Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20][C:21](C)([O-])C.[K+].C(I)C.CN(C)C=O>O1CCCC1>[C:1]([C:3]1[N:7]([CH2:20][CH3:21])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCI
Solvent: C1CCOC1
Product: CCn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC)cc1
Reaction time: 0.25 h
Yield: 11 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.160 g, 0.58 mmol) was dissolved in tetrahydrofuran (10 mL). Potassium tert-butoxide (1.25 mL of a 1 M solution, 1.25 mmol) was dropwise added and the mixture stirred 15 minutes. Ethyl iodide (0.046 mL, 0.58 mmol) was dropwise added, followed by dimethyl formamide (5 mL) and the mixture stirred for 4 hours. The mixture was then partitioned between saturated ammonium chloride and ethyl acetate. The combined organic layers were dried over magnesium sulfate, and concentrated. The residue was purified by silica gel Flash Chromatography (hexane/ethyl acetate; 7:3) to afford the title compound (0.020 g, 11%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]1[C:29]2[CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=[CH:33][C:28]=2[O:27][CH2:26][C:25]1=[O:43]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:28]4[O:27][CH2:26][C:25](=[O:43])[N:24]([CH3:23])[C:29]=4[CH:30]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN1C(=O)COc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc5c(c4)N(C)C(=O)CO5)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one. LCMS (M+H)+=485.0/487.0.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CCOCC>[F:14][C:8]1([F:13])[C:9]2[C:4](=[C:3]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:28]=3)[C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[CH2:5][CH2:6][CH:7]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCC1CCc2c(cc(F)c(F)c2-c2ccc(O)cc2)C1(F)F
Reactant: CCCCCCCCBr
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2c(F)c(F)cc3c2CCC(CCCCCCCC)C3(F)F)cc1

Procedure:
From 4-(2,3,5,5-tetrafluoro-6-octyl-5,6,7,8-tetrahydronaphthalen-1-yl)phenol and 1-octyl bromide by the Williamson ether synthesis.
Reaction SMILES: [CH2:1](CN)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:11]1[CH:12]=[C:13]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[C:27](#[N:29])C>>[CH2:1]([N:29]([CH3:27])[C:11]1[CH:12]=[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1F
Reactant: CC#N
Product: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
A mixture of N-benzylmethylamine (3.6 g, 30 mmol) and 4-(3-fluoro-4-nitrobenzyl)morpholine (2.4 g, 10 mmol) in acetonitrile (3.0 mL) is heated under reflux for 30 min and the solvent is then removed under reduced pressure. The residual oil is partitioned between ethyl acetate (70 mL) and sodium hydroxide solution (10 mL of 1 N) and the ethyl acetate phase is separated and washed twice with water (5 mL). The ethyl acetate is removed and the crude product is applied to a silica gel column. The column is eluted with 50% ethyl acetate/hexane to give 3.3 g of the title compound as an oil.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
In a 2000 ml two neck round bottom flask, 250 g of triphenylamine and 1000 ml of N,N′-dimethylformamide were charged, and the mixture was dissolved by heating to 40° C. A solution (450 ml) prepared by dissolving 190 g of N-bromosuccinimide in N,N′-dimethylformamide was slowly added dropwise using a dropping funnel at room temperature with vigorously stirring and, after the completion of the dropwise addition, the reaction was continuously performed for 1 hour. After the completion of the reaction, 1 ml of water was introduced in the reaction solution and the solvent was removed under reduced pressure. Then, 500 ml of water was added to deposit a product. The deposit was filtered, dried under reduced pressure and then purified by distillation under reduced pressure to obtain 100 g of N-(4-bromophenyl)-N-phenyl-aminobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:38]=[CH:37][C:14]([O:15][C:16]2[C:21]([F:22])=[C:20]([F:23])[C:19]([C:24]3[C:29]([F:30])=[C:28]([F:31])[C:27](F)=[C:26]([F:33])[C:25]=3[F:34])=[C:18]([F:35])[C:17]=2[F:36])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:39]([C:42]1[CH:48]=[CH:47][C:45]([O-:46])=[CH:44][C:43]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([O-:41])=[O:40].[K+]>CN(C)C=O>[N+:39]([C:42]1[CH:48]=[CH:47][C:45]([O:46][C:27]2[C:26]([F:33])=[C:25]([F:34])[C:24]([C:19]3[C:18]([F:35])=[C:17]([F:36])[C:16]([O:15][C:14]4[CH:37]=[CH:38][C:11]([C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])=[CH:12][CH:13]=4)=[C:21]([F:22])[C:20]=3[F:23])=[C:29]([F:30])[C:28]=2[F:31])=[CH:44][C:43]=1[O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([O-:41])=[O:40]
Reactant: O=[N+]([O-])c1ccc([O-])cc1OCc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(F)c(F)c3F)c(F)c2F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Oc2c(F)c(F)c(-c3c(F)c(F)c(Oc4ccc([N+](=O)[O-])c(OCc5ccccc5)c4)c(F)c3F)c(F)c2F)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
49.9 g of the 4-(4-benzyloxycarbonylphenoxy)nonafluorobiphenyl (0.092 mol) prepared as described in Example 1 and 26.1 g of potassium 4-nitro-3-benzyloxyphenoxide (0.092 mol) are dissolved in 400 ml of dimethylformamide, and the solution is heated to 80° C.; the reaction is complete after 24 hours. The solvent is then removed in a rotary evaporator. The solid residue obtained is washed three times with methanol, filtered off via a Büchner funnel and subsequently dried for 48 hours under nitrogen,at 40° C./10 mbar in a vacuum drying cabinet (yield: 94%).
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].[CH3:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:34])[CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:20][C:18]=2[N:19]=1.CCN(CC)CC>CCO>[OH:34][C@@H:26]([CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:17]2[S:16][C:15]([CH3:14])=[N:19][C:18]=2[CH:20]=1)[CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]2=[O:13])[CH2:32][CH2:33]1
Reactant: O=C1C(Cl)CCN1c1ccccc1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C4CCN(c5ccccc5)C4=O)CC3)ccc2s1
Temperature: 85 °C
Reaction time: 60 h

