Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[C:20]([S:40]([CH3:43])(=[O:42])=[O:41])[CH:19]=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:30][CH2:31]2)=[O:25])=[C:20]([S:40]([CH3:43])(=[O:41])=[O:42])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 70.1 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.0 g) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 4, the title compound (950 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[OH:10][C:9]1[C:2]([O:1][CH2:18][CH2:19][CH3:20])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH:4]=[O:5]
Reactant: CCCI
Reactant: O=Cc1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(O)cccc1C=O
Yield: 42.3 %

Procedure:
2,3-Dihydroxybenzaldehyde (1.16 g, 8.40 mmol), potassium carbonate (1.16 g, 8.40 mmol) and 1-iodopropane (0.82 mL, 1.43 g, 8.40 mmol) in dry DMF (10 mL) were stirred at ambient temperature for 20 h. The reaction mixture was poured into water and extracted with diethyl ether. The diethyl ether layer was washed with water (2×), then extracted with 1N sodium hydroxide solution (3×). The basic extracts were combined and acidified by addition of 3N hydrochloric acid, then extracted with diethyl ether. The ether layer was washed with 10% sodium hydrogen carbonate (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 3-hydroxy-2-propoxybenzaldehyde (0.64 g, 42%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1.[O:20]1[CH2:25][CH:24]=[C:23]([C:26]2[C:27](F)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1.O>CN1C(=O)CCC1>[O:20]1[CH:21]=[CH:22][CH:23]([C:26]2[C:27]([O:19][C@H:16]3[CH2:15][CH2:14][C@H:13]([NH:12][C:4]4[S:3][C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]=4)[CH2:18][CH2:17]3)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:24][CH2:25]1
Reactant: Fc1ncccc1C1=CCOCC1
Reactant: O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C1=CC(c2cccnc2O[C@H]2CC[C@H](Nc3nc4ccccc4s3)CC2)CCO1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.054 g, 1.3 mmol, 60% dispersion in mineral oil) was added to a mixture of trans-4-(benzo[d]thiazol-2-ylamino)cyclohexanol (0.17 g, 0.67 mmol) in NMP (1.5 mL) in a microwave tube. The tube was sealed and placed under an argon atmosphere. The mixture was stirred at RT for 45 min before 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine, as prepared in preparation 1a, step 1, (0.10 g, 0.56 mmol) was added via syringe. The reaction mixture was warmed to 120° C. and stirred for 1 h. Water was added, and the aqueous mixture was extracted with EtOAc (2×). The organic extracts were combined, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified via silica gel chromatography to give both N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclohexyl)benzo[c/]thiazol-2-amine and N-(trans-4-(3-(3,4-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine as white solids. [M+1] 408.1 each. IC50 (uM): 0.007281 (Example 3b) and 0.9154 (Example 3c).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[N:3]=1.C1COCC1.[NH3:29]>CCOC(C)=O>[NH2:29][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[N:3]=1
Reactant: N
Reactant: O=C(COc1nc(Cl)nc(Cl)n1)Nc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(Cl)nc(OCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: -78 °C
Yield: 25.2 %

Procedure:
To a 25 mL recovery flask was added 2-(4,6-dichloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide (293 mg, 0.798 mmol, 1.0 eq.) and a stirbar. THF (7 mL) was added and the resulting solution was cooled to −78° C. Ammonia (NH3, 2.0 M in EtOH, 2.00 mL, 6 mmol, 5 eq.) was added in 400 μl aliquots until the reaction was complete by LC/MS analysis. The reaction mixture was diluted with EtOAc (50 mL) and washed with H2O (1×50 mL) and brine (1×50 mL). The combined aqueous phases were extracted with EtOAc (2×25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid. The solid washed with EtOAc to give 2-(4-Amino-6-chloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (70 mg, 25%). LC/MSD (HP Series 1100 MSD) Expected MW: 357.04, Observed M−H, 358.1, Retention time: 1.37. 1H-NMR, DMSO-d6, Varian 400 MHz δ 10.54 (s, 1H), 8.10-8.07 (m, 2H), 8.02 (s, 1H), 7.78 (d, 1H), 7.57 (t, 1H), 7.43 (d, 1H), 4.96 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].O.S([O-])([O-])=O.[Na+].[Na+].[Br:30]Br>C(O)(=O)C>[CH2:1]([CH:3]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([Br:30])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: BrBr
Reactant: CCC(CC)Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(CC)Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reaction time: 0.5 h

