Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH2:48][CH2:49][CH:50]=[CH2:51])[C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(N(CC)CC)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:28]([O:35][C:36]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH2:48][CH2:49]/[CH:50]=[CH:51]/[C:14]2[CH:15]=[CH:16][C:17]3[C:12](=[CH:11][C:10]([N:20]4[CH2:21][C:22](=[O:27])[NH:23][S:24]4(=[O:26])=[O:25])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:18]=3)[CH:13]=2)[C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CCCOc1cccc(OCc2ccccc2)c1C(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1c(OCC/C=C/c2ccc3cc(OCc4ccccc4)c(N4CC(=O)NS4(=O)=O)cc3c2)cccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a microwave vial is added 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (36 mg, 0.082 mmol), 2-benzyloxy-6-but-3-enyloxy-N,N-dimethylbenzamide (53 mg, 0.163 mmol), Pd(OAc)2 (5 mg, 0.021 mmol) and 2-(di-t-butylphosphino)biphenyl (6 mg, 0.021 mmol). The mixture is diluted with acetonitrile (2 mL) and triethylamine (0.023 mL, 0.163 mmol). This is stirred in a microwave for 30 min at 100° C. The reaction mixture is filtered, acidified with 1 N HCl solution and extracted with EtOAc. The organic layer is concentrated and used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17].C(O[C:21](=[NH:23])[CH3:22])C.[C:24]([OH:27])(=[O:26])[CH3:25]>C(#N)C>[C:24]([OH:27])(=[O:26])[CH3:25].[NH:23]=[CH:21][CH2:22][NH:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH3:17]
Reactant: COc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Reactant: CCOC(C)=N
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(C)c(-c2c(C)n[nH]c2NCC=N)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of 5-amino-4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazole (1.89 g) (prepared from 4-methoxy-2,6-dimethyl benzaldehyde according to Example 1 C-F) in acetonitrile (30 mL) add ethylacetimidate (free base, 1.8 mL) followed by acetic acid (0.47 mL). Collect the precipitate that formed upon stirring overnight by filtration. Wash the solid with dry ether and dry to afford 2.61 g of (iminoethyl)[4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazol−5-yl]amine acetate salt as a white powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][Si:2]([CH3:12])([CH3:1])[CH3:13])=[O:18]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: C[Si](C)(C)CCc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CCc1ccccc1NC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
425 mg of 2-(2-trimethylsilylethyl)phenylamine (2.2 mmol) and 438 mg (2.0 mmol) of 2-bromo-benzoyl chloride were dissolved in 20 ml of acetonitrile, and 332 mg (2.4 mmol) of potassium carbonate were added. The reaction mixture was stirred at room temperature for 18 h, 20 ml of water were then added, the mixture was extracted with ethyl acetate and the extract was dried over sodium sulphate. Removal of the solvent and column-chromatographic purification on silica gel 60 (mobile phase: methylene chloride) gave 405 mg (54% of theory) of 2-bromo-N-[2-(2-trimethylsilyl-ethyl)phenyl]benzamide [log P (pH 2.3)=4.32].