Procedure:
To a solution of 3-chloro-1-phenylpyrrolidin-2-one (100 mg, 0.51 mmol) in EtOH (10 mL) was added 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as prepared in Example 3A (190 mg, 0.62 mmol) and Et3N (0.2 mL, 1.43 mmol). The solution was stirred at 85° C. for 60 hours. Upon cooling, the solution was concentrated to an oil and purified via flash column chromatography to afford 3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-phenylpyrrolidin-2-one.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH:12]([Cl:14])[CH3:13]>C(O)C>[Cl:14][CH:12]([CH3:13])[CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[Br:2]
Reactant: Oc1ccccc1Br
Reactant: CC(Cl)CBr
Agent: [Na]
Solvent: CCO
Product: CC(Cl)COc1ccccc1Br
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added in about 0.5 hour a solution of 173.0 g of o-bromophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hours, cooled to 0°, and treated, dropwise, with 157.5 g of 1-bromo-2-chloropropane. The last addition requires about 1 hour. The mixture is stirred at 0° for about 2 hours and slowly warmed to reflux during about 2 hours, heated under reflux for about 2 hours, filtered from the precipitated sodium bromide, and the filtrate is concentrated in vacuo at 40° to give about 240.2 g of o-bromophenyl 2-chloropropyl ether as a mobile, colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].CC([O-])(C)C.[K+].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:27]=[C:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:25][C:24]=2[S:32]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])=[O:33])[CH:20]=[CH:21][CH:22]=1>CS(C)=O.C(Cl)Cl>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:27]=[C:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[S:25][C:24]=3[S:32]([NH:35][C:36]([CH3:38])([CH3:37])[CH3:39])(=[O:33])=[O:34])[CH:20]=[CH:21][CH:22]=2)[C:3]1=[O:4]
Reactant: CN1CC(=O)NC1=O
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2cccc(CN3C(=O)CN(C)C3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of 1-methylhydantoin (33.9 mg, 0.297 mmol) in DMSO (1 mL) and t-BuOK (46.6 mg, 0.415 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (87.9 mg, 0.198 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using EtOAc:petroleum ether (35:65) as eluent to give the sub-title compound in 54% yield as a colourless syrup (51.5 mg, 0.107 mmol).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]([N:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15][C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]1=2)=[O:11].Cl.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](O)=[O:38])=[CH:31][CH:30]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:27].[Cl:27][C:25]1[CH:24]=[CH:23][C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[CH2:18][N:12]([C:10](=[O:11])[CH2:9][NH:8][C:37](=[O:38])[CH2:36][CH2:35][C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)[C:13]=2[CH:26]=1
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(O)CCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCc1ccncc1)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
Triethylamine (0.8 mL) was added to a stirred mixture of 10-(aminoacetyl)-8-chloro-10,11-dihydrodibenz-[b,f][1,4]oxazepine (0.77 gram) and 4-pyridinepropanoic acid, monohydrochloride (0.50 gram) in dimethylformamide (10 mL) at room temperature under a nitrogen atmosphere. After 5 minutes, the mixture was cooled to 5° C. in an ice bath, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (0.56 gram) was added. The reaction was stirred at room temperature under a nitrogen atmosphere for 60 hours, partitioned between saturated aqueous sodium bicarbonate (100 mL) and ethyl acetate (75 mL), and filtered. The layers of the filtrate were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The ethyl acetate extracts were combined, washed with aqueous saturated sodium bicarbonate (2×100 mL), water (100 mL), and brine (100 mL), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mL) using 9:1 ethyl acetate:ethanol. The purified product was taken up in ethyl acetate and treated with 9.5 M HCl in ethanol to pH 1. The precipitated product was collected by filtration and dried in vacuo at 80° C. Yield: 0.233 gram (19%). Analysis calculated for C23H20ClN3O3 ×1 HCl: C, 60.27; H, 4.62; N, 9.17; Cl, 15.47. Found: C, 59.88; H, 4.66; N, 8.99; Cl, 15.58.
Reaction SMILES: SN=[C:3]=[O:4].[C:5]([O-:18])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCC.C([O-])(=[O:31])CCCCCCCCCCC.C([Sn+2]CCCC)CCC>>[C:3]([OH:4])(=[O:31])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:18])=[O:17]
Reactant: O=C=NS
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: O=C(O)CCCCCCCC(=O)O
Temperature: 100 °C

