Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(=O)c2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-methoxyphenyl)acetate dihydrochloride (I106) (325 mg, 0.89 mmol) in DCM (10 ml), were added triethylamine (374 μl, 2.68 mmol) and benzoyl chloride (125 μl, 1.07 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-(4-methoxyphenyl)acetate (145 mg; 41% yield). The product was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].ClC1C=CC(N[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][CH2:26]Cl)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=C(F)C=1>CN(C=O)C.O>[CH2:1]([S:3][CH2:26][CH2:25][CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:11]=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22])[CH3:2]
Reactant: CC[S-]
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCCl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCCCOc1cc2ncncc2cc1OC
Temperature: 70 °C
Yield: 54.2 %

Procedure:
A mixture of sodium ethanethiolate (120 mg, 1.5 mmol) and 4-(4chloro-2-fluoroanilino)7-(3-chloropropoxy)-6-methoxyquinazoline (227 mg, 0.57 mmol) in DMF (10 ml) was stirred and heated at 70° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water and extracted with ethyl acetate (3×75 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was recrystallised from ethyl acetate/hexane to give 4chloro-2-fluoroanilino)-7-(3-(ethylthio)propoxy)6-methoxyquinazoline (86 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:33](Br)[CH3:34]>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[N:19]([CH2:33][CH3:34])[C:18]([C:22]4[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:29])=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2cccc(Cl)c2F)cc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(-c2c(F)cccc2Cl)nn(-c2ccc(C#Cc3cccc(Cl)c3F)cc2)c1=O

Procedure:
The title compound was prepared by following the procedure as described for Intermediate-41 by using 1-(4-((3-chloro-2-fluorophenyl)ethynyl)phenyl)-3-(2-chloro-6-fluorophenyl)-1H-1,2,4-triazol-5(4H)-one (Example-12, 0.070 g, 0.15 mmol), dry DMF (3 mL), NaH (0.010 g, 0.23 mmol) and ethyl bromide (0.026 g, 0.23 mmol) to afford 0.030 g of the crude product which was purified by column chromatography in basic alumina eluting with 0.2% methanol:DCM to afford 0.030 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 1.09 (t, 3H), 3.56 (m, 2H), 7.29 (t, 1H), 7.52-7.84 (m, 7H), 8.04 (d, J=8.1 Hz, 2H); MS (m/z): 470.06 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH:15](C)[CH2:14]2)[CH:3]=1.[CH3:27][C:28]1([NH:33][C:34](=[O:36])[CH3:35])[CH2:32][CH2:31][NH:30][CH2:29]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][C:28]([NH:33][C:34](=[O:36])[CH3:35])([CH3:27])[CH2:29]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(Cl)c2c1
Reactant: CC(=O)NC1(C)CCNC1
Product: CC(=O)NC1(C)CCN(c2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C)cc23)C1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 26 by using 4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(3-methylpyrrolidin-3-yl)acetamide.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:38][O:39][CH2:40][C:41]#[CH:42]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:42]#[C:41][CH2:40][O:39][CH3:38])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCC#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 3-methoxypropyne (350 mg, 10.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (40 mg), and copper(I) iodide (20 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed with toluene (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (1/3 to 1/2 ethyl acetate/hexane) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-methoxy-prop-1-ynyl)-pyrazin-2-yl]-propionamide (330 mg, 69.5%) as a fluffy solid: (ES)+-HRMS m/e calcd for C23H26ClN3O4S (M+H)+ 476.1406, found 476.1405.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(F)cc3F)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[F:21][C:22]([F:32])([F:31])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24]>CN(P(N(C)C)(N(C)C)=O)C>[F:32][C:22]([F:21])([F:31])[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][C:3]=2[Cl:20])[CH2:27][CH2:26]1)=[O:24]
Reactant: O=C(N1CCNCC1)C(F)(F)F
Reactant: CC1CCc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCN(C(=O)C(F)(F)F)CC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Yield: 50.6 %

Procedure:
A mixture of 3.1 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoroacetylpiperazine and 50 ml of HMPTA was heated at 160° C. for 4 hours under atmosphere of argon. After completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was washed with water. Recrystallization of the residue from dimethylformamide gave 2.3 g of 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[N:10]([CH3:21])[N:9]=2)=[C:4]([F:22])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>>[Cl:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:16])([F:14])[F:15])=[C:11]([C:17]([F:18])([F:19])[F:20])[N:10]([CH3:21])[N:9]=2)=[C:4]([F:22])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2ccc(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Product: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Temperature: 0 °C
Yield: 59 %

