Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([OH:39])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:47]([O:51][C:52](=[O:55])[CH2:53]Br)([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH2:53][C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:55])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 900 mg 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 6.7 ml of DMF, 587 mg of cesium carbonate and 351 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 5 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 1.1 g.
Reaction SMILES: [Br-:1].C1(C(C2C=CC=CC=2)(C)C(O[C@@H]2C3CC[N+](CC(=O)NC4C=CON=4)(CC3)C2)=O)C=CC=CC=1.[Br-].O[C@@H]1C2CC[N+](CC(=O)NC3C=CON=3)(CC2)C1.[Br-].[OH:56][C@@H:57]1[CH:62]2[CH2:63][CH2:64][N+:59]([CH2:65][C:66](=[O:79])[NH:67][C:68]3[C:72]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)=[CH:71][O:70][N:69]=3)([CH2:60][CH2:61]2)[CH2:58]1.[CH:80]1([C:86]([OH:96])([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C:87](O)=[O:88])[CH2:85][CH2:84][CH2:83][CH2:82][CH2:81]1>>[Br-:1].[CH:90]1([C:86]([OH:96])([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)[C:87]([O:56][C@@H:57]2[CH:62]3[CH2:63][CH2:64][N+:59]([CH2:65][C:66](=[O:79])[NH:67][C:68]4[C:72]([C:73]5[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=5)=[CH:71][O:70][N:69]=4)([CH2:60][CH2:61]3)[CH2:58]2)=[O:88])[CH2:95][CH2:94][CH2:93][CH2:92][CH2:91]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1nocc1-c1ccccc1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Agent: CC(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)(c1ccccc1)c1ccccc1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCCC1)C2)Nc1nocc1-c1ccccc1

Procedure:
This compound is prepared analogously to (R)-3-(2,2-diphenyl-propionyloxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Example 4), substituting (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) with (R)-3-hydroxy-1-[(4-phenyl-isoxazol-3-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate I) and by replacing 2,2′-diphenylpropionic acid with cyclohexyl-hydroxy-phenyl-acetic acid, yielding the titled compound as a diastereomeric mixture. (M+ 544.4)
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:9]1[CH:14]=[CH:13][C:12](F)=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])#[N:8].[H-].[Na+].Cl>CN(C)C=O.CCCCCC.O>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:11][C:10]=1[C:16]([F:17])([F:18])[F:19])#[N:8]
Reactant: C=C(C)C(N)=O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
To a solution of methacrylamide (153.00 g, 1797.88 mmol) in 800 mL of N,N-dimethylformamide was added 4-cyano-3-(trifluoromethyl)phenyl fluoride (200 g, 1057.58 mmol) at room temperature. The solution was cooled in a methanol/dry ice bath to −20° C. To this cooled solution was added sodium hydride (102 g, 2696.84 mmol), portion-wise, while keeping the reaction mixture temperature below 70° C. The reaction mixture was allowed to cool to room temperature and stirred for 4 hours under nitrogen atmosphere. Water (915 mL) was added followed by 18% HCl (250 mL) and hexane (970 mL). The resultant slurry was allowed to stir overnight. The solid was filtered, washed sequentially with water (3×150 mL) and hexane (100 mL), and dried at 60° C. to give the title product as an off white solid (260 g, 97%).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)=[O:2].[C-:8]#[N:9].[Na+].[O-]S([O-])=O.[Na+]>O>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH:1]([OH:2])[C:8]#[N:9]
Reactant: [C-]#N
Reactant: O=Cc1cccs1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#CC(O)c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
