Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[O:33])=[CH:35][CH:36]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (8) (6.27 g, 33.5 mmol) in DCM (100 mL) was added DIEA (8.75 mL, 50.3 mmol) and then 4-tert-butylbenzoyl chloride (8.0 mL, 43.6 mmol) in drop-wise manner. The mixture was stirred for 3 h at RT, diluted with DCM, washed with 1N NaOH, dried, and concentrated. The residue was subjected to flash column chromatography with 0 to 10% EtOAc in DCM to give (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (11.0 g, 91%). To a solution of (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (850 mg, 2.36 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 190 mg, 4.72 mmol). The mixture was stirred at RT for 10 min and then iodomethane (0.44 mL, 7.08 mmol) was added. The mixture was stirred at RT for 1 h, and diluted with 150 mL EtOAc. The mixture was washed with water ×2, dried, and concentrated. The residue was subjected to flash column with 0 to 3% MeOH in DCM to afford (R)-tert-butyl 3-(4-tert-butyl-N-methylbenzamido)piperidine-1-carboxylate (9) in quantitative yield. It was treated with 15 mL 4N HCl in dioxane at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-4-tert-butyl-N-methyl-N-(piperidin-3-yl)benzamide (10) HCl salt in quantitative yield.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10]B(O)O.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Br:8][C:7]1[C:2]([CH3:10])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Br)c(Br)c1
Reactant: CB(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(Cl)cc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
2,3-Dibromo-5-chloropyridine (1.3 g, 4.70 mmol), methylboronic acid (0.30 g, 5.01 mmol), bis(triphenylphosphine)palladium(II) chloride (0.50 g, 0.70 mmol) and dioxane (10 mL) were added. K2CO3 (2 M aq. solution, 7.0 mL, 14.0 mmol) was added and the reaction was put under N2 (g) atmosphere. The reaction was heated to reflux for 5 h. The reaction was stirred at 50° C. overnight and then heated to reflux for additionally 1 h. Methylboronic acid (0.14 g, 2.35 mmol) was added and the reaction was refluxed for 4 h and the allowed to cool down to r.t. The mixture was filtered through a silica plug. EtOAc and water were added and the phases were separated. The organic phase was washed two more times with water. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g SiO2, 0-20% MeOH containing 0.1 M NH3 in DCM). The fractions containing pure product were pooled and concentrated, yielding the title compound (123 mg, 13% yield): 1H NMR (DMSO-d6) δ ppm 2.56 (s, 3H), 8.29 (d, 1H), 8.52 (d, 1H); MS (CI) m/z 206 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:22][N:21]=[C:20]([Cl:23])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:23][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[S:22][N:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nc(Cl)ns3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2nc(Cl)ns2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.7 %