Procedure:
EPAQ (20.02 g) was dissolved in hot acetic acid. In a separate flask, bromine (12.03 g) was dissolved in acetic acid (ca. 10 mL). The bromine solution was slowly added to the dye solution. The reaction was allowed to proceed for 1/2 hour, with occasional shaking. The reaction mixture was poured into water (600 mL), and aqueous sodium sulfite was added to discharge the bromine. The aqueous solution was decanted off. The solid was dissolved in methylene chloride and then concentrated and slowly added to cold methanol whereupon a solid precipitated.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[CH3:18])[O:14][CH2:13][C:12]1[N:7]2[CH:8]([CH3:20])[C:9](=[O:19])[NH:10][N:11]=1.Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[CH3:18])[O:14][CH2:13][C:12]1[N:7]2[CH:8]([CH3:20])[C:9](=[O:19])[N:10]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:11]=1
Reactant: Cc1cc2c(cc1Br)N1C(=NNC(=O)C1C)CO2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1Br)N1C(=NN(COCC[Si](C)(C)C)C(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a suspension of NaH (60%, 0.387 g, 9.67 mmol) in DMF (15 mL) was added 6-bromo-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 6.45 mmol) in portions and the reaction mixture was stirred at 0° C. for 0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (1.613 g, 9.67 mmol) was added and the reaction mixture was warmed to ambient temperature and stirred for 2 h. Water (100 mL) was added and the aqueous solution was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 30% EtOAc in petroleum ether) to give 6-bromo-4,7-dimethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as solid (2.24 g, 79%). 1H NMR (DMSO-d6, 400 MHz): δ 7.52 (s, 1H), 7.12 (s, 1H), 5.01 (m, 2H), 4.95 (m, 1H), 4.68 (s, 2H), 3.60 (m, 2H), 2.28 (s, 3H), 1.32 (m, 3H), 0.89 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[NH:7][C:8]1[CH:17]=[CH:16]C=CC=1C(NC)=O)([O-:3])=[O:2].[NH2-].[Na+].[C:23]1([N:29]=[C:30]=[O:31])C=CC=CC=1.[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:35](=[CH:34][CH:33]=[CH:16][CH:17]=3)[C:36](=[O:32])[N:29]([CH3:23])[C:30]2=[O:31])[CH:18]=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: CNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Reactant: O=C=Nc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Product: Cn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.6 g of 2-(m-nitroanilino)-N-methylbenzamide and 20 ml of tetrahydrofuran was added 0.86 g of sodium amide, and the whole was stirred for 30 minutes at room temperature. To this was added dropwise under cooling 3.6 g of phenyl isocyanate, and the mixture was stirred for one hour at room temperature, and then refluxed for 4 hours. After the reaction was finished, the solvent was distilled off from the resulting mixture. The residue thus obtained was recrystallized from methanol to give 2.2 g of 1-(m-nitrophenyl)-3-methylquinazoline-2,4(1H, 3H)-dione as colorless needles, melting at 241°-242° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]2[C:14]3[CH2:15][CH2:16][CH2:17][C:13]=3[S:12][C:8]2=[N:9][C:10]=1[CH3:11].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:35]1[CH2:39]OC[CH2:36]1.ICCC>CN(C=O)C>[CH3:11][C:10]1[N:9]=[C:8]2[S:12][C:13]3[CH2:17][CH2:16][CH2:15][C:14]=3[C:7]2=[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]=1[CH:4]([CH2:36][CH2:35][CH3:39])[C:3]([O:2][CH3:1])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Yield: 85.8 %

Procedure:
This compound was prepared according to the procedure C from methyl[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.115 g; 0.341 mmol), LHMDS 1N in THF (0.375 mL; 0.375 mmol), 1-iodopropane (0.050 mL; 0.513 mmol) in DMF (5 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.111 g (86%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[N:4]([C:9](=[O:13])[CH2:10][O:11][CH3:12])[CH2:5][C:6]([CH3:8])=O.Cl.[CH3:20][O:21][NH2:22].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[N:4]([CH2:5][C:6](=[N:22][O:21][CH3:20])[CH3:8])[C:9](=[O:13])[CH2:10][O:11][CH3:12]
Reactant: COCC(=O)N(CC(C)=O)c1c(C)cccc1C
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCC(=O)N(CC(C)=NOC)c1c(C)cccc1C
Yield: 94.3 %

