Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]1=2.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[C:24]1([N:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][CH:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][O:8][C:7]4[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]3=4)[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1ccc2c(c1)C(SCCI)c1ccccc1CO2
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)C(SCCN1CCN(c3ccccc3)CC1)c1ccccc1CO2

Procedure:
After 6.1 g of Compound j obtained in Reference Example 10 and 6.0 ml of 1-phenylpiperazine were heated under reflux in 300 ml of ethanol for 7.5 hours, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate: triethylamine=30:10:3). The resulting crude product was solidified with diethyl ether to give 3.1 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1.[H-].[Na+].I[CH3:45]>CN(C=O)C.O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[N:15]([CH3:45])[CH2:14][CH2:13]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)NCCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)N(C)CCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
A solution of 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (INTERMEDIATE V, 0.045 g, 0.072 mmol) in DMF (0.719 mL) was treated with sodium hydride (4.31 mg, 0.108 mmol) to afford a dark brown solution. Iodomethane (6.74 μL, 0.108 mmol) was added dropwise to give a light-yellow solution. The reaction was stirred for 40 minutes. Additional iodomethane (6.74 μL, 0.108 mmol) was added and the reaction was heated to 70° C. and stirred for one hour. The mixture was diluted with water and a small amount of brine (to break up an emulsion) then extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (12 g column, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-4-methyl-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. m/z (ESI) 639.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33](Cl)=[O:34])(=[O:30])=[O:29].C(OCC)(=O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][N:12]([C:33](=[O:34])[C@@H:32]3[CH2:36][CH2:37][CH2:38][N:31]3[S:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)(=[O:30])=[O:29])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Reactant: O=C(Cl)[C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
To a solution of (±)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (10.01 g, 0.038 mole) in pyridine (150 ml) is added (S)-N-(2-naphthalenesulfonyl)prolyl chloride (18.57 g, 0.057 mole), and the mixture is stirred at room temperature for 4 hours. To the reaction mixture is added ethyl acetate, and the mixture is washed with 5 % hydrochloric acid, water, aqueous sodium hydrogen carbonate solution, water and saline in this order, and the ethyl acetate layer is separated, dried over sodium sulfate and distilled to remove the solvent. The resulting caramel is subjected to silica gel column chromatography (hexane:ethyl acetate=5:1 - 3:1). From the fraction eluted first there is obtained (R)-2-(4-chlorophenyl)-4-[(S)-N-(2-naphthalenesulfonyl)prolyl]-3,4-dihydro-2H-1,4-benzothiazine (10.75 g, 51 %) as crystals. M.p. 147°-151° C.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:15]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[S:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:25]=[C:23]([C:22]3[CH:26]=[CH:27][C:19]([O:18][C:15](=[O:17])[CH3:16])=[CH:20][CH:21]=3)[S:24][C:2]=2[CH2:3][C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1
Reactant: O=C(O)CC(Br)Cc1ccc(Cl)cc1
Reactant: CC(=O)Oc1ccc(C(N)=S)cc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)c(CC(=O)O)s2)cc1

Procedure:
In a similar manner to Example 1(a), 3-Bromo-3-(4-chlorobenzyl)propionic acid and 4-acetoxy-thiobenzamide are reacted in dimethylformamide solvent to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:31]2[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2NCCCO)cn1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 161.1, 72 mg, 0.15 mmol), (6-methylpyridin-3-yl)boronic acid (20.7 mg, 0.15 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (5.3 mg, 0.0075 mmol) and the mixture subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=1.87 min, m/z=447.1 [M+H]+, m/z=445.2 [M−H]−.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:15](=[O:16])[C:14]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=3[Cl:12])[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)cc1Cl

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2,4-dichlorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-1.99 (m, 3H), 2.04 (s, 1H), 2.21-2.33 (m, 4H), 3.44 (s, 2H), 3.55 (s, 4H), 4.41 (s, 1H), 7.41-7.49 (m, 2H), 7.54-7.59 (m, 1H); MS (APCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]#[N:44]>>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:15])[N:14]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]#[N:44])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1cccc(F)c1
Yield: 80.6 %