Procedure:
To a solution of [6-(3-chloro-[1,2,4]thiadiazol-5-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (135 mg, 0.502 mmol) in THF (5 mL) and H2O (2 mL) was added LiOH (0.105 g, 2.50 mmol). The resulting solution was stirred at room temperature for 2 hrs. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The crude mixture was purified by prep HPLC to give title compound (20 mg, 18%) as a white solid. 1H NMR (CD3OD) δ7.42 (d, 1H), 7.29 (d, 1H), 5.66 (dd, 1H), 3.20 (dd, 1H), 2.40 (s, 3H), 2.36 (dd, 1H). MS found: (M+H)+: 341.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@H:10]([C@@H:32]([OH:45])[CH2:33][C@H:34]([C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:35]([CH3:37])[CH3:36])[CH2:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[CH2:13][NH:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=O)(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][C@H:10]([C@@H:32]([OH:45])[CH2:33][C@H:34]([C:38](=[O:44])[NH:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:35]([CH3:37])[CH3:36])[CH2:11][C@@H:12]([CH:29]([CH3:31])[CH3:30])[CH2:13][NH:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27]
Reactant: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@H](CNC(=O)c1ccccc1OCCCOC)C(C)C)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@@H](N)C[C@H](CNC(=O)c1ccccc1OCCCOC)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 4N hydrochloric acid solution in dioxane (2 ml) is added at 0° C. to (2S,4S,5S,7S)-N-[4-(tert-butoxycarbonyl)amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonyl]-2-(3-methoxypropoxy)-benzamide (50 mg). The reaction mixture is stirred at 0° C. for 2 hours (TLC monitoring) and then the solvent is immediately concentrated under a high vacuum with vigorous stirring until frozen and is subsequently removed by lyophilisation. After drying under a high vacuum, (2S,4S,5S,7S)-N-(4-amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonyl)-2-(3-methoxypropoxy)-benzamide hydrochloride is obtained in the form of a foamy solid: Rf (W)=0.31. HPLC Rt =12.8 min. MS(FAB) m/e 522 (M+ +1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1>CN(C=O)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:16]3[CH2:21][N:20]([C:29]4[N:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: Clc1ncccn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(c2ncccn2)C3)cc1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
1-Ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (d, 0.15 mmol), chloropyrimidine (0.21 mmol) and i-PrN2Et (0.6 mmol) were mixed in DMF (0.6 mL) in a microwave reaction tube. The mixture was heated to 120° C. and stirred for 15 min. After cooling to room temperature, the mixture was diluted with DMF. The resulting mixture was purified by reverse-phase HPLC to give 1-ethyl-3-(4-(4-morpholino-6-(pyrimidin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (e): 1H NMR (500 MHz, DMSO) δ 8.71 (s, 1H), 8.47 (d, J=4.8, 2H), 8.21 (d, J=8.8, 2H), 7.51 (d, J=8.8, 2H), 6.77 (t, J=2.5, 1H), 6.18 (m, 1H), 4.99 (s, 2H), 4.68 (s, 2H), 3.78 (m, 8H), 3.20-3.15 (m, 2H), 1.26 (t, J=6.9, 3H); LC-MS: m/z=+447 (M+H)+.
Reaction SMILES: O[C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1.C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C>[Br:24][C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@H](O)CN12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@@H](Br)CN12
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a solution of (6S,7aR)-6-Hydroxy-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 33, step f) (900 mg, 2.848 mmol) in acetonitrile (10 ml) was added CBr4 (2.24 g, 8.544 mmol) at room temperature and stirred for 10 min. PPh3 (2.83 g, 8.544 mmol) was added and left stirring for 12 h at room temperature. The mixture was concentrated and the residue was purified through column chromatography over silica (elution with 10% ethyl acetate in hexane) to yield 850 mg (79%) of the title compound as white solid. LC-MS: 381.1 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[CH:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: O=Cc1cn(C(c2ccccc2)c2ccccc2)c2ccccc12

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-3-carbaldehyde and benzhydryl chloride in place of the benzyl bromide used in Example 1 to give 852 mg of 1-benzhydrylindole-3-carbaldehyde as brown crystals. The yield thereof was found to be 46%.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:18]([N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCOC(=O)CCCI
Product: CCOC(=O)CCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
In step b, the 4-iodo functionality of the appropriate ethyl 4-iodobutyrate of structure (52) is displaced with dibenzylamine to give the corresponding 4-dibenzylaminobutyric acid, ethyl ester of structure (53).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH2:29]O)[CH:26]=[CH:27][CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1cccc(F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4cccc(F)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 21.7 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (3-fluorophenyl)-methanol (134 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (100 ml), and the DCM layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as a white solid.
Reaction SMILES: C(=O)=O.CC(C)=O.[Li]CCCC.Br[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>CC(OC)(C)C>[F:20][C:17]1[N:18]=[CH:19][C:14]([B:25]([OH:26])[OH:24])=[CH:15][CH:16]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: OB(O)c1ccc(F)nc1
Temperature: 6 °C
Reaction time: 0.83 h
Yield: 79 %