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNc1cccc(F)c1)Nc1ccccc1C(=O)O
Yield: 78.3 %

Procedure:
A solution of 2-(N-bromoacetylamino) benzoic acid from Example 79 (8.00 g, 31.0 mmol), meta-fluoroaniline (7.45 mL, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature, and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. to yield 7.00 g (78%) of the title compound as a grey solid; 1H NMR (DMSO-d6) δ 13.5 (broad s, 1H), 11.94 (s, 1H), 8.70 (d, J=8.4, 1H), 7.94 (dd, J=7.8, J=1.4, 1H), 7.60 (td, J=8.0, J=1.4, 1H), 7.15-7.07 (m, 2H), 6.83 (broad s, 1H), 6.43-6.35 (m, 3H), 3.88 (s, 2H); 13C NMR (DMSO-d6) δ 170.29, 169.12, 163.25 (J=240.3), 150.17 (J=10.6), 140.52, 134.18, 131.13, 130.43 (J=10.6), 122.73, 119.40, 115.98, 108.42, 103.09 (J=21.2), 98.97 (J=25), 48.48; MS (EI, m/z) 388 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([S:11][CH3:12])=[C:9](Cl)[N:8]=[C:7]([Cl:14])[N:6]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:10]([S:11][CH3:12])=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[C:7]([Cl:14])[N:6]=1
Reactant: C1COCCN1
Reactant: COC(=O)Cc1nc(Cl)nc(Cl)c1SC
Solvent: C1CCOC1
Product: COC(=O)Cc1nc(Cl)nc(N2CCOCC2)c1SC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2,6-dichloro-5-methylsulfanyl-pyrimidin-4-yl)-acetic acid methyl ester (860 mg, 3.22 mmol.), morpholine (336 mg, 3.86 mmol, 1.2 eq.) and THF (10 ml) was stirred at room temperature for 2.0 hrs. The reaction mixture was dried and the solvent was evaporated. The reaction mixture was subjected to addition of 0.1 N HCl washing free morpholine, extraction with EA and evaporation to remove the EA so as to give a crude. Purification of the crude by flash chromatography on silica gel (Hexane/EtOAc 2:1) gave a gray solid of 427 mg (42.7%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:29]2[CH2:32][CH:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:30]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: C1CN(C2CNC2)CCO1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)n(C)c2n1
Reaction time: 64 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (80 mg, 0.21 mmol), 4-azetidin-3-ylmorpholine (36 mg, 0.25 mmol) and 4 Å powdered molecular sieves (100 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (90 mg, 0.42 mmol). The reaction mixture was stirred for 64 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 328 as a cream solid (71 mg, 67%). LCMS (Method G): RT 5.18 min [M+H]+ 504.2. 1H NMR (CDCl3, 400 MHz): δ 8.10-8.05 (m, 1 H); 7.73-7.69 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.91-3.82 (m, 9 H); 3.73 (m, 4 H); 3.58 (m, 2 H); 3.18-3.04 (m, 3 H); 2.94 (s, 3 H) and 2.35 (m, 4 H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([S:32]([C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCCCCCNCc1ccc(-c2ncccn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCN(Cc1ccc(-c2ncccn2)cc1)S(=O)(=O)c1cccnc1

Procedure:
The title compound of Step B was prepared from 7-(4-pyrimidin-2-yl-benzylamino)-heptanoic acid methyl ester of Step A and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.07 (d, 1H), 8.80 (m, 3H), 8.37 (d, 2H), 8.10 (m, 1H), 7.46 (m, 1H), 7.37 (d, 2H), 7.19 (m, 1H), 4.43 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H), 2.20 (t, 2H), 1.48 (m, 2H), 1.38 (m, 2H), 1.14 (m, 4H); MS 469 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][NH2:30]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:30][CH3:29])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (4.70 g, 11.9 mmol) in ethanol (80 ml) was treated with methylamine (33% w/v in ethanol, 12.0 ml, 96.0 mmol) and the solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (9:1) gradually changing to dichloromethane:ethyl acetate (8:2) to afford the title compound as a pale yellow oil which crystallised on standing (4.23 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([F:10])([F:9])[F:8])=[C:4]([CH2:11][NH2:12])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]([C:27]2[S:28][C:29]([C:33]([NH:12][CH2:11][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][C:5]=3[C:7]([F:10])([F:8])[F:9])=[O:34])=[C:30]([CH3:32])[N:31]=2)[C:23](=[O:36])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(CN)c(C(F)(F)F)o1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1cc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)c(C(F)(F)F)o1
