Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][C:11]3([O:18][C:17](=[O:19])[NH:16][C:15]4[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=4)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl.[CH2:25]([O:27][NH2:28])[CH3:26]>N1C=CC=CC=1.CO>[CH2:25]([O:27][N:28]=[C:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH2:13][CH2:12][C:11]3([O:18][C:17](=[O:19])[NH:16][C:15]4[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=4)[CH2:10][CH2:9]2)[CH2:6][CH2:7]1)[CH3:26]
Reactant: CCON
Reactant: O=C1CCC(N2CCC3(CC2)OC(=O)Nc2ccccc23)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCON=C1CCC(N2CCC3(CC2)OC(=O)Nc2ccccc23)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1′-(4-oxocyclohexyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (Compound No. 64) (31 mg, 0.10 mmol) was dissolved in anhydrous pyridine (500 μL), treated with of O-ethylhydroxylamine hydrochloride (7 mg, 0.12 mmol) and stirred at 60° C. for 30 minutes. The reaction was cooled to room temperature, diluted with methanol (500 μL) and subjected to reverse-phase HPLC purification (2-30% CH3CN gradient [w/0.1% TFA (aq)] over 10 minutes, 1.0 mL injected, 35 mL/min) to provide 1′-(4-(ethoxyimino)cyclohexyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 3). LC/MS m/z 358.0 [M+H]+, retention time 1.64 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([S:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=2)=[CH:11][N:12]=1.[NH2:23][CH2:24][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[OH:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[OH:26][C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:20](=[O:22])[C:16]1[CH:15]=[C:14]([S:13][C:10]2[S:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:12][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Reactant: NCC(O)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(NCC(O)(c1ccccc1)c1ccccc1)c1cc(Sc2cnc(Nc3ccccn3)s2)ccn1
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 0 %

Procedure:
To a solution of 4-(2-(pyridine-2-ylamino)thiazol-5-ylthio)picolinic acid (0.063 g, 0.19 mmol) and 2-amino-1,1-diphenylethanol (0.060 g, 0.28 mmol, 1.5 eq, described in Example D) in NMP (3 mL), was added EDAC (0.055 g, 0.28 mmol, 1.5 eq), HOBt (0.026 g, 0.19 mmol, 1 eq) and diisopropylethylamine (0.100 mL, 0.57 mmol, 3 eq). The resulting mixture was stirred at 23° C. for 3.5 h. The mixture was purified on preparative HPLC (ammonium acetate/water/acetonitrile) and freeze dried to give the title compound as a solid (0.024 mg, 24%). The product was converted to the HCl salt by dissolving it in ethyl acetate (2 mL) and tetrahydrofuran (2 mL) and treating the mixture with a solution of HCl (4.0 M in dioxane, 0.011 mL, 0.045 mmol, 1 eq). The mixture was concentrated, then diluted with water and lyophilized to give the HCl salt of the title material (0.029 g) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.10 (2H, d, J=5.56 Hz), 6.30 (1H, s), 7.01 (1H, dd, J=6.69 and 5.43 Hz), 7.11-7.20 (3H, m), 7.28 (4H, t, J=7.71 Hz), 7.37 (1H, dd, J=5.31, 2.02 Hz), 7.42-7.48 (4H, m), 7.66 (1H, d, J=1.52 Hz), 7.79 (1H, ddd, J=9.22, 6.32 and 1.89 Hz), 8.31 (1H, dd, J=5.43 and 1.39 Hz), 8.40 (1H, t, J=4.80 Hz), 8.41 (1H, d, J=4.8 Hz), 11.86 (1H, s). LC/MS (M+H)+: 526. Ret. time: 2.00 (Condition D). HRMS: calcd: 526.1371; found: 526.1387.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[Cl:11][C:12]1[C:13]([OH:41])=[C:14]([S:19]([N:22]([CH2:27][C:28]2[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH:31]=[C:30]([Cl:40])[CH:29]=2)[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])=[O:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1.CCN(CC)CC>C1COCC1>[Cl:40][C:30]1[CH:31]=[C:32]([CH:33]=[C:28]([CH2:27][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:19]([C:14]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[C:13]=2[OH:41])(=[O:21])=[O:20])[CH:29]=1)[CH2:34][N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)CNCc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
To a solution of pyridine-3-sulfonyl chloride (70 mg, 0.40 mmol) in THF (4 mL) were added 3,5-dichloro-N-(3-chloro-5-((isobutylamino)methyl)benzyl)-2-hydroxy-N-isobutylbenzenesulfonamide (100 mg, 0.20 mmol) and Et3N (0.14 mL, 0.98 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was concentrated. To the residue was added 1 N NaOH/THF/MeOH. After 4 h, the mixture was concentrated and the residue was purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the desired product as a white solid (60 mg, 40%).
Reaction SMILES: [OH-].[K+].[Cl:3][CH:4](Cl)[CH:5]([Cl:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1>C(O)C>[Cl:3][CH:4]=[C:5]([Cl:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(C(Cl)C(Cl)Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C(Cl)=CCl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.5 g. KOH in 30 ml. of ethanol is added from a dropping funnel to a solution of 9.0 g. of 1,1,2-trichloro-2-(3-nitrophenyl)ethane in 20 ml. of ETOH during 20 minutes and after that the reaction mixture is boiled in the steam bath for 2 hours. It is cooled to room temperature poured an 100 ml. of water and extracted with ether. After removel of the ether in vacuo the residue is distilled in high vacuo to yield pure 1,2-dichloro-2-(m-nitrophenyl)ethylene.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 55.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (17 mg) was obtained.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[CH2:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[N:11]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nn1nc(Cc2ccccc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Cc2ccccc2)c2ccccc2c1=O