Procedure:
To stirred and cooled (dry ice-acetone bath) anhydrous [TBME] (620 mL; in a 3 L three-necked round-bottomed flask equipped with mechanical stirrer, temperature probe with adapter, and nitrogen inlet) was added (via syringe) 2 M BuLi (352 mL, 0.704 mol, 1.2 eq). To this rapidly stirred and cooled (<−75° C.) mixture was added a solution of 3 (102.2 g, 0.581 mol) in anhydrous TBME (100 mL) over a period of 13 min during which time the internal temperature rose to −62° C. The reaction was stirred for another 45 min (the temperature was maintained between −62° C. and −80° C.), followed by the rapid and sequential addition of four portions of triisopropylborate (total of 180 g, 0.957 mol, 1.65 eq). At the end of the addition the internal temperature had risen to −33° C. After stirring an additional 45 min over the cold bath (internal temperature lowered from −33° C. to −65° C.), the cold bath was removed and the stirred mixture on its own rose to −22° C. over a period of 50 min. After warming (via water bath) to 6° C. over a period of 15 min, the stirred reaction mixture was placed in an ice-water bath and then quenched under nitrogen with a cooled solution of NaOH (160 g) in water (500 mL). Once the addition was complete, the internal temperature was 20° C. This mixture was stirred at room temperature for 1.5 h. The aqueous layer was removed, neutralized to pH 7 with ˜350 mL concentrated HCl, and then extracted with EtOAc (3×1 L). Because the pH was now 8-9, the aqueous layer was adjusted to pH 7 using 15 mL concentrated HCl and extracted further (2×1 L) with ethyl acetate. The combined EtOAc extracts were dried (Na2SO4), filtered, and concentrated to a volume of ˜150 mL. With swirling of the concentrate, heptane was added in portions (total volume of 300 mL) resulting in the precipitation/crystallization of the product. Filtration, washing of the solid with heptane (100 mL, 300 mL, then another 300 mL), and air drying gave the title product as an off-white solid (68.6 g, yield of 79-90%*; LC purity of 96.4%, NMR showed an estimated 5.5% w/w of heptane), which was used successfully without further purification. LC/MS showed it to be a mixture of the two following entities, the intensity of the higher molecular weight entity being major (*Note: yield of reaction is 79% if the boronic acid is assumed to be the only constituent and is 90% if it is assumed that the cyclic borate is the only constituent):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=O)[C:13]=3[N:12]=[C:11]2[C:22](=[O:33])[NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[OH:34][CH:35]1[CH2:38][NH:37][CH2:36]1>>[CH:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:22]([C:11]2[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([N:37]4[CH2:38][CH:35]([OH:34])[CH2:36]4)=[O:21])[C:13]=3[N:12]=2)=[O:33])[CH2:25][CH2:26]1)([CH3:31])[CH3:32]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CCc2ccc(Cl)cc2)CC1
Reactant: OC1CNC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CC(O)C4)cccc3n2CCc2ccc(Cl)cc2)CC1

Procedure:
1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-hydroxy-azetidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 150 mg (0.29 mmol) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 23.4 mg (0.32 mmol) 3-hydroxy-azetidine. The title compound was obtained as its formiate in form a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][Se:7][N:8]=[C:4]2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][Se:7][N:8]=[C:4]2[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Clc1ccc2n[se]nc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ccc2n[se]nc12
Temperature: 0 °C