Yield: 28 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (5-methyl-2-(trifluoromethyl)furan-3-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 28% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.75 (t, J=5.7 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.52-7.30 (m, 5H), 6.39 (dd, J=8.1, 2.7 Hz, 1H), 6.26 (s, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.30 (d, J=5.7 Hz, 2H), 2.53 (m, 3H), 2.26 (m, 3H); MS (ES+) m/z 504.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O)(C)C.[CH:8]1([C:14](=O)[CH:15]([CH3:24])[C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O>[CH:8]1([C:14]2[C:15]([CH3:24])=[C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:2]([CH3:1])[N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C(=O)C1CCCCC1)C(=O)C1CCCCC1
Reactant: CNN
Solvent: O
Solvent: CC(C)O
Product: Cc1c(C2CCCCC2)nn(C)c1C1CCCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
Methylhydrazine (1.0 g, 0.022 mole) is added at 60° C-70° C with stirring to an isopropanol (200 ml) solution of 1,3-dicyclohexyl-2-methyl-1,3-propanedione (5.0 g, 0.02 mole) having a m.p. =36°--37° C and prepared by the procedure of Example 3 above. The reaction is heated at reflux for 4 hours, then cooled, water (300 ml) added and the resulting solid filtered off. The solid is dissolved in anhydrous toluene, methyl hydrazine (1.0 g, 0.022 mole) added and the reaction mixture heated at 90° C for 4 hours. Then additional methyl hydrazine (1.0 g, 0.022 mole) is added and heating continued for 3 hours. The reaction mixture is cooled. The solvent removed on a rotary evaporator and the resulting solid crystallized from hexane/benzene to give 1.7 g (32%) of the desired product, m.p. 120° C to 122° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=3[CH3:26])=[O:19])[CH2:10][CH2:9]2)=[CH:2]1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43](=[O:44])[N:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:25]([CH3:26])=[N:24][CH:23]=[N:22][C:21]=3[CH3:27])=[O:19])[CH2:12][CH2:13]2)[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(NCc2ccsc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccsc2)C(=O)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 79.8 %

Procedure:
Following general procedure E: a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (41 mg, 0.1 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.22 mmol), EDCI (39 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and DIPEA (0.05 ml, 0.3 mmol) in CH2Cl2 (2 ml) was stirred overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH, 9:1) afforded 4-{[(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-carbamoyl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8]([CH2:21][O:22][CH3:23])=[C:9]([CH:18]=[N:19][OH:20])[N:10]=[CH:11][C:12]=1[NH:13]2.Cl[O-].[Na+].[CH3:31][O:32][CH2:33][C:34]#[CH:35]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8]([CH2:21][O:22][CH3:23])=[C:9]([C:18]3[CH:35]=[C:34]([CH2:33][O:32][CH3:31])[O:20][N:19]=3)[N:10]=[CH:11][C:12]=1[NH:13]2
Reactant: C#CCOC
Reactant: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cc(-c2ncc3[nH]c4cccc(Cc5ccccc5Cl)c4c3c2COC)no1
Reaction time: 0.33 h
Yield: 8 %

Procedure:
1.06 g (0.0028 mol) of 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carbaldehyde-oxime in 25 ml tetrahydrofuran is mixed with 10 ml of sodium hypochlorite solution at 35° C. under argon. After 20 minutes no more initial material can be detected by thin-layer chromatography. 0.32 ml (0.004 mol) of methylpropargylether is instilled at room temperature and it is stirred for 3 more hours. After being left standing overnight it is diluted with ethyl acetate, washed neutral with water, dried and concentrated by evaporation. The residue is chromatographically separated on silica gel with a mixture of 2 parts tetrahydrofuran and one part of toluene. First a fraction is isolated, which after recrystallization from a dichloromethane/cyclohexane mixture yields 0.1 g (8% of theory) of 5-(2-chlorobenzyl)-4-methoxymethyl-3-(5-methoxymethylisoxazol-3-yl)-β-carboline, melting point 178°-180° C.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl.[NH2:14][OH:15].C(N(CC)CC)C>C(O)C>[F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9](=[N:14][OH:15])[NH2:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: NO
