Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4]([CH3:9])[N:3]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.N#CBr.C(N(CC)CC)C>CC(C)=O>[O-:10][C:4]#[N:3].[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][N:3]=1)=[CH:15][C:14]1[CH:17]=[CH:18][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: O=Cc1ccc(O)cc1
Agent: N#CBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C(=Cc1ccccn1)c1ccccc1
Product: N#C[O-]
Reaction time: 0.67 h

Procedure:
A portion of the reaction product of a 1 to 1.5 to 1 mole ratio of 2,4,6-trimethyl pyridine to p-hydroxy benzaldehyde to 2,6-dimethylpyridine (100.0 grams, 0.473 mole of hydroxyl groups) from 3-A above and acetone (750 milliliters) were added to a 2-liter glass resin kettle and maintained under a nitrogen atmosphere. Stirring was started and allowed to progress for 40 minutes (2400 s) then cooling of the reactor commenced. When the reaction temperature reached -5° C., cyanogen bromide (105.67 grams, 0.9975 mole) was added. After five minutes (300 s), triethylamine (96.64 grams, 0.955 mole) was added dropwise over a 20 minute (1200 s) period and so as to maintain the reaction temperature between -5° and 0° C. The reaction was allowed to progress for an additional 45 minutes (2700 s) between reaction temperatures of -5° to 5° C. After this time, the reaction slurry was filtered. The recovered filtrate was added to 1 gallon (3.79 l) of deionized water producing an amber oil precipitate. The oil product was recovered by extraction with three 500 milliliter portions of methylene chloride. The combined methylene chloride extract was washed with 1500 milliliters of deionized water, dried over anhydrous sodium sulfate and then filtered. The dry methylene chloride solution was rotary evaporated under vacuum to a constant weight of 118.6 grams. Infrared spectrophotometric analysis of a film sample of the amber colored, viscous oil product confirmed the product structure for the styryl pyridine cyanate (presence of cyanate group absorbance accompanied by total absence of hydroxyl group absorbance, retention of trans-unsaturation absorbance and aromatic carbon-oxygen absorbance).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[NH:44]([C:45]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:18])[S:10][N:9]=2)=[CH:6][CH:7]=1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3ccccc3)cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (12 mg, 0.030 mmol), N,N-diisopropylethylamine (0.021 mL, 0.120 mmol), and phenyl isocyanate (0.0056 mL, 0.051 mmol) in 1.0 mL THF was stirred at rt for 19 hours. The reaction was quenched with 0.2 mL aqueous Na2CO3 solution, stirred 5 min at rt, and then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to a white solid. The solid was chromatographed eluting with CHCl3, then gradient 2.5% to 10% MeOH in CHCl3. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove the presence of any silica gel impurity. Upon evaporation of the EtOAc layer the title compound was obtained as a white solid (12 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8](OC2C=CC=CC=2)=[O:9])[S:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].O.[NH2:23][NH2:24]>O1CCCC1>[NH:23]([C:8]([NH:7][C:5]1[S:4][C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([CH3:1])[CH:6]=1)=[O:9])[NH2:24]
Reactant: CCOC(=O)c1sc(NC(=O)Oc2ccccc2)cc1C
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NC(=O)NN)cc1C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
To a stirred suspension of ethyl 3-methyl-5-(phenoxycarbonylamino)-thiophene-2-carboxylate (18.89 g, 61.86 mmol) in tetrahydrofuran (130 mL) was added hydrazine monohydrate (19.0 mL, 391.7 mmol). The resulting reaction mixture was stirred for 2.5 h, and then concentrated in vacuo. The residue was triturated with ethyl acetate to afford ethyl 5-(hydrazinecarboxamido)-3-methylthiophene-2-carboxylate as a yellowish solid in 89% yield (13.30 g): MS (ES+) m/z 244.2 (M+1).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][CH:46]([CH3:48])[CH2:45][C:44]=3[CH:49]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:50])[N:20]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][CH:46]([CH3:48])[CH2:45][C:44]=3[CH:49]=2)[C:21](=[O:39])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][C:25]=1[F:38])[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.86 g), sodium hydrogen carbonate (1.25 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.63 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (14 mL), N,N′-carbonyldiimidazole (0.30 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.42 g, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[O:11][CH2:10][C@H:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1.O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:7][CH:6]=3)[C@H:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][O:11]2)=[CH:16][CH:15]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Temperature: 75 °C