In this example 25.0 g of 2-formylthiophene was added to a stirred solution containing 10.93 g of sodium cyanide in 37 ml of water at room temperature. 63 ml of aqueous saturated sodium acid sulfite was then slowly added to the stirred mixture. During the addition of the sodium acid sulfite solution, small amounts (about 20 g) of ice were periodically added. The mixture was then stirred for another 15 minutes and extracted with ethyl ether. The ethyl ether extracts were combined, dried over magnesium sulfate and evaporated under vacuum affording 18.4 g of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[CH2:9]P(OC)(OC)=O)([CH3:6])([CH3:5])[CH3:4].C(OC(=O)N[C@@H]1[CH2:29][CH2:28][C@H:27]([NH:30][CH2:31][CH2:32][C:33](=O)[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C@H:26]([CH2:45][S:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH2:25]1)(C)(C)C.[Cl-].[NH4+:57]>O1CCCC1>[C:3]([O:7][C:8](=[O:16])[CH:9]=[C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[CH:35]=1)[CH2:32][CH2:31][N:30]([NH2:57])[C@H:27]1[CH2:28][CH2:29][C@@H:9]([C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:16])[CH2:25][C@H:26]1[CH2:45][S:46]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)(=[O:47])=[O:48])([CH3:6])([CH3:5])[CH3:4]
Reactant: [NH4+]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NCCC(=O)c2cccc(C(F)(F)F)c2)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C(CCN(N)[C@H]1CC[C@@H](C(=O)OC(C)(C)C)C[C@H]1CS(=O)(=O)c1ccccc1)c1cccc(C(F)(F)F)c1

Procedure:
A suspension of sodium hydride (60%, 176 mg, 4.4 mmol) in tetrahydrofuran (5 mL) was stirred on an ice bath and treated dropwise over 5 min with dimethylphosphonoacetic acid tert-butyl ester (0.79 mL, 4.0 mmol). The mixture was stirred at room temperature for 25 min, then was cooled on an ice bath and treated with a solution of (1R,3R,4S)-{3-benzenesulfonylmethyl-4-[3-oxo-3-(3-trifluoromethylphenyl)-propylamino]cyclohexyl}carbamic acid tert-butyl ester (1.138 g, 2.0 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 2.5 h, then was treated with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 25% ethyl acetate-hexane, to provide the E isomer of 5-([1S,2R,4R]-2-benzenesulfonylmethyl-4-tert-butoxycarbonyl-aminocyclohexylamino)-3-(3-trifluoromethylphenyl)pent-2-enoic acid tert-butyl ester (511 mg) as a white solid. MS found: (M+H)+=667.41. Further elution with 40% ethyl acetate-hexane provided the corresponding Z isomer (567 mg) as a white glassy solid. MS found: (M+H)+=667.41.
Reaction SMILES: [C:1]([O:4][C:5]1[C:9](=[O:10])[O:8][CH:7]([CH2:11][CH2:12][C:13](O)=[O:14])[C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:3])[CH3:2].C(Cl)(=O)OCC>O1CCCC1.C(N(CC)CC)C>[OH:4][C:5]1[C:9](=[O:10])[O:8][CH:7]([CH2:11][CH2:12][CH2:13][OH:14])[C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:1]([O:4][C:5]1[C:9](=[O:10])[O:8][CH:7]([CH2:11][CH2:12][CH2:13][OH:14])[C:6]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1=C(c2ccccc2)C(CCC(=O)O)OC1=O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC1=C(c2ccccc2)C(CCCO)OC1=O
Product: O=C1OC(CCCO)C(c2ccccc2)=C1O
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
3-(4-Acetoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionic acid (58 mg) was dissolved in a mixture of tetrahydrofuran (3 ml) and triethylamine (28 μl), and a solution of ethyl chlorocarbonate (19 μl) in tetrahydrofuran (1 ml) was added dropwise slowly at -5° C. over 10 minutes. The mixture was stirred at -5° C. for 30 minutes and filtered. To the filtrate was added a solution of sodium borohydride (23 mg) in water (1 ml) at 10° C. Then, the mixture was stirred at room temperature for 1.5 hours, acidified with cooled 1N hydrochloric acid, and extracted with ethyl acetate. After drying, the solvent was distilled off, and the residue was subjected to preparative silica gel thin layer chromatography (0.5 mm×4, Merck) using 35% ethyl acetate-chloroform as the developing solvent to give 3-hydroxy-5-(3-hydroxypropyl)-4-phenyl-2(5H)-furanone (Compound I, 10 mg) and 3-acetoxy-5-(3-hydroxypropyl)-4-phenyl-2(5H)-furanone (Compound II, 12 mg).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:17]([S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])=[CH2:18].CC[O:26]CC>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[S:19]([C:22]1[CH:23]=[CH:5][C:4]([CH3:6])=[CH:3][CH:2]=1)([OH:20])(=[O:21])=[O:26].[CH:17]([S:19]([CH:22]=[CH2:23])(=[O:21])=[O:20])=[CH2:18]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOCC
