Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16]([O:18][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a solution of 1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (540 mg, 2.01 mmol) (obtained as described in Reference Example 11(2)) in methylene chloride (27 ml) were added methanesulfonyl chloride (0.467 ml, 6.03 mmol) and triethylamine (0.845 ml, 6.03 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 5% methanol in ethyl acetate as the eluant to afford 1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (688 mg, yield 99%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N(C)CCCN(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)N(C)CCCN(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-(3-dimethylamino-propyl)-4,N-dimethyl-benzenesulfonamide (Intermediate 151), the title compound was obtained after purification by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1([CH:13]2[CH2:18][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[CH2:16][CH2:15][NH:14]2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1>CO>[N+:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([N:17]1[CH2:16][CH2:15][NH:14][CH:13]([C:2]2([OH:1])[CH2:5][NH:4][CH2:3]2)[CH2:18]1)(=[O:21])=[O:20])([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCN2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCNC(C2(O)CNC2)C1
Temperature: 60 °C

Procedure:
To a solution of 1,1-dimethylethyl 3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate (308 mg, 0.70 mmol) in methanol (10 mL) was added HCl in dioxane (4 N, 1.75 mL, 7.0 mmol), and the mixture was heated to 60° C. for 30 minutes. The solution was concentrated to provide 3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a sticky white solid. This material was dissolved in dichloromethane (7 mL). To the solution was added N,N-diisopropylethylamine (1.16 mL, 7.0 mmol) followed by 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (277 mg, 0.7 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 16 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane:5% methanol) to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a pale yellow foam (453 mg, 0.63 mmol, 90% yield). 1H NMR. (400 MHz, CDCl3): 8.49 (s, 1H), 7.96 (dd, 1H), 7.71 (m, 2H), 7.53 (dd, 1H), 7.39 (dd, 1H), 7.33 (d, 1H), 7.15 (m, 1H), 6.84 (br s, 1H), 6.62 (m, 1H), 4.29-3.97 (br m, 4H), 3.79-3.62 (m, 3H), 3.26-2.99 (br m, 3H), 2.92-2.62 (br m, 3H); MS (EI) for C26H23F3IN5O6S: 718 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1/C=C/c1cccc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: Clc1cccc(/C=C/[C@H]2CCCN2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 111.2 %

Procedure:
1 g of tert-butyl (R)-2-[(E)-2-(3-chlorophenyl)vinyl]pyrrolidine-1-carboxylate are dissolved in 10 ml of THF, and 5 ml of ethanolic hydrochloric acid are added. The mixture is stirred at 80° C. for 4 h and, for work-up, partitioned between 50 ml of water and 50 nil of ethyl acetate at room temperature. Conventional work-up and purification by chromatography on silica gel gives 750 mg of (R)-2-[(E)-2-(3-chlorophenyl)vinyl]pyrrolidine; Rt.: 1.554 min; [M+H]+208.2.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[CH2:27]([O:26][C:24]([C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2ccccc21
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1
Product: CC(C)(C)OC(=O)n1c(N2CCCC[C@H]2C(=O)OCc2ccccc2)nc2ccccc21

Procedure:
The title compound was prepared by a similar method to Preparation 2 from tert-butyl 2-chloro-1H-1,3-benzimidazole-1-carboxylate [see Preparation 46] and benzyl (2S)-2-piperidinecarboxylate [see J.A.C.S. (1 996), 118(7), 1629-1644]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 90:10 changing to 80:20, by volume, hexane:ethyl acetate, in 5% increments to afford tert-butyl 2-[(2S)-2-[(benzyloxy)carbonyl]-1-piperidinyl]-1H-1,3-benzimidazole-1-carboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.[Cu][C:35]#[N:36]>CN(C=O)C.CCOCC>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14]([C:35]#[N:36])[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(I)ccc3-4)CC21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(C#N)ccc3-4)CC21
Temperature: 110 °C