Procedure:
Following the procedure described for Example 5, Step A, the anion derived 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (250 mg, 0.684 mmol) and NaHMDS (1M in THF, 0.80 mL, 0.80 mmol) was alkylated with 7-bromoheptanenitrile (142 mg, 0.748 mmol) at 70° C. for 72 h. Purification by medium pressure chromatography (1:1 hexanes:EtOAc to EtOAc to 5% MeOH in CH2Cl2) provided 7-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (261.7 mg). 1H NMR (CDCl3) δ7.26 (m, 1H), 6.92 (m, 3H), 3.89 (m, 1H), 3.59 (m, 2H), 2.89 (m, 1H), 2.75 (m, 2H), 2.36 (m, 4H), 2.11 (m, 1H), 1.72-1.26 (m, 13H), 0.89 (s, 9H), 0.09 (s, 6H); MS 475.3 (M+1).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[O:1][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]2)[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3cccs3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a cold (0° C.) solution of tert-butyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (8 g, 32.7 mmol) in anhydrous DCM (150 mL) was added thiophene-2-carbonyl chloride (4.8 g, 32.7 mmol) followed by DIEA (7.2 mL, 39.2 mmol). The reaction mixture was stirred at RT for 12 hours and then filtered. The filtrate was evaporated and the residue was refluxed in pyridine (100 mL) for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM. The organic layer was washed with a 10% aq. solution of sodium bicarbonate, water, brine and dried. The solvent was concentrated and the residue was purified by chromatography (Pet. Ether/EtOAc 7/3) to give 2.2 g (20%) of The title compound as a solid. TLC—Pet ether/EtOAc (9/1): Rf=0.75. HPLC purity>97%.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.CS(O[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=1)(=O)=O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:28]=[CH:29][CH:30]=3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: Cc1ncc2c(N3CCNCC3)cccc2n1
Reactant: CS(=O)(=O)Nc1cccc(CCOS(C)(=O)=O)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc2c(N3CCN(CCc4cccc(NS(C)(=O)=O)c4)CC3)cccc2n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 37.6 %

Procedure:
A mixture of 2-methyl-5-(1-piperazinyl)quinazoline (50 mg), 2-{3-[(methylsulfonyl)amino]phenyl}ethyl methanesulfonate (65 mg), diisopropylethylamine (192 μL) and DMF (0.5 mL) was heated to 100° C. in a sealed tube and stirred for 24 hours. The mixture was cooled to room temperature and partitioned between aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed (water, brine), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; DCM-MeOH: (100:0)→(95:5)] to give the title compound as a beige foam (35 mg).
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][C:7]2=O.Cl.[NH2:22]O.Cl>C(O)C.O>[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][C:7]2=[N:22][OH:1]
Reactant: O=C1CC(c2ccccc2)Oc2ccc(O)cc21
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CC(c2ccccc2)Oc2ccc(O)cc21