Agent: C=CS(=O)(=O)C=C
Product: CC(C)C[C@H](N)C(=O)O
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An Et2O solution of anhydrous p-Tosic acid (3 equiv.) was added to dry oil of Boc-Leu-vinylsulfone (1 equiv.) and stirred at room temperature overnight. The product formed a white precipitate which was recovered by centrifugation.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]([C:17](OCC)=[O:18])([C:12](OCC)=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)Cl>CO.[Cl-].[Na+].O>[CH2:1]([N:8]1[CH2:11][C:10]([CH2:12][OH:13])([CH2:17][OH:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OCC1(CO)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of diethyl 1-benzylazetidine-3,3-dicarboxylate (4.8 g, 16.5 mmol) in CH3OH (10 mL) was added NaBH4 (1.25 g, 33 mmol). The mixture was stirred at RT for 1 hr. 100 mL of brine and 200 mL of DCM were added. Organic layers were separated from aqueous layers, dried over Na2SO4, concentrated to afford 2.328 g (68%) of (1-benzylazetidine-3,3-diyl)dimethanol as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.21-7.31 (m, 5 H), 4.15-4.05 (m, 2 H), 3.48 (d, J=4.8 Hz, 2H), 3.17 (d, J=4.8 Hz, 4 H) and 2.89 (s, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]#[C:12][Si](C)(C)C)[OH:10])=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]#[CH:12])[OH:10])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(O)C#C[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
Place a mixture of 4-dimethylamino-α-[(trimethylsilyl)ethynyl]-benzenemethanol (2.26 g, 9.13 mmol) and tetrahydrofuran (11 mL) under argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between ethyl ether and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter, and concentrate in vacuo to yield 1.37 g, (85.6%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[C:30]([N:33]1[CH2:37][C@@H:36]([NH2:38])[CH2:35][C@H:34]1[CH2:39][OH:40])(=[O:32])[CH3:31]>ClCCl.O>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:38][C@@H:36]2[CH2:37][N:33]([C:30](=[O:32])[CH3:31])[C@H:34]([CH2:39][OH:40])[CH2:35]2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@@H](N)C[C@H]1CO
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N[C@H]1C[C@@H](CO)N(C(C)=O)C1
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
9.84 g of 4-acetylamino-5-chloro-2-methoxybenzoic acid, and 4.5 g of triethylamine were dissolved in 40 ml of dichloromethane, and 4.60 g of ethyl chlorocarbonate was added dropwise to the solution at not higher than 10° C. After stirring at the same temperature for 30 minutes, a solution of 7.03 g of (2S,4S)-(−)-1-acetyl-4-amino-2-hydroxymethylpyrrolidine in dichloromethane (20 ml) was added dropwise. After stirring at the same temperature overnight, water (20 ml) was added, precipitated crystals were filtered, and the resulting crystals were dried in a warm air at 50 to 55° C. to obtain 11.74 g of 4-acetylamino-5-chloro-2-methoxy-N-[(2S,4S)-1-acetyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]([O-])=O.[Na+].[CH2:21]1[C:29]2[C:24](=[CH:25][C:26]([N:30]3[C:34](=[O:35])[CH2:33][C:32]([CH3:36])=[N:31]3)=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>Cl>[OH:16][C:3]1[C:2]([NH:1][N:17]=[C:33]2[C:34](=[O:35])[N:30]([C:26]3[CH:25]=[C:24]4[C:29](=[CH:28][CH:27]=3)[CH2:21][CH2:22][CH2:23]4)[N:31]=[C:32]2[CH3:36])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=1
Reactant: Nc1cccc(-c2c[nH]c(C(=O)O)c2)c1O