Procedure:
The product from Example 102A (24.7 mg, 0.044 mmol) was treated with copper(I) cyanide (27.5 mg, 0.307 mmol) in DMF (0.5 mL) heated at 110° C. overnight, cooled, diluted with Et2O (25 mL), washed with water (2×20 mL), washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with hexane:EtOAc (2:1, 1:1, 4:1) to provide the title compound. MS (M+H)+ m/z 463.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:31][CH2:30]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=[O:33].[K+].[K+].OO>CS(C)=O>[CH:29]1([C:27]([NH:26][C:24]2[N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:6]5[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:33])=[N:8][CH:7]=5)=[CH:16][CH:15]=4)[N:22]3[N:23]=2)=[O:28])[CH2:30][CH2:31]1
Reactant: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution of cyclopropanecarboxylic acid{5-[4-(6-cyano-pyridin-3-ylmethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide (30 mg, 0.073 mmol, 1 equiv) and K2CO3 (10 mg, 0.073 mmol, 1 equiv) in DMSO (0.2 mL) at 10° C., 30% H2O2 (17 μL, 0.146 mmol, 2 equiv) was added dropwise. After stirring at room temperature the mixture for 4 h, the mixture was diluted with DMSO and filtered. The filtrate was submitted for preparative HPLC purification: HPLC system (XBridge™ Prep C18, 5 μm, 19×100 mm column); 8 min LC; flow: 20 mL/min; gradient: from 30% to 70% acetonitrile in water 0.1% TFA; isolating the final product (25 mg, 81% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].O>O1CCOCC1>[C:18]([NH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([NH:12][CH:13]([CH3:15])[CH3:14])=[N:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(C)NC1=NS(=O)(=O)c2cc(N)ccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(NC(C)C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-amino-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.18 g) and acetic anhydride (0.6 mL) in dioxane (2 mL) was stirred for 1 h at room temperature. The medium was then mixed with water (5 mL) and stirred for 1 h. The solvents were removed by distillation under reduced pressure and the residue of the crude title compound was recrystallized from methanol-water to give the title compound (yield: 0.16 g); m.p. 260-262° C.; IR (KBr): 3353, 3316, 3240, 3101, 3069, 2974, 1672, 1624, 1608, 1581, 1546, 1497, 1467, 1391, 1279, 1159, 1142, 1123, 1104 cm−1; 1H-NMR (DMSO-d6, HMDS; d ppm): 1.10 (d, 6H, 2×CH3), 2.00 (s, 3H, COCH3), 3.90 (m, 1H, NH—CH), 6.85 (bd, 1H, NH—CH), 7.05 (d, 1H, 5-H), 7.60 (bd, 1H, 6-H), 8.00 (bs, 1H, 8-H), 10.00 (bs, 1H, CONH), 10.10 (bs, 1H, NH).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with methyl 4-formylbenzoate was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give methyl 4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzoate.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[C:37]1[N:41]([CH2:42][C:43]2[O:47][C:46]([CH3:48])=[N:45][CH:44]=2)[C:40]2[CH:49]=[CH:50][CH:51]=[CH:52][C:39]=2[N:38]=1>C(Cl)Cl>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([C:37]3[N:41]([CH2:42][C:43]4[O:47][C:46]([CH3:48])=[N:45][CH:44]=4)[C:40]4[CH:49]=[CH:50][CH:51]=[CH:52][C:39]=4[N:38]=3)[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Reactant: Cc1ncc(Cn2c(Cl)nc3ccccc32)o1
Solvent: ClCCl
Product: Cc1ncc(Cn2c(N3CCN([C@H]4CCN(C(=O)c5cc(C(F)(F)F)cc(C(F)(F)F)c5)[C@@H](Cc5ccccc5)C4)CC3)nc3ccccc32)o1
Yield: 40 %

Procedure:
Compound 15 (0.005 mol), 2-chloro-1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazole (0.005 mol) and Cupper (0.005 mol) were stirred at 140° C. for 2 hours. The mixture was cooled, dissolved in CH2Cl2, filtered and washed with CH2Cl2 and a diluted NH4OH solution. The organic layer was separated, washed with a diluted NH4OH solution, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5, 99/1, 98.5/1.5 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 1.42 g (40%) (±)-cis-1-[3,5-bis(trifluoromethyl)-benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 70).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:9]/O)[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>[Zn].C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(/C=N/O)n1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(CN)n1
Reaction time: 0.5 h