Procedure:
10.5 g (30 mmol) of 3-(4-chloro-2-fluorophenyl)-l-methyl-4,5-di(trifluoromethyl)-1H-pyrazole were added, at (-40)° C. to 90 ml of concentrated nitric acid, whereupon the mixture was stirred for 1 hour. Then, the mixture was stirred in 0.8 1 of ice-water. The product of value was subsequently extracted with dichloromethane. The organic phase was dried over magnesium sulfate and finally concentrated. Yield: 59%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:36]C(=O)C)[CH:10]=1.[CH:40]1([S:43](Cl)(=[O:45])=[O:44])[CH2:42][CH2:41]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:36][S:43]([CH:40]2[CH2:42][CH2:41]2)(=[O:45])=[O:44])[CH:10]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCN(C)CC5)nn4)ccc32)c1
Product: CN1CCC(n2cc(-c3ccc4c(c3)ncn4-c3cc(NS(=O)(=O)C4CC4)cc(-c4ccc(F)cc4F)c3)nn2)CC1

Procedure:
The compound was prepared from the compound of Example 164 using the procedures of Example 165 and cyclopropane sulfonyl chloride. LC-MS (ESI): Calculated mass: 553.61; Observed mass: 554.2 [M+H]+ (rt: 0.57 min).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([OH:26])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.Cl.[NH:28]1[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:24]([C:16]2[CH:15]=[C:14]([O:13][CH:4]3[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[O:7][CH2:6][CH2:5]3)[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=2)=[O:26])[CH2:31][CH2:30][CH2:29]1
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Reactant: C1CNC1
Agent: Cl
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CCC3)cc2[nH]1

Procedure:
The title compound was prepared as a white solid (132 mg, 79%) from (−)-4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid (150 mg, STEP 1) and azetidine hydrochloride (117 mg, 1.25 mmol) by the same manner in STEP 5 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])=[O:21])=[CH:17][CH:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CNCCOC
Reactant: O=C(O)c1ccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)cc1
Product: COCCN(C)C(=O)c1ccc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)cc1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield (10.1 mg) prepared from 4-(4-(4-chlorophenoxy)piperidine-1-carbonyl)benzoic acid (Step-2) according to the procedure similar to that described in Step-2 of Example 349, using 2-methoxy-N-methylethanamine instead of 25% ammonium water.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:16]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2ccccc2)c1
Reactant: O=[Se]=O
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
The invention relates to a process for the oxidation of meta-phenoxytoluene by selenium dioxide in the presence of a dehydrating agent to produce meta-phenoxybenzaldehyde containing less than 250 ppm dissolved selenium. The invention relates to a process whereby the benzaldehyde can be recovered from the reaction mixture as the bisulfite addition product at the rate of 90%/hr. The invention further relates to a stoichiometric selenium dioxide oxidation of meta-phenoxytoluene to yield a selectivity of about 90% or greater based on the toluene.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[NH4+].[Cl-]>CCOCC.C1COCC1>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[B:18]([OH:23])[OH:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(I)c(I)cc1OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(I)c(B(O)O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 1,2-diiodo-4,5-dimethoxybenzene (Example 6(b), 2.0 g, 5.13 mmol) in 120 mL of a mixture of THF and Et2O (1:1) was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 2.67 mL, 5.39 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (10.89 ml, 15.39 mmol) was added. The solution was warmed to room temperature overnight; then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to give 1.05 g of the pure product (67%).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[N+:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([OH:28])=[C:20]([CH:6]([C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[O:3][CH3:2])[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:19]=1
Reactant: COc1ccccc1C=[N+]1CCCCC1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: [Cl-]
Product: COc1ccccc1C(c1cc(Cl)c2ccccc2c1O)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(2-methoxy-benzylidene)-piperidinium chloride and 4-chloro-1-naphthol.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][CH:14]=1)=[O:12].[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][CH:14]=2)=[O:12])=[O:28])[N:26]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1cnc2sccn12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2cnc3sccn23)c1