Procedure:
20 g (0.08 mol) of 2,6-dimethyl-N-methoxyacetyl-N-acetonylaniline, 7.5 g (0.09 mol) of O-methyl-hydroxylamine hydrochloride and 9.1 g (0.09 mol) of triethylamine in 100 ml of ethanol were heated under reflux for 5 hours. After distilling off the solvent in vacuo, the residue was partitioned between water/methylene chloride. The organic phase was separated off, dried over sodium sulphate and concentrated. After adding petroleum ether, the residue crystallized. 21 g (94% of theory) of 2,6-dimethyl-N-(2-methoxyimino-prop-1-yl)-N-methoxyacetylaniline of melting point 56°-57° C. were obtained.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][C:19]=1[CH3:28]>CO>[NH2:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:14]([C:10]2[CH:9]=[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[C:19]([CH3:28])[CH:20]=1)(=[O:25])=[O:26]
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: CO
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-3-methyl-benzenesulfonamide (Biofocus), the title compound was obtained as a white solid after trituration in methanol.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:7][CH:8]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=[O:28].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:10](=[O:13])[CH2:11][CH2:12][C:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[O:28])=[N:7][CH:8]=1
Reactant: O=Cc1ccccn1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)nc1
Temperature: 25 °C
Yield: 37 %

Procedure:
To a solution of 4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (55.4 mg) in ethanol (1 mL) were added pyridine-2-carbaldehyde (21.7 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (5.6 mg) and triethylamine (11.4 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (27.7 mg, yield 37%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][NH:6][C:7]1[N:12]=[C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[C:10]2[C:21](=[O:24])[NH:22][CH2:23][C:9]=2[CH:8]=1.[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.CCOC(C)=O.C1COCC1.CCOC(C)=O>[F:34][C:8]1[C:9]2[CH2:23][NH:22][C:21](=[O:24])[C:10]=2[C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:12][C:7]=1[NH:6][CH2:5][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:3][O:2][CH3:1]
Reactant: F[B-](F)(F)F
Reactant: COC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC[C@@H](CNc1nc(Nc2cccc(C)c2)c2c(c1F)CNC2=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a screw-top vial was added (R)-tert-butyl 1-methoxy-3-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)propan-2-ylcarbamate (27 mg, 0.061 mmol) in a mixture of DCM and MeOH (1/1, 1.2 mL). The resulting colorless solution was cooled to 0° C. SELECTFLUOR® (21.66 mg, 0.061 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. Next, the reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aq sodium bicarbonate (5 mL), water (5 mL), and brine (5 mL). The organic layer was collected, dried over Na2SO4, and concentrated to give the title compound as a brown residue, which was used without further purification (32 mg, 114%). [M+H] calc'd for C23H30FN5O4, 460. found, 460.
Reaction SMILES: C([N:4]1[CH2:12][CH2:11][CH:7]([C:8]([Cl:10])=O)[CH2:6][CH2:5]1)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[ClH:10].[C:7]1([CH3:8])[CH:11]=[CH:12][C:8]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:12][CH2:11]2)=[CH:5][CH:6]=1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C2CCNCC2)cc1
Product: Cl

Procedure:
By following the manipulative procedures described above in Examples 1(c) and (d), 1-acetylisonipecotoyl chloride, Example 1(b), toluene, and aluminum chloride are reacted to produce 4-(4-toluyl)piperidine hydrochloride. The salt is recrystallized thrice from a methanol-ether mixture (one charcoal treatment) to give colorless needles, mp 275°-277° C., (dec.).
Reaction SMILES: [C:1]1([S:7][CH2:8][N:9]=[C:10]=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH-:12].[K+:13]>CC(C)=O.C(O)(C)(C)C>[C:1]1([S:7][CH2:8][NH:9][C:10](=[S:12])[S-:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+:13]
Reactant: [SH-]
Reactant: S=C=NCSc1ccccc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CC(C)=O
Product: S=C([S-])NCSc1ccccc1