Procedure:
To (E)-6-methylpicolinaldehyde oxime (0.635 g, 4.66 mmol)/acetic acid (267 μL, 4.66 mmol)/ethanol (10 mL) solution was added portionwise zinc dust (5.19 g, 79 mmol) over 30 min. The resulting mixture was stirred for additional 30 min. LCMS of reaction aliquot indicated reaction was completed. The zinc precipitates in reaction mixture was removed by filtration, and the filtrate was concentrated. The residue was basified to pH>12 with excess sat. KOH (˜7 mL), and stirred with Et2O (30 mL). The Et2O layer was collected, dried over Na2SO4, and concentrated. The residue was redissolved in EtOAc(15 mL), dried over Na2SO4, and concentrated. (6-Methylpyridin-2-yl)methanamine was obtained as a colorless oil (385 mg, 3.15 mmol, 67.6%). LCMS (m/z) 123.2 (MH+) 0.15 min.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:21][NH2:22]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH:9]=1)[C:3]([NH:21][NH2:22])=[O:2])([O-:12])=[O:11]
Reactant: NN
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Product: NNC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Yield: 74 %

Procedure:
A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (4.0 g, 14.7 mmol) and hydrazine (5 mL, 80%) was refluxed for 4 h to yield 5-nitro-2-phenoxy-benzoic acid hydrazide (2.97 g, 74%). The title compound was prepared from 5-nitro-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=6.6 Hz, 1H), 7.81 (m, 1H), 7.75 (t, J=6.6 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.35 (m, 2H), 7.27 (d, =J=7.2 Hz, 1H), 7.03 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Br:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Br:15][C:16]1[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:18][CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (CAS number 71701-92-3; 2.86 g, 10.98 mmol), DIPEA (1.74 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol), then by column chromatography (silica, 0-15% ethyl acetate/petrol) and then by column chromatography (silica, 0-10% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH:1]([N:14]1[CH2:22][C:21]2[C:16](=[CH:17][C:18](I)=[C:19]([F:23])[CH:20]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:31][CH2:32][O:33][CH2:34][CH:35]=1)CCC>>[CH:1]([N:14]1[CH2:15][C:16]2[C:21](=[CH:20][C:19]([F:23])=[C:18]([C:30]3[CH2:35][CH2:34][O:33][CH2:32][CH:31]=3)[CH:17]=2)[CH2:22]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2c(cc1I)CN(C(c1ccccc1)c1ccccc1)C2
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Product: Fc1cc2c(cc1C1=CCOCC1)CN(C(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A49(a) from 2-benzhydryl-5-fluoro-6-iodo-2,3-dihydro-1H-isoindole and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 386.1 ([M+H]+, 100%).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[S:14][C:13]([CH:15]=[N:16][OH:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:11]1[CH:12]=[C:13]([CH:15]=[N:16][OH:17])[S:14][C:10]=1[N+:7]([O-:9])=[O:8])[CH3:24]
Reactant: CCOC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(C=NO)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(C=NO)sc1[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Potassium tertiary-butoxide (960 mg, 8.6 mmol) was dissolved in N,N-dimethylformamide (10 ml) and the solution cooled to −30° C. A solution of 5-nitro-2-thiophenecarboxaldehyde oxime (400 mg, 2.86 mmol) and ethyl chloroacetate (356 mg, 2.86 mmol) was added dropwise in dry N,N-dimethylformamide (5 ml) over 5 minutes. The reaction mixture was stirred at −30° C. for 30 minutes then quenched with 2M HCl (50 ml), diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using hexane/diethyl ether (1:2) as eluent to give 200 mg of ethyl-5-[(hydroxyimino)methyl]-2-nitro-3-thiopheneacetate as a tan solid. MS(ES): m/e 227 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20].[CH:21]([OH:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([O:24][CH:21]([CH3:23])[CH3:22])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20]
Reactant: CC(C)O
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)Cl)c(Cl)cc2F)C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1=C(C)C(=O)N(c2cc(C(=O)OC(C)C)c(Cl)cc2F)C1=O