Procedure:
prepared by reaction of imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[S:27][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([OH:23])=O)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Cl.CN.C[CH2:32][N:33](C(C)C)C(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[S:27][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH:33][CH3:32])=[O:23])[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: O=C(O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)c1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
3-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)benzoic acid (118 mg, 0.29 mmol) was heated in 3 mL of thionylchloride at 80° C. for 3 h. The reaction was cooled to room temperature and the thionylchloride was removed under reduced pressure. The residue obtained was dissolved in 25 mL of DCM followed by addition of methylamine hydrochloride (60 mg, 0.88 mmol) and DIEA (227 mg, 1.76 mmol). The reaction was allowed to stir at room temperature for 16 h and washed with 25 mL of water. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure; the crude product was purified by silica chromatography in 5% MeOH-DCM to obtain 58 mg of product in 48% yield. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.76 (s, 1H), 7.65 (d, 1H), 7.45 (d, 1H), 7.39 (t, 1H), 7.02 (s, 1H), 6.22 (bs, 1H), 4.96 (bs, 1H), 4.18 (m, 1H), 3.57 (s, 2H), 3.03 (d, 3H), 2.87 (d, 2H), 2.23 (t, 2H), 2.08 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C20H23ClN5OS, 416.13; Observed: 416.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][N:13]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]1[C:21]([OH:23])=O>>[CH3:12][N:13]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]1[C:21]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH:11][C:21]([C:14]3[N:13]([CH3:12])[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=3)=[O:23])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:23]
Reactant: Nc1ccc2nc(N)sc2c1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)Nc1ccc2nc(NC(=O)c3cc([N+](=O)[O-])cn3C)sc2c1

Procedure:
The compound 8b was prepared according to the above described method using compound 7 (165 mg, 1 mmol) and 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid (340 mg, 2 mmol). Yield 290 mg, 60%; 1H NMR (DMSO-d6) δ 10.9 (bs, 1H, —NH), 8.54 (s, 1H), 7.95 (s, 2H), 7.74-7.71 (m, 2H), 7.50 (s, 2H), 3.96 (s, 6H); ESIMS: m/z 470 (M+H)+.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][OH:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Product: Clc1ccc(-c2nc(OCc3ccc(Cl)c(Cl)c3)ncc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 3,4-dichlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(3,4-dichlorobenzyloxy)-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=509 (M++1); Rt=5.14 min; 1H-NMR 400 MHz (CDCl3): δ 5.56 (s, 2H), 7.12 (d, J=9 Hz, 1H), 7.22-7.25 (m, 4H), 7.27-7.40 (m, 3H), 7.28 (m, 1H), 7.68 (d, J=2 Hz, 1H), 8.45 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](Cl)=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: CNCCO
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)N(C)CCO)cccc2c1=O
Reaction time: 2.5 h

Procedure:
A solution of 1.6 ml of 2-methylaminoethanol in 10 ml of water was added dropwise over a period of 5 minutes to a suspension of 6 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride (prepared as described in Da Re, P. et al., J. Med. Pharm. Chem. 2: 263 (1960)) and 1.52 g of potassium carbonate in 60 ml of acetone. After stirring for 2.5 hours at 20°-25° C., the solvent was removed in vacuo and the residue was taken up in 150 ml of acetone. The mixture was refluxed for 15 minutes, and was then filtered. The solvent was evaporated from the filtrate and the residue was dissolved in 20 ml of dimethylformamide, treated with 14 ml of a 1.4% sodium carbonate solution, stirred for 30 minutes at 20°-25° C. and diluted by addition of 150 ml of water. The mixture was extracted with chloroform and the organic layer was washed with 0.5N hydrochloric acid and then with water. The solution was dried on anhydrous sodium sulphate, filtered and evaporated to dryness in vacuo. The resulting oil was taken up in 200 ml of diethyl ether and stirred for 2 hours at 20°-25° C. The solid was collected by filtration and crystallized from ethyl acetate to give 2.97 g of the title compound, melting point 128°-130° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[N:9]([CH2:12][C:13](OCC)=[O:14])=[C:10]=[S:11].C(N(CC)CC)C>C(#N)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]1[C:13](=[O:14])[CH2:12][NH:9][C:10]1=[S:11])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)CN=C=S
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1C(=O)CNC1=S
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Glycine ethyl ester hydrochloride (140 mg, 1 mmol) and ethyl isothiocyanatoacetate (145 mg, 1 mmol) were dissolved in acetonitrile (6 mL), triethylamine (0.6 mL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 10 minutes. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (1/1 (volume ratio)) as an eluent, to give ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate in a yield of 170 mg (yield 84.2%).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])[CH2:12][CH2:13]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1ccccc1C1=CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC(c2ccccc2C(F)(F)F)CC1
Yield: 83.4 %

Procedure:
Using the procedure from Example 14A, Step 14D, 1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with 4-chlorobenzenesulfonyl chloride (165 mg, 0.78 mmol) to afford the title compound (219 mg), a white solid, in 84% yield.