Procedure:
cis-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane (74.3 g) was dissolved in a mixture of toluene (700 ml), water (12 ml) and sodium hydroxide (24.3 g) by heating the mixture to 75° C. 2-Chloroethylpyrrolidin hydrochloride (46.2 g) was added in six portions at 75° C. with half an hour between each portion. After the last addition the mixture was heated at 75° C. for 4 hours. Water (1000 ml) was added and the mixture stirred until all salt was dissolved. The aqueous phase was separated and extracted with another portion of toluene (300 ml). The combined organic phases was dried over potassium carbonate and evaporated to an oil. The oil was dissolved in refluxing methanol (1000 ml) and the product crystallised by cooling in an ice bath.
Reaction SMILES: C[O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[O-:18][C:19]#[N:20].[K+].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:19]([NH2:20])=[O:18])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH2:4]1
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Reactant: N#C[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22.3 g (0.1 moles) of 10-methoxy-5H-dibenz(b,f)azepine prepared according to U.S. Pat. No. 27,622 are dissolved in 150 ml of toluene. 8.92 g (0.11 moles) of potassium cyanate and 10.8 g (0.11 moles) of 96% sulfuric acid are added. The mixture is heated between 40° and 50° C. stirring vigorously for 24 hours. When the analytical control detects a starting product content<2%, 50 ml of water are dropped into the mixture, which is stirred and the phases are separated. The organic phase is evaporated to dryness under vacuum and taken up into 100 ml of 10% sulfuric acid. The mixture is refluxed for 2-3 hours, cooled at room temperature and pump-filtered, washing with water; then it is recrystallized from dimethylacetamide (50 ml), filtered through charcoal washing the precipitate on the filter with acetone, and dried under vacuum. The product is identified by IR, NMR and mass spectroscopies.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]#[C:15][CH3:16].C(N(CC)CC)C>C(OCC)C>[CH2:19]([O:18][C:13]([C:14]1[C:4]([C:3]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:15]=1[CH3:16])=[O:17])[CH3:20]
Reactant: ON=C(Cl)c1ccc(F)cc1F
Reactant: CC#CC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(-c2ccc(F)cc2F)noc1C
Yield: 58.3 %

Procedure:
In a fashion similar to that for preparation 15, 2,4-difluorobenzoyl chloride oxime (2.00 g, 10.4 mmol), ethyl 2-butynoate (1.76 g, 15.7 mmol), triethyl amine (2.9 ml, 21 mmol) in diethyl ether (10 ml), and diethyl ether 30 ml) gave 4-ethoxycarbonyl-5-methyl-3-(2,4-difluorophenyl)isoxazole (1.62 g, 58%) after column chromatography (silica gel, hexanes/diethyl ether gradient).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O:12][CH2:13][CH3:14])=[O:11].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)c1cccc(N=C(C)c2ccccc2)c1