Procedure:
6 g of N-(2-fluoro-5-chlorocarbonyl-4-chlorophenyl)-2,3-dimethylmaleic acid imide are added dropwise, while stirring at room temperature, to a mixture of 4 ml of isopropanol, 4 ml of triethylamine and 100 ml of toluene. After a reaction time of 6 hours, the triethylamine hydrochloride is separated off by filtration and the filtrate is concentrated by evaporation. By recrystallising the residue from ethanol/water, 4.2 g of N-(2-fluoro-4-chloro-5-isopropoxycarbonylphenyl)-2,3-dimethylmaleic acid imide having a melting point of 161°-162° are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][S-:29].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][S:29][CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)C(CCOS(C)(=O)=O)C1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCCC1CN(c2ccccc2C)CCN1C(=O)OC(C)(C)C

Procedure:
A stirred solution of 1-t-butyloxycarbonyl-2-(2-methylsulfonyloxyethyl)-4-(2-methylphenyl)piperazine from Step 1 above (0.39 g; 0.98 mmol) and sodium thiomethoxide (0.21 g; 3.0 mmol) in dry THF (15 mL) was heated to reflux for 18 h. The solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was separated and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc:hexanes as eluant. The title compound was isolated as a gum (1H-NMR: consistent with structure; TLC: silica gel, 1:4 EtOAc:hexanes: single component, Rf =0.50; FABMS: M+H @ m/e=351; HPLC: >99%, retention time 12.0 min).
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:10]1[N:11]=[CH:12][C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23](C(O)=O)[CH2:22][CH2:21]3)[N:16]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:14]=2[N:15]=1)#[N:9]>CCOCC>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:29][N:16]1[C:14]2[N:15]=[C:10]([C:8]#[N:9])[N:11]=[CH:12][C:13]=2[CH:18]=[C:17]1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)Cn1c(CN2CCN(C(=O)O)CC2)cc2cnc(C#N)nc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)Cn1c(CN2CCNCC2)cc2cnc(C#N)nc21
Yield: 58.1 %

Procedure:
4N HCl/dioxane is added to 4-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-piperazine-1-carboxylic acid .tert.-butyl ester at 0° C. and stirred at 25° C. for 90 min. Ether is added to the residue to afford a precipitate, which is collected by filtration. The crude product is dissolved in MeOH and purified by reverse phase HPLC. The fractions (fraction Nos. 23-25) are collected and evaporated. The residue is extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and brine, and dried over magnesium sulfate and filtrated. The solvent is removed by evaporation and dried in vacuo to afford the title compound. yield 58.1%, Rf=0.30 (CH2Cl2:MeOH=8:2). 1H-NMR (400 MHz, CDCl3) δ 1.01(s, 9H), 2.43(br, 4H), 2.90(br, 4H), 3.76(s, 2H), 4.36(s, 2H), 6.57(s, 1H), 8.89(s, 1H),
Reaction SMILES: CO.[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][N:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[CH:17][CH2:16]3)=[N:11][C:10]2=[O:28])=[CH:6][CH:5]=1.[H][H]>[Pd].C(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)=[N:11][C:10]2=[O:28])=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: O=c1nc(N2CC=C(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1nc(N2CCC(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Yield: 87.7 %

Procedure:
A methanol (1 mL) solution of 1-(4-chlorobenzyl)-4-[4-(4-fluorophenyl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2(1H)-one (30 mg, 0.08 mmol) synthesized in Synthesis Example 112 and palladium-activated carbon (3 mg) was stirred in a hydrogen atmosphere at room temperature for 1 day and at 80° C. for 7 hours. To the resultant mixture, chloroform was added and the resultant mixture was stirred further for 1 day. After the completion of the reaction, the reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain the title compound (28 mg, yield: 92%).