Procedure:
The product of Example 139A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (s, 1H), 8.30 (dd, J=7.8, 1.5 Hz, 1H), 7.96-7.99 (m, 1H), 7.91 (ddd, J=8.0, 7.2, 1.5 Hz, 1H), 7.85 (ddd, J=7.8, 7.2, 1.4 Hz, 1H), 7.35-7.47 (m, 4H), 7.25-7.33 (m, 4H), 7.16-7.23 (m, 1H), 4.31-4.32 (bs, 2H), 3.71 (s, 2H); LC/MS (APCI) M/Z 404 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc2cccnc2c1)c1ccccc1

Procedure:
The title product was prepared from 7-hydroxyquinoline and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (28%, white solid). HPLC-MS: m/z=279.1 (M+1); Rt: 2.55 min.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12]CC3C=CC(OC)=CC=3)=[N:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.FC(F)(F)C(O)=O>ClCCl.CC(C)=O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([OH:12])=[N:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: COc1ccc(COc2ccc(-n3ccnn3)cn2)cc1
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc(-n2ccnn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(1H-1,2,3-triazol-1-yl)-2-(4′-methoxybenzyloxy)pyridine from step 3 of this example (890 mg, 3.15 mmol) was dissolved in dichloromethane (11 ml). Trifluoroacetic acid (3.64 ml, 47.3 mmol) was added and the mixture stirred at RT. Within 10 minutes the reaction had turned light purple. The reaction mixture was evaporated 40 minutes after TFA addition, then reconstituted in CH2Cl2/heptane and evaporated again. The residue was purified by column chromatography on a Biotage 40 g SiO2 column, eluting with 0-15% methanol in CH2Cl2 to give a white solid. The white solid was suspended in acetone and filtered over celite to remove silica from the crude. The filtrate was then evaporated and pumped on high vacuum overnight to give the title compound as a complex with acetone.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:6](=[O:7])[CH2:5]1.C[OH:11]>>[O:7]1[CH2:2][CH2:3][CH:4]([C:9]([OH:8])=[O:11])[CH2:5][CH2:6]1
Reactant: O=C1CC(CCO)CO1
Reactant: CO
Product: O=C(O)C1CCOCC1