Procedure:
A solution of acetophenone (95 ml), m-carbethoxy aniline (75 ml), benzene (150 ml) was refluxed in the presence of molecular sieve (50 g) with continuous removal of water. The crude product was distilled under reduced pressure to give N-(α-methyl benzylidene)-m-carbethoxyaniline (XIII). XIII had a boiling point of 205° C. at 0.1 millimeter.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH:44]([S:47](Cl)(=[O:49])=[O:48])([CH3:46])[CH3:45]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([S:47]([CH:44]([CH3:46])[CH3:45])(=[O:49])=[O:48])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(S(=O)(=O)C(C)C)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 0.15 g (0.28 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) in CH2Cl2 (1.3 mL) was added 3 mL of saturated sodium bicarbonate followed by isopropylsulfonyl chloride (0.1 mL, 0.9 mmol). The reaction mixture was stirred overnight, taken up in ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica chromatography (silica pre-washed with methanol) eluting with a gradient of 1-5% MeOH/CH2Cl2 to afford (3S,4R)-N-tert-butoxy-1-(isopropylsulfonyl)-3-methyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-3-carboxamide (0.12 g, 66%) as a colorless solid. MS: 647.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([OH:23])[C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].I[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23][CH:31]([CH3:33])[CH3:32])[C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: CC(C)I
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)C1CCN(c2cc(O)c(Cl)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)C1CCN(c2cc(OC(C)C)c(Cl)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-hydroxyphenyl)piperidin-4-yl)ethanone (30 mg, 0.064 mmol) in anhydrous acetonitrile (1.5 mL) was treated with 2-iodopropane (0.019 mL, 0.191 mmol) and cesium carbonate (41.5 mg, 0.127 mmol) and the mixture stirred at 50° C. for 1 h. After this time, the mixture was concentrated on a rotary evaporator and the resultant residue was partitioned between water and EtOAc. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated to give 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-isopropoxyphenyl)piperidin-4-yl)ethanone. LC-MS: 512.20, [M+H]; tR=2.30 min (method a).
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>ClCCl.CCCCCC>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([O:1][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2sccc12
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc2sccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
Into a solution of 4-hydroxybenzo[b]thiophene (7.60 g, 50.6 mmol) and tert-butyldimethylsilyl chloride (8.39 g, 55.7 mmol) in dichloromethane (300 mL) is added imidazole (3.79 g, 55.7 mmol) and the mixture is stirred overnight at ambient temperature. The mixture is diluted with hexane (500 mL), filtered and concentrated to a pink oil. The crude material is subjected to chromatography on silica (in hexane) to provide the title compound as a colorless oil (12.9 g, 96% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(N=[N+]=[N-])C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-trans-[3-azido-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Example 112, 1.24 mmol, 0.3 g) in DCM (4 mL) at 0° C. was added Dess-Martin periodinane (1.48 mmol, 0.63 g) portion wise, and the reaction was stirred for 8 h. The reaction was diluted with DCM (5 mL), cooled to 0° C., and quenched with Na2S2O3 solution, organic layer was separated and washed with saturated NaHCO3 solution, water, brine and dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 5% ethyl acetate in hexanes -30% ethylacetate in hexanes to provide 3-azido-4-oxo-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:11][C:12](=[O:15])[CH2:13]Cl)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:24](O)[CH3:25]>>[CH2:24]([CH:13]([C:12]([OH:11])=[O:15])[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:25]
Reactant: CCOC(=O)CCl
Reactant: CCO
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCC(C(=O)O)N(C)c1ccccc1

Procedure:
A mixture of N-methyl aniline (198 g, 1.85 mol), ethylchloroacetate (227 g, 1.85 mol), potassium carbonate (256 g, 1.85 mol), potassium iodide (15 g, 0.93 mol), and 750 mL of absolute ethanol was stirred at reflux for 72 hours, then cooled and filtered. The solvent was removed from the filtrate at reduced pressure, and the residue was fractionally distilled in vacuo. A slightly yellow oil was obtained.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:56])[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:52]([O:54][CH3:55])=[O:53])([C:22]3[CH:27]=[C:26]4[C:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:50][CH3:51])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([OH:47])[C@:33]3([CH2:48][CH3:49])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH2:4]1.[NH2:57][CH2:58][CH2:59][CH2:60][NH2:61]>CN(C=O)C>[CH3:1][CH2:2][C@@:3]1([OH:56])[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:52]([O:54][CH3:55])=[O:53])([C:22]3[CH:27]=[C:26]4[C:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:50][CH3:51])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([OH:47])[C@:33]3([CH2:48][CH3:49])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH2:4]1.[NH2:57][CH2:58][CH2:59][CH2:60][NH-:61]
Reactant: NCCCN
Agent: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](O)[C@]3(O)C(=O)OC)C2)C1
Solvent: CN(C)C=O
Product: [NH-]CCCN
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a cooled (−15° C.) a DMF solution (3 ml, 0.0624 mmol) of deacetylvinblastine acid azide (synthesis described in Example 9, Step C) was added 120 μl of 1,3-diaminopropane in DMF (2 ml). The reaction was stirred at −10° C. for 1 hr, filtered and concentrated to dryness to yield (11).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24]>C(O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[N:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC1(C)CC(=NO)c2cc(OCc3ccccc3)ccc2O1
Yield: 105.1 %