Procedure:
About 50 grams of the mercaptoisocyanate solution prepared in Example 1 along with 0.01 g of dibutyltin dilaurate should be added to about 40 grams of the above prepared polyester and heated for about 3 hours at 100° C. to form a polyester having reactive mercapto groups.
Reaction SMILES: [N:1]([N:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:3]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)[NH2:1])=[CH:14][CH:15]=1
Reactant: COc1ccc(N(Cc2ccc(Cl)cc2)N=O)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Product: Cl
Temperature: 0 °C

Procedure:
A solution of N-nitroso-N-(4-chlorobenzyl)-4-methoxyaniline (98.7 g; 357 mmol), prepared as above, in 1200 mL THF was cooled to 0° C. and 1230 mL of a 1M solution of diisobutylaluminum hydride in hexanes was added dropwise. The ice bath was removed and the reaction was heated at reflux overnight. The reaction was cooled to ambient temperature and poured into 10% aqueous HCl. The layers were separated and the aqueous was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and then concentrated. The crude material was dissolved in 400 mL of 1:1 ethyl acetate, hexane and treated with HCl gas. The resultant solid was collected to yield 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)-hydrazine hydrochloride which was used with no further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([NH2:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.N1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1.C(OC(=O)C)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]#[N:14])[S:11][C:7]=2[C:6]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(N)=O)nc12
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2)c2sc(C#N)nc12
Yield: 89.9 %

Procedure:
A suspension of 3.51 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1.78 g 1,1′-carbonyl-diimidazol in 30 ml DMF was stirred at room temperature for 18 hours. 0.8 ml Ammonium hydroxide (25% in water) was added and stirring was continued for 5 hours. Extraction with water/ethylacetate and crystallization from dichloromethane yielded 1.17 g (40%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid amide as a yellow solid; M.p.: 228–231° C.; MS (ISP): m/e=294 (M+H+). To a solution of 4.67 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid amide and 2.18 g imidazole in 95 ml pyridine were added at 0° C. 5.95 ml phosphoroxychloride. After 5 hours the cold solution was diluted with ethylacetate and extracted with water. The organic solution was dried with sodiumsulfate and the solvents were distilled off to yield 3.94 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonitrile as yellow solid; M.p.: 145–147° C.; MS (ISP): m/e=276 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=3Br)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[CH:32](=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=3[CH:32]([OH:34])[CH3:33])[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN2CCC(Cc3cc(OC)ccc3Br)CC2)c1
Reactant: CC=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(CCN2CCC(Cc3cc(OC)ccc3C(C)O)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of N-(2-(3-methoxyphenyl)ethyl)-4-(2-bromo-5-methoxybenzyl)piperidine (the compound of Example 64) (500 mg, 1.2 mmol) in tetrahydrofuran (5 ml) was cooled to −78° C., and n-butyllithium (a 1.57M hexane solution, 910 μl, 1.4 mmol) was added dropwise thereto. After the resulting solution was stirred at the same temperature for 30 minutes, acetaldehyde (135 μl, 2.4 mmol) was added dropwise thereto, and the reaction mixture was stirred at the same temperature for another 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added thereto and the resulting mixture was slowly heated to room temperature. Then, the mixture was extracted with ethyl acetate and the combined extract layer was washed with a saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column chromatography (chloroform/methanol=30/1 to 10/1) to obtain the title compound (386 mg, 84%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1>C(#N)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:19][C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(F)cc2s1
Reactant: Cc1nc(CCl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(Cn2c(=O)sc3cc(F)ccc32)no1
Yield: 91.3 %