Procedure:
A solution of 5-chloro-2,1,3-benzoselenadiazole from Step A (800 mg, 1.80 mmol) in conc. H2SO4 (12 mL) was cooled to 0° C. and 90% HNO3 (0.8 mL) was added. After 30 min the reaction was cooled to 0° C. and diluted with H2O (10 mL). The solid was filtered off and washed with cold 1420 to yield the title compound. MS: m/z=263 (M+1).
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>C(#N)C.C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:44][C:45]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:46])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 4.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2CO3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3OH in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 90 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:19]=1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Nc1cccnc1
Product: O=c1[nH]c2ncccc2c2cc(Nc3cccnc3)ccc12
Yield: 48.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 3-aminopyridine (61 mg, 0.65 mmol) to provide 232 (31 mg, 54% yield) as a white solid. LC-MS (M+H=289, obsd.=289). 1H NMR (400 MHz, d6-DMSO): δ 11.74 (s, 1H), 9.10 (s, 1H), 8.54 (m, 2H), 8.47 (dd 1H), 8.23 (dd, 1H), 8.19 (d, 1H), 7.91 (d, 1H), 7.75 (m, 1H), 7.39 (m, 1H), 7.30 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][C:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
A mixture of 0.95 g (3.8 mmol) 2-isopropylanthraquinone, 0.81 g (4.6 mmol) N-bromosuccinimide (NBS) and 6 mg benzoyl peroxide in 7 mL CCl4 was refluxed for 2 h under N2 with mild stirring. After cooling to room temperature, the solution was filtered through glass wool and then the CCl4 was removed under vacuum to yield a yellow liquid that solidified upon cooling. 1H-NMR showed the conversion to be complete and so the product was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:14][N:15]=[C:16]=[S:17]>>[CH3:13][O:12][C:11]1[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:16]([NH:15][CH3:14])=[S:17])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN=C=S
Reactant: COc1cccnc1CCCCN
Product: CNC(=S)NCCCCc1ncccc1OC

Procedure:
Reaction of 2-(4-aminobutyl)-3-methoxypyridine with methyl isothiocyanate gives N-[4-(3-methoxy-2-pyridyl)butyl]-N'-methylthiourea.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[N:9]=[C:8](SC)[C:7]([C:14]#[N:15])=[CH:6][C:5]=2[C:4](=[O:16])[CH2:3]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[N:9]=[C:8]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:7]([C:14]#[N:15])=[CH:6][C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: CSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Reactant: C1CCNCC1
Solvent: CCO
Product: CC1(C)CC(=O)c2cc(C#N)c(N3CCCCC3)nc2C1
Yield: 28.2 %

Procedure:
A solution of 7,7-dimethyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.25 g, 1 mmol) and piperidine (0.32 ml, 4 mmol) in dry ethanol (3 ml) was stirred at reflux for 36 h. The reaction mixture was then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (chloroform-methanol, 50:1) to give the title compound (0.08 g, 28%) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].CN1C=CN=C1.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C1(C)C=CC=CC=1>[CH3:3][C:1]1([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][CH:5]=2)[CH2:2][CH:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(C)c1ccc(C(F)(F)F)cc1
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1(C)c1ccc(C(F)(F)F)cc1
Yield: 82 %

Procedure:
To a toluene (50 ml) solution of 1-isopropenyl-4-(trifluoromethyl)benzene (4.93 g, 26.5 mmol) [Tetrahedron (2003), 59(17), 2999-3002], Co(TPP) (534 g, 0.795 mmol) and 1-methyl-1H-imidazole (6.53 g, 79.5 mmol), ethyl diazoacetate (4.23 g, 37.0 mmol) was added. Then the reaction and the following work-up were carried out according to the procedure described in Example 2H. The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and EtOAc (20/1) to afford 5.92 g (82% yield, trans) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.O.[CH:18]1[CH:23]=CC=C[CH:19]=1>C(O)(C)C>[CH:18]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11])([CH3:23])[CH3:19]
Reactant: c1ccccc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(Br)ccc1C(=O)OC(C)C

Procedure:
A solution of 4-bromo-2-methyl-benzoic acid (Aldrich, 5.4 g, 25 mmol) in benzene (75 mL) and isopropanol (75 mL) was treated with concentrated sulfuric acid (1.5 mL) and heated to reflux over 4 days using a Dean-Stark water trap. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and saturated, aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a clear oil that was used as such for the next step (6.12 g, 95%).