Procedure:
Potassium phenylthiomethyldithiocarbamate was prepared by the reaction of phenylthiomethyl isothiocyanate and potassium hydrosulfide in a t-butyl alcohol acetone mixture.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:11][C:12](=O)[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[N:24]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]2=[N:22][N:21]=1)(C)(C)C>C1COCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([C@@H:16]3[CH2:17][CH2:18][CH2:19][N:15]3[CH2:14][CH2:13][CH2:12][OH:11])=[N:21][N:22]=2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)CCN1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Lithium aluminium hydride solution (2M in THF, 1.64 mL, 3.28 mmol) was added to a solution of Intermediate 84d (550 mg, 1.64 mmol) in THF (15.0 mL) at −10° C. The reaction was stirred for 1 h then quenched by dropwise addition of water (125 μL), sodium hydroxide (3M aqueous, 125 μL) and water (375 μL). The reaction was stirred for 10 min then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 2-10% (2M NH3 in MeOH) in DCM, to give the title compound (145 mg, 33%). LCMS (Method 4): Rt 0.32 mins, m/z 265.2 [MH+].
Reaction SMILES: C[Si](C)(C)[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH3:10][C:11]1([CH3:18])[NH:15][C:14](=[O:16])N[C:12]1=[O:17].N>S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.C1(C)C=CC=CC=1>[CH3:5][Si:4]([CH3:7])([CH3:6])[N:15]1[C:11]([CH3:18])([CH3:10])[C:12](=[O:17])[N:3]([Si:4]([CH3:5])([CH3:6])[CH3:7])[C:14]1=[O:16]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N([Si](C)(C)C)C(=O)N1[Si](C)(C)C
Reaction time: 1 h
Yield: 152.6 %

Procedure:
80 ml of hexamethyldisilazane (0.38 mole) were added over 30 minutes to a refluxing suspension of 50 ml of toluene, 40 mg (0.22 mmole) of saccharin and 38.45 g (0.30 mole) of 5,5-dimethylhydantoin and evolution of ammonia started immediately. When half of the hexamethyldisilazane had been added, all solids had gone into solution and after the addition of the hexamethyldisilazane, reflux was continued for 1 hour. Toluene was distilled off and the residue was vacuum dried at 45° C. to obtain 79.0 g (97%) of 1,3-bis-(trimethylsilyl)-5,5-dimethylhydantoin melting at 46°-49° C. According to NMR analysis, the purity of the compound was 91%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=[O:14].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:18]=1[CH2:19]Br>CN(C)C=O>[CH3:26][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[C:18]=1[CH2:19][N:8]1[C:7](=[O:14])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([OH:3])[CH:5]=2)[N:10]=[CH:9]1
Reactant: COc1cccc(OC)c1CBr
Reactant: O=c1[nH]cnc2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1Cn1cnc2ccc(O)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
76 mg of sodium hydride (80% in mineral oil) are added to a suspension of 400 mg of 6-hydroxy-3H-quinazolin-4-one in 20 ml of dry dimethylformamide. After stirring for 30 minutes at room temperature, 560 mg of 2,6-dimethoxybenzylbromide are added, and stirring is continued overnight. The solvent is distilled off in vacuo, and the residue partitioned between aqueous pH7-buffer solution and ethyl acetate. The organic phase is separated, dried over magnesium sulfate and evaporated in vacuo. Silica gel chromatography yields a minor amount of the N,O-bis-alkylated product followed by the pure title compound as colourless crystals. mp: 243-245°.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:21](=O)[CH2:22][C:23](OC)=[O:24])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:21]3[CH:22]=[C:23]([OH:24])[N:1]([C:3]4[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=4)[N:2]=3)[CH2:19][CH2:20]2)=[CH:16][CH:17]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COC(=O)CC(=O)C1(c2ccc(Cl)cc2)CC1
Product: N#Cc1ccnc(-n2nc(C3(c4ccc(Cl)cc4)CC3)cc2O)c1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 3-[1-(4-chlorophenyl)cyclopropyl]-3-oxopropanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]#[N:11].[C-]#N.[Na+]>>[C:1]([C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C#N
Agent: [C-]#N
Agent: [Na+]
Product: N#CC(=O)c1ccccc1

Procedure:
Process as claimed in claim 1 wherein benzoyl chloride is heated in the presence of hydrocyanic acid anhydrous pyridine and sodium cyanide, to form benzoyl cyanide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][S:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCSCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-thiomorpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J7) (189 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (150 mg, 0.61 mmol) according to the general procedure M. Obtained as a yellow solid (273 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([SiH3])[CH:16]=C(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]([OH:11])[CH2:16][CH:15]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CC(C)[SiH3]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of the product of step b (20 mmol, 3.74 g) in 20 ml of CH2Cl2 at -78° C., 22 ml of a solution 1 M of TiCl4 in CH2Cl2 is added. After 10 min, trimethyallylsilane (22 mmol, 3.5 ml) in 20 ml of CH2Cl2 is added. After one hour the reaction is quenched with water. The organic layer is separated and extracted with CH2Cl2 (3×25 ml). The solution is anhydrified (Na2SO4) and after concentration 1.14 g of product is obtained.