Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc2[nH]cnc2cc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc2c(cc1Br)ncn2C1CCCCO1
Yield: 106.3 %

Procedure:
A mixture of 100 (550 mg, 2.57 mmol), TsOH.H2O (50 mg, 0.26 mmol), and 3,4-dihydro-2H-pyran (1.08 g, 12.85 mmol) in THF (10 mL) was heated at reflux overnight. After the solvent was removed in vacuo, the residue was partitioned between DCM (300 mL) and water (100 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0.5 to 1% MeOH) to afford 817 mg (100%) of 5-bromo-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (102) as yellow oil: MS (ESI) m/z=299 [M+1]+.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:15]=1[Cl:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([B:22]([OH:27])[OH:23])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1ccc(I)cc1OCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)c(OCc2ccccc2)c1
Temperature: -50 °C

Procedure:
Add dropwise 374 mL (748 mmol) of a solution of iPrMgCl 2N in THF to a solution of 198 g (575 mmol) of 2-(benzyloxy)-1-chloro-4-iodobenzene in 1.2 L of anhydrous THF under argon and stirred at −50° C., maintaining the temperature between −40 and −50° C. Allow the reaction mixture to return to −10° C. and continue stirring for 1 h. Then add 172 mL (748 mmol) of triisopropyl borate and leave the reaction mixture to return slowly to RT. After stirring for 2 h, treat the mixture with 1 L of aqueous solution of HCl 5N, then extract with ether (2×600 mL). Wash the organic phase with 2×1 L of water, dry over Na2SO4 then concentrate under reduced pressure. Solidify the residue obtained in pentane, filter on a frit and wash with pentane. We thus obtain 113 g of [3-(benzyloxy)-4-chlorophenyl]boronic acid in the form of a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)=[CH:8][C:7]=1[CH3:28].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH3:28][C:7]1[CH:8]=[C:9]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C1CCNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCBr)c(C)c3)nc2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (340 mg, 0.76 mmol) in DMF (10 mL) was added pyrrolidine (433 mg, 6.08 mmol). Then, the reaction mixture was stirred at room temperature for 16 hours. Then, water was added and the solids were filtered. The solids were washed with water and dried to give the title compound as a white solid. Yield: 307 mg (92%). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 7.87 (s, 2H), 6.71 (d, J=2.0 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.86 (s, 3H), 3.82 (m, 5H), 2.59 (t, J=6.8 Hz, 2H), 2.42 (m, 4H), 2.26 (s, 6H), 1.89 (m, 2H), 1.67 (m, 4H). MS (ES) m/z: 438.16 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13](O)=[O:14])[CH2:10][CH2:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].CO>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][OH:14])[CH2:10][CH2:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCc2cc([N+](=O)[O-])ccc2O1
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CCC(CO)O2
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred mixture of 11.1 parts of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-carboxylic acid and 63 parts of tetrahydrofuran were added dropwise, during a 30 minutes-period, 23.6 parts of a borane dimethyl sulfide complex solution 2M in tetrahydrofuran (slightly exothermic reaction: temp. rose to 27° C.). Upon completion, the whole was heated to reflux and stirring was continued for 2 hours at reflux temperature. The reaction mixture was decomposed by the dropwise addition of 8 parts of methanol at reflux temperature. After stirring and refluxing for 10 minutes, the solvents were distilled off and the residue was taken up in water. The solution was treated with concentrate hydrochloric acid and extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated. The solid residue was suspended in warm 2,2'-oxybispropane. The product was filtered off and dried, yielding 7.0 parts (70%) of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-methanol; mp. 96.5° C. (intermediate 8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].I[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)CCI
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CCC(F)(F)F)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of m-chlorophenylacetic acid (2.38 g, 14 mmol) in tetrahydrofuran (85 ml) was added at −78° C. lithium diisopropylamide solution (31 ml 1M in THF, 31 mmol). After stirring the mixture for 20 min 1-iodo-3,3,3-trifluoropropane (4.38 g, 20 mmol) was added and the mixture was allowed to warm to room temperature overnight. Water (5 ml) was added followed by 2N hydrochloric acid (10 ml). The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated and the residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1) to yield a colourless oil, (1.75 g, 47%); MS (EI): 264.9 (M+.).
Reaction SMILES: [C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:32][N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH2:35][CH:36](O)[CH2:37]2>CN(C=O)C>[C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][CH:36]2[CH2:37][CH:38]3[N:33]([CH3:32])[CH:34]([CH2:40][CH2:39]3)[CH2:35]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1C2CCC1CC(O)C2
Reactant: O=C(O)C(Nc1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1C2CCC1CC(OC(=O)C(Nc1ccccc1)c1ccccc1)C2
Temperature: 100 °C
Yield: 7 %