Reactant: CC(C)(F)c1ccc(C#N)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(F)c1ccc(C(N)=NO)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(2-fluoropropan-2-yl)benzonitrile (Step 1, 675 mg, 4.14 mmol), hydroxylamine hydrochloride (632 mg, 9.10 mmol) and triethylamine (1.27 mL, 9.10 mmol) in ethanol (20 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the title compound was obtained (756 mg, 93%): 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H), 7.41 (d, 2H), 4.89 (broad s, 2H), 1.72 (s, 3H), 1.68 (s, 3H); ES-MS m/z 197, HPLC RT (Method F) 1.04 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[N:3]=1.[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:23][CH3:24]>>[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:19]2[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]4[N:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[CH:8][CH:9]=3)[CH2:17][CH2:18]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(-c2ccc(CC(=O)N3CCNCC3)cc2)no1
Product: CCCc1ccc(S(=O)(=O)N2CCN(C(=O)Cc3ccc(-c4noc(C)n4)cc3)CC2)cc1

Procedure:
Similarly to Example 1, reaction of 2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-1-piperazin-1-ylethan-1-one (“B”) and 4-propylphenylsulphonyl chloride gives the compound 1-[4-(4-propylphenylsulphonyl)piperazin-1-yl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]ethan-1-one and, after hydrogenation, 4-{2-oxo-2-[4-(4-propylphenylsulphonyl)piperazin-1-yl]ethyl}benzamidine, FAB 429.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)ccn1
Yield: 47.3 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (143 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (100 mg, 47%). MS (ISP) 423.0 [(M+H)+]; mp 275° C.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[Na+]>O>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:3][S:4][N:5]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=c1c(Cl)nsnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c(Cl)nsnc1Oc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A suspension of 1.83 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 100 ml of water is stirred mechanically at room temperature while a solution of 1.29 g of p-chlorophenol, 20 ml of H2O and 5 ml of 2N aqueous sodium hydroxide solution is added dropwise to it. The mixture is stirred an additional 1 hour. The resulting precipitate is collected and recrystallized from alcohol. The white crystals melt at 142°-145°. The compounds described in Table II can be prepared by the same procedure as Example 2 substituting the appropriate phenol for p-chlorophenol.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].[Cl-].[NH4+]>C(Cl)Cl>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(C2CCCCC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 10.6 ml of phenylcyclohexane in 100 ml of methylene chloride was added at 5° C. within 30 minutes to 13.8 ml of chlorosulfonic acid. The mixture was stirred at 5° C. for 1 hour, poured into 400 ml of a 20% ammonium chloride solution and extracted twice with 300 ml of methylene chloride each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. 13.6 g of 4-cyclohexyl-benzenesulfonyl chloride separated as a reddish oil, which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]4[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=4)[N:18]=3)=[CH:15][N:16]=2)[CH2:8][CH2:7]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:30][C:28]1[CH:27]=[CH:26][N:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:14]3[S:13][C:12]([N:9]4[CH2:8][CH2:7][CH:6]([CH2:5][CH2:4][C:3]([OH:31])=[O:2])[CH2:11][CH2:10]4)=[N:16][CH:15]=3)[CH:22]=[CH:21][CH:20]=2)[CH:29]=1
Reactant: COC(=O)CCC1CCN(c2ncc(-c3cccc(Nc4cc(C)ccn4)n3)s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(CCC(=O)O)CC4)s3)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.8 %

Procedure:
To a mixed solution of 3-(1-{5-[6-(4-methyl-pyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}piperidine-4-)propionic acid methyl ester (250 mg, 0.57 mmol) obtained in Step 3 in tetrahydrofuran (5 ml) and methanol (5 ml), 4N sodium hydroxide (1.5 ml, 6.0 mmol) was added and the mixture was stirred at room temperature for 12 hours. The concentrate obtained by concentrating the reaction solution in vacuo was neutralized with 0.1N hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and the title compound (142 mg, 59%) was obtained.