Procedure:
Sodium hydroxide (122 mg) was added into a cooled solution of 6-hydroxyflavanone (2 g) and hydroxylamine hydrochloride (900 mg) in ethanol (5 ml) and water (2 ml). Resulting mixture was refluxed for 6 hours and hydroxylamine hydrochloride (450 mg) and sodium hydroxide (61 mg) were added after every 45 min. After cooling into room temperature water (23 ml) and concentrated hydrochloric acid (5.6 ml) were added into the mixture. Precipitate was filtered, washed with water and dried in vacuum. 1H-NMR (400 MHz, d6-DMSO): 11.3 (s, 1H), 9.11 (s, 1H), 7.50-7.48 (m, 2H), 7.43-7.33 (m, 3H), 7.21 (d, 1H, J 2.9 Hz), 6.80 (d, 1H, J 8.8 Hz), 6.72 (dd, 1H, J 2.9, 8.8 Hz), 5.07 (dd, 1H, J 3.2, 11.9 Hz), 3.28 (dd, 1H, J 3.2, 17.1 Hz), 2.64 (dd, 1H, J 11.9,17.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Br)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-bromobenzenesulfonyl chloride according to METHOD A, giving 0.14 g (31%) of a pink solid after recrystallization from acetone/ether/petroleum ether: mp 183° C.; MS (Ionspray, [M+H]+) m/z 405; Anal. Calcd (found) for C13H13BrN2O4S2: C, 38.5 (38.5)%, H, 3.2 (3.0)%, N, 6.9 (6.6)%
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[O:25])=[N:4][C:5]([C:18]#[C:19][Si](C)(C)C)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CCO.C1COCC1>[C:18]([C:5]1[N:4]=[C:3]([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[O:25])[C:2]([CH3:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=1)#[CH:19]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C#C[Si](C)(C)C)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: C#Cc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Reaction time: 4 h
Yield: 78.3 %

Procedure:
A solution of 0.65 g (1.27 mmol) of [3-methyl-5-(3-trifluoromethyl-phenyl)-6-trimethylsilanylethynyl-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 12) in 12 ml of EtOH/THF (5:1) was treated at RT with 0.35 g (2.53 mmol) of potassium carbonate. After 4 hours, the reaction mixture was poured into crashed ice, the pH was adjusted to 3-4 with hydrochloric acid (2 molar) and the mixture was extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.439 g (79%) of the title compound as brown solid. MS: 442.3 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[CH2:13](NN(CC)NCC)[CH3:14].[C:22]1([S:28][CH:29]2[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH2:13]([N:10]([CH2:9][CH3:36])[CH2:11][CH2:12][NH:8][C:1]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:29]([S:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:30]1)=[O:2])[CH3:14]
Reactant: CCNN(CC)NCC
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: c1ccc(SC2CCCCNC2)cc1
Agent: O=C(O)C(=O)O
Product: CCN(CC)CCNC(=O)N1CCCCC(Sc2ccccc2)C1

Procedure:
Following the procedure of Example 16, 1,1'-carbonyldiimidazole, N,N-diethylaminoethylamine and 3-(phenylthio)homopiperidine and oxalic acid are reacted to give the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:13])([F:12])/[CH:5]=[CH:6]/[C:7]([O:9]CC)=[O:8].CC1C=CC(S([CH2:24][N+:25]#[C-:26])(=O)=O)=CC=1.[CH3:27]I>CS(C)=O.C(OCC)C.C(O)C.[OH-].[Na+]>[CH3:24][N:25]1[CH:26]=[C:5]([C:4]([F:13])([F:12])[F:3])[C:6]([C:7]([OH:9])=[O:8])=[CH:27]1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(C(F)(F)F)c1