Procedure:
It is known that 3-(2-hydroxyethyl)butyrolactone can be reacted with methanol to give esters of tetrahydropyran-4-carboxylic acid (EP-A-284 969). This reaction results in a mixture containing esters of tetrahydropyran-4-carboxylic acid, 3-(2-hydroxyethyl)butyrolactone, 3-(2-methoxyethyl)butyrolactone, 3-spirocyclopropylbutyrolactone, methanol, possibly water, possibly acetic acid and possibly methyl acetate, which involves problems in working up.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:32]([CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:34])=[O:33])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Reactant: CC(C)CS(=O)(=O)Cl
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNS(=O)(=O)CC(C)C)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and isobutanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:15]=[CH:14][NH:13][N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[Na+].CS(O[CH2:23][C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:25])(=O)=O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:15]=[CH:14][N:13]([CH2:25][C@@H:24]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH3:23])[N:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(-c2cc[nH]n2)ccc(C#N)c1Cl
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)OC(C)(C)C)n2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2-Chloro-3-methyl-4-(1H-pyrazol-3-yl)benzonitrile (1.96 g, 8.96 mmol) was dissolved in toluene (20 ml). To this solution an aqueous solution of NaOH (1M, 20 ml) and tetrabutylammonium bromide (0.58 g, 1.79 mmol) was added, respectively. (S)-2-(tert-butoxycarbonylamino)propyl methanesulfonate (4.54 g, 17.92 mmol) was dissolved in toluene (20 ml) and added to the reaction mixture. After 96 h of vigorous stirring at RT the reaction mixture was diluted with toluene and washed several times with water, dried with Na2SO4, filtered and evaporated. After CombiFlash purification using heptane/EtOAc as eluents, 1.85 g of the product was collected. 1H-NMR (400 MHz; d6-DMSO): δ 1.02 (d, 3H), 1.31 (s, 9H), 2.57 (s, 3H), 3.91 (m, 1H), 4.13 (m, 2H), 6.62 (m, 1H), 6.87 (d, 1H), 7.66 (d, 1H), 7.79 (d, 1H), 7.84 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20]([C:22]([C:27]#[N:28])=[CH:23]OCC)#[N:21]>C(O)(=O)C>[NH2:28][C:27]1[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=3)[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]2[N:1]=[CH:23][C:22]=1[C:20]#[N:21]
Reactant: CCOC=C(C#N)C#N
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: CC(=O)O
Product: N#Cc1cnc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1N
Yield: 59.3 %

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (100 mg) and 1,1-dicyano-2-ethoxyethylene (49 mg) in acetic acid (2 ml) was refluxed for 1 hour. The reaction mixture was concentrated in vacuo and the residue was crystallized from ethanol to give 7-amino-6-cyano-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (77 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]([C:18]#[N:19])[S:14][C:15]=2[S:16][CH3:17])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CO.C(Cl)(Cl)Cl>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([S:8]([C:11]3[CH:12]=[C:13]([C:18]#[N:19])[S:14][C:15]=3[S:16][CH3:17])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:22]1
Reactant: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(N2CCN(C)CC2)c1
Temperature: 100 °C
Yield: 9.8 %

Procedure:
To a flask containing 0.15 g (0.4 mmol) of 4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carbonitrile (Example 286: step f), 44.1 μL (0.4 mmol) of N-methylpiperazine, 4.5 mg (0.02 mmol) of Pd(OAc)2, 24.8 mg (0.04 mmol) of BINAP, and 195 mg (0.6 mmol) of CsCO3 was added 2.5 mL of toluene. The flask was purged with Ar, and heated to 100° C. for 16 h. The reaction was then concentrated in vacuo and purified by preparative TLC (50%-EtOAc-Hexane), isolating the low Rf material, which was subjected to preparative TLC again (10% MeOH-CHCl3) to give 15.5 mg (10% yield) of 4-[3-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2-carbonitrile in greater than 98% purity.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:14]=[CH:13]2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[OH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:16]=2)[CH:11]=1
Reactant: CCCN(CCC)CCCc1ccc2cc(CO[Si](C)(C)C(C)(C)C)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCN(CCC)CCCc1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
The compound (1.28 g) obtained in Example 121-8 was added with a 1 mol/l TBAF/THF solution (6.20 ml) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with distilled water, followed by stirring. The solution was extracted with chloroform and the extract was then washed with saturated saline solution. The resulting organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (472 mg) as a brown liquid.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH:10]=[C:9]([CH3:12])[CH2:8][CH:7]1[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.CCOCC>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]([CH:7]2[CH2:8][C:9]([CH3:12])=[CH:10][CH2:11][N:6]2[CH3:4])([CH3:15])[CH3:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)N1CC=C(C)CC1C(C)(C)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C(C)(C)C2CC(C)=CCN2C)cc1
Yield: 81.1 %

