:25]([O:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:26]=[CH:27][C:28]=3[O:32]2)[CH2:7][CH2:6]1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: OC1(Cc2ccc(F)cc2F)CCNCC1
Product: OC1(Cc2ccc(F)cc2F)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=466.6 (M+H+) was prepared from 4-(2,4-difluoro-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH:7]=[CH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:2]=12.S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:12]=[C:11]1[C:2]2[NH:1][C:6](=[O:19])[CH:5]=[CH:4][C:3]=2[CH:7]=[CH:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: O=c1c2ccccc2ccc2ccc[n+]([O-])c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ccc3ccccc3c(=O)c2[nH]1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 0.75 gram (0.0034 mole) of the N-oxide thus obtained and 0.77 gram (0.0043 mole) of tosyl chloride in 37.5 milliliters of chloroform was added a solution of 0.58 gram (0.0042.mole) of potassium carbonate in 5.8 milliliters of water and the resulting mixture was stirred vigorously at room temperature for about 60 hours. At the end of this time the reaction mixture was washed with 10 percent aqueous sodium hydroxide whereupon a solid precipitated in the chloroform phase. The solid was recovered by filtration and recrystallized from isopropyl alcohol/methanol to obtain purified 1-oxo-benzo[5,6]cyclohepta[1,2-b]pyrid-2(1H)one product, m.p. 195°-196° C. The elemental analyses were as follows:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][OH:20])[CH:14]=[CH:15][CH:16]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[C:11]1[CH:12]=[C:13]([S:17][CH2:18][CH2:19][O:20][S:30]([CH3:29])(=[O:32])=[O:31])[CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCC(OC(c2cccc(SCCO)c2)c2nc3ccccc3s2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(OC(c2cccc(SCCOS(C)(=O)=O)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)-methyl]phenylsulfanyl}ethanol (400 mg) in dichloromethane (5 mL) is added methanesulfonylchloride (1.25 molar equivalent) in dichloromethane (1.5 mL) and triethylamine (1.5 molar equivalent). The reaction mixture is stirred overnight at room temperature. Volatiles are removed under reduced pressure to dryness. Water is added and the aqueous phase is extracted by diethylether. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (dichloromethane/methanol from 98/2) to afford methanesulfonic acid 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl ester that will be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8]C)=[C:4]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:17][CH2:16]2)[CH:3]=1.Br.O.[OH-].[K+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])[CH2:17][CH2:16]2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: COc1ccccc1N1CCN(CCCCNc2cc(Cl)nnc2OC)CC1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1N1CCN(CCCCNc2cc(Cl)n[nH]c2=O)CC1
Yield: 99.7 %

Procedure:
4.00 g (0.00985 mol) of 6-chloro-3-methoxy-4-((4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl)amino)-pyridazine are dissolved in 40 ml of glacial acetic acid, and 40 ml of 63% strength HBr are added. The mixture is refluxed for 2 hours, 200 ml of water are added, 30% strength KOH is added to pH 6, and the precipitated substance is filtered off with suction and thoroughly washed with water. 3.85 g (99.7% of theory) of 6-chloro-4-((4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl)amino)-3(2H)-pyridazinone are obtained, purified by recrystallization from ethanol with addition of charcoal, and immediately added to a solution of ethanolic hydrochloric acid, resulting in 3.26 g (68.7% of theory) of pure dihydrochloride, m.p. 247°-252° C.; C 47.2%, H 6.0%, Cl(tot) 21.9%, Cl- 14.6%, N 14.4%, O 10.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(N(C(C)C)C(C)C)C.[O:30]=[C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33](=[O:40])[N:32]1[CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:17][C:52](=[O:53])[CH2:51][CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][N:32]2[C:31](=[O:30])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:40])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)CCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)CCOCCOCCOCCN3C(=O)c4ccccc4C3=O)c2)C1
Temperature: 25 °C
Yield: 16 %

Procedure:
To 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine (intermediate 31.5) (600.0 mg, 1.95 mmol, 1.00 equiv) in anhydrous DCM (5.0 mL) was added N-ethyl-N,N-diisopropylamine (DIEA; 0.5 mL). Then a solution of 3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanoyl chloride (intermediate 179.5) (794 mg, 2.15 mmol, 1.10 equiv) was added dropwise with stirring at room temperature. The resulting solution was stirred for 2 h at ambient temperature and then concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (100˜50:1). This resulted in 870 mg (66%) of N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)-3-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)propanamide as a pale yellow syrup. The other fractions was collected and evaporated to get an additional 200 mg of impure product.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)[CH3:9]
Reactant: O=Cc1cncs1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cncs1

Procedure:
prepared by reaction of the commercially available thiazole-5-carbaldehyde with 2M ethylamine in THF.