Reactant: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1=NNc1cccc(-c2c[nH]c(C(=O)O)c2)c1O
Yield: 31.6 %

Procedure:
4-(3-Amino-2-hydroxy-phenyl)-1H-pyrrole-2-carboxylic acid 57i (240 mg, 0.8 mmol) was dissolved in hydrochloric acid (3 mL, 1 mol/L) upon cooling by an ice-water bath, followed by dropwise addition of 1.1 mL of aqueous sodium nitrite (61 mg, 0.88 mmol). After the mixture was reacted for 20 minutes, 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (154 mg, 0.72 mmol) was added. The mixture was adjusted to pH 8˜9 with saturated aqueous sodium bicarbonate. The reaction mixture was reacted at room temperature for 24 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with ethanol. The mixture was filtered and the filter cake was dissolved in 15 mL of water. The mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid upon cooling by an ice-water bath. The mixture was filtered and the filter cake was purified by silica gel column chromatography to obtain the title compound 4-{2-hydroxy-3-[N′-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene)-hydrazino]-phenyl}-1H-pyrrole-2-carboxylic acid 58 (101 mg, yield 28.4%) as a red solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:10][CH2:9]1)=[O:7].[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[NH:19][C:18]2=[O:26])[CH2:13][CH2:12]1.C1C=CC=CC=1.CO>ClC(Cl)Cl>[O:26]=[C:18]1[N:17]([CH:14]2[CH2:13][CH2:12][N:11]([CH2:9][CH2:10][NH:8][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:16][CH2:15]2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(c1cccs1)N1CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Solvent: CO
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1cccs1

Procedure:
A mixture of 7.7 parts of 1-(2-thienylcarbonyl)aziridine, 10.8 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled and trichloromethane is added. The undissolved product is filtered off and stirred in 2,2'-oxybispropane. It is filtered off again and crystallized twice: first from a mixture of methanol and N,N-dimethylformamide and then from a mixture of trichloromethane and methanol, yielding 4 parts of N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-thiophenecarboxamide; mp. + 300° C (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[C:19](Br)[CH:20]=[N:21][C:15]=2[NH:14][C:13](=[O:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[C:19](/[CH:26]=[CH:25]/[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]=[N:21][C:15]=2[NH:14][C:13](=[O:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)Cc2cc(Br)cnc2N1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
A suspension of 7-bromo-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepine-4-carboxylic acid benzyl ester (0.52 g, 1.4 mmol) in propionitrile (10 mL) and DMF (3 mL) was de-oxygenated with Ar for 20 min. The mixture was treated with tert-butyl acrylate (0.83 mL, 10 mmol) and (i-Pr)2EtN (0.50 mL, 2.9 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (34 mg, 0.15 mmol) and P(o-tol)3 (84 mg, 0.27 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux overnight, then allowed to cool. The resulting precipitate was isolated by filtration, washed with EtOAc and dissolved in CH2Cl2. The solution was filtered through Celite and the solvent was removed in vacuo to give the title compound (0.31 g, 53%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.49-8.57 (m, 1H), 8.30 (s, 1H), 7.43-7.73 (m, 2H), 7.33 (s, 4H), 7.17-7.18 (m, 1H), 6.21-6.40 (m, 1H), 5.05-5.11 (m, 2H), 4.46-4.68 (m, 4H), 1.54-1.57 (m, 9H); MS (ESI) m/e 424 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([CH:11]([CH3:13])[CH3:12])([CH2:8][CH:9]=C)[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[O:14]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([C:3]([CH:11]([CH3:13])[CH3:12])([CH2:8][CH:9]=[O:14])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CCC(CC)(C(=O)OC)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(CC=O)(C(=O)OC)C(C)C