Procedure:
By heating 11.3 g (40 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-one with 3.1 g (44 mmol) of hydroxylamine hydrochloride in 27 ml of ethanol and 27 ml of pyridine to 70° C. for 3 h, 12.5 g of product, m.p. 105-108° C., were obtained after distilling off the solvt in vac. and precipitating with water. The product was dissolved in EA, dried, concentrated and crystallized using petroleum ether; m.p. 118-120° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9](=[CH:26][CH2:27][CH3:28])[C:10](N3CCN(C)CC3)=[N:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.[S].C(N(CC)CC)C.Cl.C[S:39](C)=O>C(O)CC.ClCCl>[CH3:28][C:27]1[S:39][C:10]2[NH:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:9]=2[CH:26]=1
Reactant: CCC=C1C(N2CCN(C)CC2)=Nc2ccccc2N=C1N1CCN(C)CC1
Reactant: CS(C)=O
Agent: Cl
Agent: [S]
Solvent: CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 100 °C
Yield: 12 %

Procedure:
A suspension of 2,4-bis(4-methyl-1-piperazinyl)-3-propylidene-3H-[1,5]benzodiazepine (11.90 g, 31.3 mmol), sulphur (20.07 g, 626 mmol) and triethyl amine (4.34 ml, 31.3 mmol) in dimethyl sulfoxide (100 ml) and 1-propanol (100 ml) was heated at 100° C. for five days. The resulting black suspension was cooled and filtered off and the filtrate was evaporated at reduced pressure to obtain a viscous black oil. Dichloromethane (600 ml) and HCl (0.2 M, 600 ml) were added and the phases were separated. The organic phase was extracted again with HCl (0.5 M, 100 ml). The combined water phases were made alkalic at a pH of 9 to 10. Dark brown precipitate was filtered off. Dichloromethane (250 ml) was added to the filtrate. The phases were separated and the water phase was extracted with dichloromethane (2×60 ml). The organic phase was dried over anhydrous Na2SO4 and the solvent was evaporated at reduced pressure. The black oil was combined with precipitate and purified by chromatography on silica gel, eluted with ethyl acetate/triethylamine 50/1 to obtain 1.195 g (12%) of the title product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])N=1.[CH3:23]N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C1(C)C=CC=CC=1>[Br:22][C:18]1[CH:23]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cn1ccnc1
Reactant: Oc1cccc(Oc2ccccn2)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Brc1cccc(Oc2cccc(Oc3ccccn3)c2)c1
Temperature: 140 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
Under a nitrogen atmosphere, a pressure vessel was charged with a magnetic stir bar, 3-(pyridin-2-yloxy)phenol (50 mmol), 2,6-dibromopyridine (50 mmol), 1-methylimidazole (25 mmol), and potassium carbonate (100 mmol). Toluene (80 mL) was added and bubbled with nitrogen for 20 minutes before copper(I) iodide (5 mmol) was added and the solution bubbled for 10 minutes further. The vessel was sealed and heated to 140° C. while stirring. After 2 days, the solution was allowed to cool and the solids were filtered off and rinsed with dichloromethane. The filtrate was added to a separatory funnel containing DCM and water. The water phase was washed 3 times with 75 mL DCM, and the combined organic layers were washed once with pure water. The organic layer was collected, dried with magnesium sulfate, filtered, and the filtrate reduced by rotary evaporation. The resulting oil was purified by column chromatography using DCM over silica resulting in the pure product 2-(3-(3-bromophenoxy)phenoxy)pyridine with a 60% yield. 1H NMR (CDCl3): 6.80-6.85 (m, 2H), 6.91 (s, 1H), 6.94 (s, 1H), 6.97-7.03 (m, 2H), 7.19 (vt, 1H), 7.21-7.24 (m, 2H), 7.36 (vt, 1H), 7.70 (dd, 1H), 8.21 (dd, 1H).