Procedure:
A mixture of 2-phenyl-2-(phenylamino)acetic acid I1 (250 mg, 0.90 mmol), EDC (255 mg, 1.35 mmol), HOBt (245 mg, 1.80 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-ol (380 mg, 2.71 mmol) in dry DMF (10 mL) is heated under microwave irradiation at 100° C. for 1 hour (LC-MS monitoring: complete conversion). The reaction is concentrated under reduced pressure and the residue is portioned between EtOAc and water. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by preparative HPLC. The collected compound is partitioned between 1N NaHCO3 and DCM, the organic phase is separated dried over Na2SO4, filtered and evaporated under vacuum to give 20.1 mg of the title compound as a colorless oil (7% yield, mixture of diastereoisomers).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15]OS(C)(=O)=O)(=O)=O.[S-2:32].[Na+].[Na+]>CS(C)=O>[CH2:14]1[C:13]2[CH:12]=[CH:11][C:10]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:9][C:8]=2[CH2:7][CH2:6][S:32][CH2:15]1
Reactant: CS(=O)(=O)OCCc1ccc(NC(=O)OCc2ccccc2)cc1CCOS(C)(=O)=O
Reactant: [S-2]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(Nc1ccc2c(c1)CCSCC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a stirred solution of the bis mesylate (from step 4) (5.0 g, 10.6 mmol) in dry DMSO (72 mL) is added anhydrous sodium sulfide (2.48 g, 31.8 mmol). The reaction mixture is stirred at RT for 1 h. The reaction mixture is partitioned between H2O (250 mL) and ethyl acetate (250 mL). The phases are separated, the aqueous phases is extracted with ethyl acetate (3×200 mL). The combined organic phases are dried (MgSO4), filtered and concentrated. The residue is dissolved in CH2Cl2, absorbed onto silica gel and is purified on a Biotage 40M column with SIM using 10-20% ethyl acetate in hexane as the eluent to afford 2.37 g (7.6 mmol, 71%) of the desired product as a white solid. mp 118-120° C.
Reaction SMILES: C[O:2][NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].B(Br)(Br)Br.CO.C1OC1C>ClCCl>[OH:2][NH:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])=[O:6]
Reactant: CONS(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Agent: CC1CO1
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(NO)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 179.4 %

Procedure:
To a solution of methoxyphenylsulfonamide 13 (35.9 g, 70.8 mmol) in dichloromethane (3.5 L) at 0° C. was charged boron tribromide (1M in DCM, 40.1 mL, 425 mmol). The reaction content was allowed to warm to room temperature, stirred over two hours, and monitored by TLC assay (SiO2, 10% methanol in dichloromethane as eluent, dibenzyl product Rf=0.16, visualization by UV). To the contents at 0° C. was slowly charged propylene oxide (82 g, 1.42 mmol). Methanol (200 mL) was added and the reaction mixture was concentrated via rotary evaporator to afford a viscous oil. The crude product mixture was purified by silica gel column chromatography using 10% methanol in dichloromethane to afford the product 14 as a foam (22 g, 80% yield). 1H NMR (DMSO) δ 7.60 (d, 2H), 7.30-7.20 (m, 5H), 6.95 (d, 2H), 3.90-3.75 (m, 1H), 3.45-3.20 (m, 5H), 3.00-2.55 (m, 5H), 2.50-2.40 (m, 1H), 1.95-1.85 (m, 1H), 0.85 (d, 3H), 0.80 (d, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)/[C:11](=[N:30]/[NH:29][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: COc1ccc2c(c1)N(Cc1ccccc1)C(=O)C2=O
Product: COc1ccc2c(c1)N(Cc1ccccc1)C(=O)/C2=N\NC(=O)c1ccccc1

Procedure:
The title compound was prepared as a yellow solid, using 1-benzyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. 1H NMR (CDCl3): δ 3.77 (s, 3H), 4.94 (s, 2H), 6.35 9d, 1H), 6.62 (dd, 1H), 7.29-7.36 (m, 4H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.01 (d, 2H), 13.95 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6][C:5]2[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=2[O:3]1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:30]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][C:2]2([CH3:1])[CH2:7][CH2:6][C:5]3[C:8]([CH3:15])=[C:9]([OH:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:4]=3[O:3]2)[CH2:18][CH2:19]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN1CCNCC1)O2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN1CCN(C(=O)c3ccccc3)CC1)O2
Reaction time: 1 h