Procedure:
The reaction of the olefinic ester, methyl 2-ethyl-2-(1-methylethyl)-4-pentenoate (9.20 g, 50 mmol), with ozone in CH2Cl2 (200 mL) at -78° C., followed by the treatment of the resulting ozonide with Ph3P (19.65 g, 75 mmol) as described above in the preparation of Example 7, gave 14.36 g of an oily residue. Flash chromatography over silica gel (hexanes-EtOAc, 9:1) afforded the aldehyde (8.20 g, 88%) as a colorless oil.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1)=O.N(O)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH2:29])=[NH:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Li+]>CC(O)CC>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27]2[N:29]=[C:5]([C:7]3[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(NC(=N)N)c1
Reactant: CN(C)C=CC(=O)c1cccnc1Cl
Agent: O=NO
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: COc1cccc(Nc2nccc(-c3cccnc3Cl)n2)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-3-pyridyl)-2-propen-1-one (3.50 g, 16.5 mmol), 3-methoxy-phenyl-guanidine nitrite (3.70 g, 16.2 mmol), lithium hydroxide (412 mg, 16.5 mmol) in 2-butanol (15 mL) is heated to reflux overnight. The reaction mixture is cooled to room temperature, concentrated and water (60 mL) is added. The resultant solid is filtered, washed with water, isopropanol and dried to give N-[3-methoxy-phenyl]-4-(2-chloro-3-pyridyl)-2-pyrimidineamine (3.95 g); ESI-MS (m/z): 313 (M++H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[I:7][CH:8](O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:22]([O-:25])([O-])=O.[K+].[K+]>CCOCC>[I:7][CH2:8][CH2:22][O:25][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: O=C([O-])[O-]
Reactant: CC(O)I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CCOCC
Product: ICCOC1CCCCO1
Reaction time: 1 h

Procedure:
Freshly distilled dihydropyran (Aldrich, 59.0 g, 0.7 mol) was added dropwise to a cooled solution of iodoethanol (Aldrich, 98 g, 0.57 mol) in Et2O (1 L) containing 0.1 g of p-toluenesulfonic acid (Eastman). The solution was then stirred for 1 h at 5°. Solid K2CO3 (Mallinckrodt, 5 g) was then added to the reaction mixture and the resulting suspension stirred an additional 1 h at RT. The reaction was then filtered and the remaining solid washed with Et2O (1 L). The organic solutions were combined and concentrated on a rotary evaporator (in a flask washed with 1% NEt3 in H2O). The crude 2-(2-iodoethoxy)tetrahydro-2-H-pyran (100 g, 68.9%) was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([NH:23][CH3:24])=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([NH:23][CH3:24])=[O:22])=[O:18])[CH2:13][CH2:12]3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CNC(=O)COC(=O)N1CCN(CCCc2cccc(Br)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)COC(=O)N1CCN(CCCc2cccc(-c3cccc(Cl)c3)c2)CC1
Temperature: 150 °C
Yield: 51.4 %

Procedure:
A suspension of 0.14 g (0.35 mmol) of 2-(methylamino)-2-oxoethyl 4-[3-(3-bromophenyl)propyl]piperazine-1-carboxylate, prepared in step 7.2., in a mixture of 4 ml of toluene and 0.6 ml of ethanol is admixed with 0.08 g (0.07 mol) of the tetrakis(triphenylphosphine)palladium complex, 1.05 ml (2.1 mmol) of a 2M aqueous solution of sodium carbonate and 0.22 g (1.4 mmol) of 3-chlorobenzeneboronic acid. The mixture is heated to 150° C. under microwave irradiation for 5 minutes and the organic phase is recovered by filtration on a cartridge equipped with a frit and containing celite and sodium sulphate. The cartridge is rinsed with toluene and the filtrate is concentrated under reduced pressure. The product is purified by chromatography on silica gel, eluting with a 90/10 mixture of ethyl acetate and methanol. The eluate is subsequently taken up in n-heptane, to give 0.086 g (0.18 mmol) of product in the form of white crystals.