Procedure:
1-Ethoxycarbonyl-1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]-4-methylpyridine (3.17 g) dissolved in 10 ml of dried tetrahydrofuran was added dropwise to a suspension of 0.9 g of lithium aluminium hydride in 5 ml of dried tetrahydrofuran while stirring under cooling with ice and then the mixture was refluxed for 30 minutes. After cooling, water-containing ether (150 ml) and then 10 ml of a 30% sodium hydroxide aqueous solution was added dropwise to the mixture while stirring under cooling with ice. An diethyl ether-tetrahydrofuran layer was decanted and combined with the diethyl ether portions with which the remaining matter had been washed. The combined liquid was dried over potassium carbonate, stripped of the solvent and distilled under reduced pressure to obtain 2.1 g of 1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]-1,4-dimethylpyridine as a colorless viscous mass.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: BrCCCCBr
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,4-dibromobutane (5 mL, ca 42 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,4-dibromobutane; the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 984 mg (61%). 1H-NMR (400 MHz, d6-DMSO) δ=1.53-1.60 (m, 2H), 1.87-1.94 (m, 2H), 3.56 (t, J=6.6 Hz, 2H), 3.87 (t, 37.4 Hz, 2H), 6.64 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 8.99 (s, 2H). LRMS (FAB+): 320.0 (100, [M+H]+)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1([C:21]2[CH:30]=[CH:29][C:24]3[O:25][CH2:26][CH2:27][O:28][C:23]=3[CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:18]2[CH2:19][CH2:20][N:15]([C:21]3[CH:30]=[CH:29][C:24]4[O:25][CH2:26][CH2:27][O:28][C:23]=4[CH:22]=3)[CH2:16][CH2:17]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: BrCCCCn1cnc2ccccc21
Reactant: c1cc2c(cc1N1CCNCC1)OCCO2
Solvent: CC#N
Product: c1ccc2c(c1)ncn2CCCCN1CCN(c2ccc3c(c2)OCCO3)CC1

Procedure:
Analogously to Example 1, reaction of 1-(4-bromobutyl)benzimidazole with 6-piperazino-1,4-benzodioxane ("A") in 200 ml of acetonitrile gives 6-[4-(4-(benzimidazol-1-yl)butyl)piperazino]-1,4-benzodioxane, m.p. 247-248°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=CC2C=CC=CC=2)[N:4]=1)#[N:2].[O:17]=[O+][O-]>CO.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[O:17])[N:4]=1)#[N:2]
Reactant: O=[O+][O-]
Reactant: N#Cc1ccnc(C=Cc2ccccc2)n1
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccnc(C=O)n1
Temperature: 25 °C

Procedure:
2.238 g (10.81 mmol) of 4-cyano-2-(2-phenylethenyl)-pyrimidine in 150 ml of absolute methanol and 75 ml of absolute methylene chloride are cooled to -70° C. Ozone is passed through until a blue solution is produced (about 0.5 hour). Nitrogen is passed through the solution until the excess ozone has been removed (about 0.75 hour) and then 3.5 ml of dimethyl sulfide are added to the reaction mixture. The solution is allowed to warm up to room temperature and is concentrated in a rotary evaporator. The crude product is purified over silica gel (eluant: n-hexane/ethyl acetate 1:3). 1H-NMR (CDCl3): δ=10.11 (s, 1H); 9.23 (d, 1H); 7.82 (d, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][C@H:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[CH3:8][C@H:6]1[CH2:5][N:4]([S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])[CH2:3][C@@H:2]([CH3:1])[N:7]1[C:36](=[O:37])[CH2:35][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@H](C)N1C(=O)COc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a two neck round bottom flask (3S,5R)-3,5-dimethyl-1-(naphthalen-2-yl-sulfonyl)piperazine (100 mg, 0.33 moles) was dissolved in 25 mL of acetonitrile. K2CO3 (71 mg, 0.53 moles) was added to the reaction flask at room temperature under nitrogen atmosphere and allowed the reaction mixture to stir for about 10 min. The flask was then cooled to 0° C. and phenoxy acetyl chloride (83 μl, 0.49 moles) was added to the reaction flask drop wise at the same temperature. After addition, the reaction mixture was slowly warmed to room temperature and allowed it to stir for 3 hr. TLC indicated complete consumption of the starting material. The reaction was quenched with cold water (25 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phase was washed with brine solution and dried over sodium sulphate. Solvent was removed under reduced pressure to give crude material which was purified by column chromatography (20% ethyl acetate and hexane) to afford the title compound with 98% purity.