Procedure:
Sodium hydride (8.0 g of a 75% dispersion in oil) is suspended at +5° C. in a mixture of DMSO (300 ml) and diethylether (100 ml). A solution of ethyl 4,4,4-trifluorocrotonate (20 g) and TOSMIC (23 g) in DMSO (100 ml) is added through a dropping funnel at such a rate that the temperature does not exceed 10° C. After stirring the reaction mixture for an additional hour at room temperature methyl iodide (15.6 ml) is added with cooling. After 2 hours at room temperature the reaction mixture is poured onto crushed ice. Repeated extraction with ether, washing of the combined organic phases with brine and evaporation of the solvent under reduced pressure gives a product mixture in form of a light amber oil. The crude product mixture is heated at 60° C. in a mixture of ethanol (100 ml) and sodium hydroxide (50 ml of a 30% aqueous solution). Washing of the solution with ether, acidifying of the aqueous phase with concentrated hydrochloric acid and filtering gives the 1-methyl-4-trifluoromethylpyrrol-3-carboxylic acid in form of a crystalline solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:5])[CH3:4].CC([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)=O.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1>O>[CH2:16]([O:15][C:11]1[CH:10]=[CH:9][CH:14]=[CH:13][C:12]=1[C:3](=[O:5])[CH:4]=[CH:29][C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(C=Cc1cccnc1)c1ccccc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of NaOH (0.488 g) in 10 ml of H2O was added 5 ml of 95% ethanol, followed by 3-benzyloxyacetophenone (2.5 g). The resulting solution was cooled to 0°-5° C. and pyridine-3-carbaldehyde (0.903 ml) added. After standing at 0°-5° C. for 18 hours, present title product was recovered by filtration and purified by chromatography on silica gel using 1:4 ethyl acetate:CH2Cl2 as eluant to yield 1.5 g of purified title product as an off-white solid; mp 117°-119° C.; IR (KBr) 1660 cm-1;Anal. C 79.83, H 5.50, N 4.22, calcd. C 79.98, H 5.43, N 4.44.
Reaction SMILES: [C:1]([CH:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)#[N:2].N1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC[O:26][CH2:27][CH3:28]>C1C=CC=CC=1>[CH:8]([CH:28]([C:19]1[CH:6]=[CH:5][C:4]2[C:21](=[CH:22][CH:23]=[CH:1][CH:3]=2)[CH:20]=1)[C:27]([O:17][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:26])([CH3:9])[CH3:7]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CCOCC
Reactant: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of α-isopropyl-2-naphthlyacetyl chloride (219 g, 0.887 mole) in benzene (350 ml) is added to a solution of α-cyano-m-phenoxybenzyl alcohol (179.8 g, 0.798 mole) and pyridine (70.2 g, 0.887 mole) in ether (750 ml) at 0°-10° C. over a 11/2 hour period. Pyridine hydrochloride precipitates out during the addition. The reaction mixture, after stirring overnight at room temperature, is diluted with more ether (500 ml) and poured into water (1200 ml). The organic phase is separated, washed with water, 10% H2SO4 and water and dried over Na2SO4. Evaporation gives an orange-brown gum (348 g, 100% crude yield, 87.5% pure by liquid chromatography).
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].C(O[CH:14](N(C)C)[N:15]([CH3:17])[CH3:16])(C)(C)C>CCCCCC>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:2]/[C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1ccc[nH]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCCCCC
Product: CN(C)/C=C/C(=O)c1ccc[nH]1
Reaction time: 6 h
Yield: 42.1 %

Procedure:
A mixture of 39.6 g of 2-acetylpyrrole and 104 ml (87.7 g) of tert-butoxy bis(dimethylamino)methane was heated on a steam bath for 20 minutes. The reaction was allowed to subside, then heating was continued for 6 hours. The mixture solidified then was slurried in hexane with chilling. The crude product was collected, washed with hexane and dried. The solid was dissolved in chloroform containing 5% methanol and filtered through magnesium silicate. The eluent was evaporated in vacuo and the residue was recrystallized from dichloromethane/hexane containing a small amount of methanol. The solid was collected, washed with hexane then dried in vacuo giving 25.1 g of the desired compound as yellow crystals, mp 192°-193° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.Br.[NH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])=[O:16].C(N(CC)CC)C.Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:11])[NH:13][CH2:14][C:15]([NH:17][C:18]2[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=2[C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: COc1cccc(N=C=O)c1
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of m-methoxyphenylisocyanate (734 mg, 4.92 mmol) in tetrahydrofuran (8 ml) is added to a solution of the salt 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (50 ml). Triethylamine (558 μl, 4 mmol) is added at 0° C., and the mixture is stirred at 0°0 C. for 30 minutes and then at room temperature overnight. Water and then 10% hydrochloric acid are added, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried (sodium sulfate), and distilled under reduced pressure to remove the solvent. The residue is recrystallized from dichloromethane/diisopropylether to obtain the objective compound 6x (1.29 g, 80%).