Procedure:
To stirred solution of 3,4-dihydro-2,5,7,8-tetramethyl-2-(1-piperazinylmethyl)-2H-1-benzopyran-6-ol (EXAMPLE 126, 0.3 g, 1.0 mmol), triethylamine (0.11 g, 1.1 mmol) and methylene chloride (3 ml) is added dropwise over 1-2 min a solution of benzoyl chloride (0.16 g, 1.1 mmol) in methylene chloride (2 ml). The mixture is stirred at 20°-25° for 1 hr and diluted with methylene chloride (20 ml), washed with water (20 ml), dried over sodium sulfate and the solvent removed at reduced pressure to leave a residue. The residue is flashed chromatographed on silica gel (25 g) eluting with ethyl acetate/hexane (1/1) to give the product as an oil that is crystallized from ether to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](O)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.BrC1C=CC(C(NC(Cl)C(Cl)(Cl)Cl)=O)=CC=1.[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([NH:44][C:43]2[CH:45]=[CH:46][C:40]([Cl:39])=[CH:41][CH:42]=2)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(Nc1ccc(Cl)cc1)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)benzamide (0.67 g, 1.93 mmol) in chloroform (15 mL) was treated with PCl5 (0.42 g, 1.91 mmol). The mixture was heated to 50° C. for 30 minutes before cooling to room temperature and pouring into crushed ice. The organic layer was dried over MgSO4 and filtered. The solution of 4-bromo-N-(1,2,2,2-tetrachloroethyl)benzamide was cooled to room temperature before addition of 4-chloroaniline (0.52 mL, 4.0 mmol), and the mixture was allowed to stir for 18 hours. The mixture was quenched with 2 M HCl and extracted with ether. The organic solution was dried over MgSO4, filtered, and concentrated onto silica gel. The material was purified on an MPLC with 7:3 CH2Cl2:hexanes to give 4-bromo-N-(2,2,2-trichloro-1-(4-chlorophenylamino)ethyl)benzamide (Compound 6) as a solid. The product may be further purified by an appropriate recrystallization such as in ether.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.ClC1C=CC([O:30][C:31](=O)[CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=C(Cl)C=1Cl.C(N1CCOCC1)C>CN(C)C=O>[CH2:37]([O:36][C:34]([NH:33][CH2:32][C:31]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:30])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1ccc(Cl)c(Cl)c1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
16.5 g of phenylalanine are suspended in 150 ml of dimethylformamide (DMF), 13.5 g of 1-hydroxybenzotriazole, 38.8 g of benzyloxycarbonylglycine-trichlorophenyl ester and 12.8 ml of N-ethylmorpholine are added and the batch is stirred for 8 hours at room temperature. The product is concentrated in vacuo, dissolved in 1 liter of ethyl acetate and submitted to repeated extractions with200ml portions of 2 N citric acid and of saturated sodium chloride solution, respectively. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue crystallizes from ethyl acetate/diisopropyl ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3([OH:16])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[BH4-].[Na+].O.[CH3:20]O>>[CH3:20][N:12]1[CH2:13][CH2:14][CH2:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)([OH:16])[CH2:11]1
Reactant: OC1(c2cccc3[nH]ccc23)CCCNC1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CN1CCCC(O)(c2cccc3[nH]ccc23)C1
Reaction time: 0.25 h

Procedure:
5.8 g of a solution of 40% aqueous formal were added at 0° to -5° C. to a mixture of 13.3 g of 3-(1H-indol-4-yl)-3-piperidinol in 120 ml of methanol and after stirring the mixture for 15 minutes, 4.9 g of 95% sodium borohydride were added thereto. Water was added to the mixture which was then extracted with chloroform containing 20% of methanol. The organic phase was washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and the 11.8 g of residue were crystallized from benzene to obtain 9 g of 1-methyl-3-(1H-indol-4-yl)-3-piperidinol melting 145° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH3:8])[CH:7]=1.[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1>>[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH2:2][C:3]2[N:4]=[CH:5][N:6]([CH3:8])[CH:7]=2)[N:13]=[C:12]([OH:17])[CH:11]=1
Reactant: Cn1cnc(CCl)c1
Reactant: Cc1cc(O)nc(S)n1
Product: Cc1cc(O)nc(SCc2cn(C)cn2)n1
Yield: 60 %