Procedure:
A mixture of 6-fluoro-2(3H)-benzothiazolone (8.45 g), acetonitrile (100 ml) and potassium carbonate (7.6 g) was prepared. To this mixture was added dropwise 3-chloromethyl-5-methyl-1,2,4-oxadiazole (7.3 g) at a temperature of 40° to 50° C. under stirring. The reaction mixture was heated under refluxing for 5 hours. The reaction mixture was then cooled and filtered. The filtrate was distilled under a reduced pressure, and the residue was admixed with ethyl acetate (200 ml) and water (100 ml). The resultant organic layer was separated and washed with a 5% aqueous potassium hydroxide solution, with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was dissolved in a minimum amount of ethanol under heating. The solution thus formed was cooled to a temperature of 0° to 5° C. to precipitate a crystalline product, which was then separated by filtration, and dried, so that the aimed compound, i.e. 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (12.1 g) was obtained. m.p. 142°-144° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH:12]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1>>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][C:23]([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCC(c1ccc(F)cc1)c1ccc(Br)cc1)OCc1ccccc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(-c2cn[nH]c2)cc1)OCc1ccccc1

Procedure:
[2-(4-Bromo-phenyl)-2-(4-fluoro-phenyl)-ethyl]-carbamic acid benzyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 416.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[N:6]=[C:5]2[N:13]([CH3:15])[CH3:14].C[O:17][CH:18]1[CH:22]([CH:23]=O)[CH2:21][CH:20](OC)O1>CC(O)=O>[CH3:14][N:13]([CH3:15])[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([N:12]2[CH:20]=[CH:21][C:22]([CH:18]=[O:17])=[CH:23]2)[N:6]=1
Reactant: CN(C)c1nc(N)nc2ccc(F)cc12
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CC(=O)O
Product: CN(C)c1nc(-n2ccc(C=O)c2)nc2ccc(F)cc12
Temperature: 90 °C
Yield: 50 %

Procedure:
A stirring mixture of 6-fluoro-N4,N4-dimethylquinazoline-2,4-diamine (20.0 mg, 0.10 mmol), 2,5-dimethyoxy-3-tetrahydrofurancarboxaldehyde (43 μL, 0.30 mmol), and AcOH (500 μL) was heated at 90° C. for 30 minutes. The mixture was evaporated to dryness and the obtained residue was purified via silica gel chromatography using 70% hexanes/30% EtOAc to obtain the desired aldehyde as a white solid (15 mg, 0.05 mmol, 50% yield). LC/MS (10-99%) M/Z 285.1 retention time 3.23 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:16])[NH:14][CH3:15])=[O:11].[C:17](#N)C>CN(C=O)C.CC(N(C)C)=O>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH:15]=[N:14][C:13]([NH:16][CH3:17])=[N:12][C:10]1=[O:11]
Reactant: CC#N
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Temperature: 105 °C

Procedure:
About 200 mg. of 1-(2',6'-dimethylphenyl)-3-methylamidinourea is introduced into a gas chromatograph hypo vial and dissolved in 1 ml. of acetonitrile. To the solution is added 0.2 ml. of DMF DMA reagent. The vial is sealed with crimper and heated at 105° C. for 15 minutes in an oven. Seven vials are made. The contents of the vials are then put into a long-neck round bottom flask and evaporated to dryness by a flask evaporator. The solid mass is dissolved in a mixture of 30 ml. of CH Cl3 and 20 ml. of water and shaken vigorously in a 60 ml. separatory funnel. The aqueous layer is discarded and 20 ml. of water is added and shaken. The CH Cl3 layer is then taken off and about 10 g. of anhydrous Na2SO4 is added, the CH Cl3 solution is decanted into a flask and evaporated to a dryness. The solid material is dissolved in pentanone-2 (about 80 ml.) at 70° C. The solution is concentrated and crystallizes upon cooling. The crystals are collected and dried in a desiccator with P2O5 with vacuum for one hour.