Procedure:
This example was synthesized from 4-(chloromethyl)-1-methyl-1H-imidazole and 6-methyl-2-sulfanylpyrimidin-4-ol following the general procedure as shown in the last step of Example 109. This provided the title compound as a white solid (260 mg, 60% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 3.60 (s, 3H), 4.24 (s, 2H), 5.97 (bs, 1H), 7.06 (s, 1H), 7.52 (s, 1H); M+ 237.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:16]12[CH2:23][CH2:22][CH2:21][C:20]1([CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18][CH2:17]2>>[N:16]12[CH2:23][CH2:22][CH2:21][C:20]1([CH2:24][CH2:25][NH:26][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]3[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:19][CH2:18][CH2:17]2
Reactant: NCCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1c(Br)c[n+]([O-])c2ccccc12
Product: O=[N+]([O-])c1c(NCCC23CCCN2CCC3)c[n+]([O-])c2ccccc12
Yield: 87.4 %

Procedure:
3-Bromo-4-nitroquinoline 1-oxide and 2-(1-azabicyclo[3.3.0]octan-5-yl)ethylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 87.4%.
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:28])[CH:23]=2)[N:18]=1.[K][S:30][C:31](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[S:32][K]>>[CH3:28][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[S:30][C:31](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[S:32][C:26]1=[N:25]2
Reactant: N#CC(C#N)=C(S[K])S[K]
Reactant: Cc1ccc2nc(Cl)c(Cl)nc2c1
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: Cc1ccc2nc3c(nc2c1)SC(=C(C#N)C#N)S3
Yield: 73 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 3.0 g of 2,3-dichloro-6-methylquinoxaline and 3.84 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a yellow powder weighing 2.9 g with a calculated overall yield of 73 percent and has a melting point of 265° to 267° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8]2[N:9]=[C:10](N)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:2].[OH-].[K+].[Cl:15][CH2:16]C(OC)(OC)OC>COCCO.O>[Cl:15][CH2:16][C:10]1[S:11][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=2[N:9]=1
Reactant: COC(CCl)(OC)OC
Reactant: CCc1cccc2sc(N)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CCc1cccc2sc(CCl)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
A solution of 4-ethyl-1,3-benzothiazol-2-amine (1.0 g, 5.6 mmol, 1 equiv.) and KOH (7.4 g, 112.2 mmol, 20 equiv.) in 2-methoxy-ethanol (9 ml) and H2O (9 ml), was stirred under N2 and under reflux, for 20 h. After cooling at r.t., the mixture was poured into water (150 ml) and extracted with CH2Cl2 (2×40 ml). The aqueous phase was neutralised with conc. HCl and extracted again with CH2Cl2 (3×70 ml). The combined neutral extracts were washed with water (2×60 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure. The yellow-green semi-solid residue (790 mg) was mixed with 2-chloro-1,1,1-trimethoxy ethane (1.62 g, 10.4 mmol) and the mixture was stirred, under N2, at 60° C., for 4 h. Volatiles were removed by evaporation under reduced pressure and the brown liquid residue was purified by column chromatography on silica, eluted with CH2Cl2/hexane (10% and 50%), to give a yellow liquid (406 mg, 34% yield over two steps). HPLC-MS (method 1): m/z 212 [M+H]+, Rt=5.00 min
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.1 %

Procedure:
To a solution of 1-(2-hydroxy-phenyl)-ethanone (5 g, 0.03672 mole) in DMF (75 mL) was added NaH (60% w/w dispersion in oil) (1.66 g, 0.0416 mole) and the resulting mixture was stirred at ambient temperature for 15 minutes. Benzyl bromide (7.23 g, 0.0422 mole) was then added and the mixture as stirred for an additional 4 hours. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 8.4 g (100%) of 1-(2-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 84.14%. To a mixture of THF (200 mL) and NaH (60% w/w dispersion in oil) (4.4 g, 0.11 mole) cooled to 0° C. was added diethyl oxalate (10.73 g, 0.07345 mole). The resulting mixture was heated to reflux for 15 minutes. After cooing to ambient temperature, 1-(2-benzyloxy-phenyl)-ethanone (8.3 g, 0.0376 mole) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 8.7 g (71%) of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 78.6%. A solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole), acetic acid (20 mL) and hydrazine hydrate (0.632 g, 0.01264 mole) was heated to reflux for 3 hours. The reaction mixture was then poured into iced water basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.703 g (100%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 97.14%.