Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.C1(CC([NH:22][CH:23]2[C:49](=[O:50])[N:25]3[C:26]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=4)=[O:38])=[C:27](/[CH:30]=[CH:31]\[C:32]4[N:33]=[N:34][S:35][CH:36]=4)[CH2:28][S:29][C@H:24]23)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O.CO.C(Cl)Cl>[NH2:22][CH:23]1[C:49](=[O:50])[N:25]2[C:26]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)=[O:38])=[C:27](/[CH:30]=[CH:31]\[C:32]3[N:33]=[N:34][S:35][CH:36]=3)[CH2:28][S:29][C@H:24]12
Reactant: COc1ccc(COC(=O)C2=C(/C=C\c3csnn3)CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(COC(=O)C2=C(/C=C\c3csnn3)CS[C@@H]3C(N)C(=O)N23)cc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
Phosphorus pentachloride (8.12 g, 39 mmol) was added to methylene chloride (70 ml) and cooled to 5° C. It was stirred for 1 hour by addition of pyridine (10.39 g, 130 mmol). p-Methoxybenzyl 7-phenylacetamido-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (7.27 g, 13 mmol) was added to this reaction solution and it was stirred at 5° C. for 4 hours. The reaction solution was cooled to -30° C. and stirred for 1 hour by addition of dehydrated methanol (53 ml). The temperature of the reaction solution was returned to -10° C. and it was stirred for 10 minutes by addition of water (10 ml). Saturated sodium bicarbonate was added to the reaction solution to adjust to pH 4, and then the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, then washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography thereby p-methoxybenzyl 7-amino-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (3.9 g, 70% yield) was obtained as a light yellow powder substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(C([O-])=O)[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]1.[Na+].Cl>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=C(O)C1=CC(C(=O)[O-])(c2ccccn2)Nc2ccccc21
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(-c2ccccn2)nc2ccccc12

Procedure:
The free acid is prepared by neutralizing an aqueous solution of the sodium 2-(2-pyridyl)4-carboxyquinoline carboxylate 3 with 10% HCl. The acid is somewhat soluble in acidic solution, and care should be taken not to overacidify; a pH of 7 is optimum. The solid is filtered, washed with 40 mL of acetone and allowed to air dry.
Reaction SMILES: C(N(C(C)C)C(C)C)C.I[C:11]1[CH:22]=[CH:21][C:14]([CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[C:34]#[CH:35])=[CH:28][CH:27]=1)#[C:24][CH3:25]>[Cu]I>[C:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[C:34]#[C:35][C:11]2[CH:22]=[CH:21][C:14]([CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=2)=[CH:28][CH:27]=1)#[C:24][CH3:25]
Reactant: Ic1ccc(CN2CCCC2)cc1
Reactant: C#CC(=O)Nc1ccc(C#CC)cc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: CC#Cc1ccc(NC(=O)C#Cc2ccc(CN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 mL of acetonitrile is degassed and combined with 0.35 mL (2 mmol) of ethyldiisopropylamine and 0.2 g (0.69 mmol) of 1-(4-iodobenzyl)pyrrolidine. Then the mixture is again degassed and 13 mg of copper (I) iodide, 34 mg of tetrakistriphenylphosphine palladium, and 137 mg (0.75 mmol) of propynoic acid-(4-prop-1-ynylphenyl)amide are then added in succession. The reaction mixture is stirred for 24 hours at ambient temperature and then combined with 60 mg of propynoic acid-(4-prop-1-ynylphenyl)amide. After 24 hours, the mixture is evaporated down. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol/ammonia (30:1:0.1 to 20:1:0.1)). Yield: 24 mg (10% of theory); C23H22N2O (M=342.44); calc.: molecular ion peak (M+H)+: 343; found: molecular ion peak (M+H)+: 343; Rf value: 0.2 (silica gel, dichloromethane/methanol/ammonia=10:1:0.1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([O:20]C)[C:13]=3[CH:12]=2)=[N:8][N:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:13]=3[CH:12]=2)=[N:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnc(-c2cc3c(OC)cccc3o2)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1nnc(-c2cc3c(O)cccc3o2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
5-Ethoxycarbonyl-2-(4-methoxybenzo(b)furan-2-yl)-1,3,4-oxadiazole (5.0 g) was dissolved in dichloromethane (40 ml) and boron tribromide (4.0 ml) was added dropwise with stirring under ice-cooling. Then, the mixture was stirred at room temperature for 5 hr, and the reaction mixture was poured into ice water. The mixture was stirred at it was at room temperature for 1 hr. The crystals were collected by filtration and dissolved in chloroform. The solution was washed with saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2.5 g) as yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].Cl>N1C=CC=CC=1.N1CCCCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#Cc1ccc(C=CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.2mol of p-cyanobenzaldehyde and 0.3mol of malonic acid were dissolved in 80ml of pyridine at room temperature, and 30 drops of piperidine were added thereto. The mixture was heated and stirred for 4 hours at about 100° C. After the reaction, the solution was poured slowly into dilute hydrochloric acid (250ml hydrochloric acid/250g water). Then, the resulting white precipitate was separated by filtering and washed with dilute hydrochloric acid and water, and was recrystallized by use of glacial acetic acid to obtain p-cyanocinnamic acid. 0.3mol of thionyl chloride was added to 0.1mol of the p-cyanocinnamic acid and the mixture was heated and stirred at about 80° C for 3 hours. An excess thionyl chloride was then removed under reduced pressure to obtain p-cyanocinnamic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([O:20][C:21](=[O:66])[CH2:22][C:23]1([CH2:55][C:56](=[O:65])[O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[O:27][N:26]=[C:25]([C:28]2[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:29]=2[CH2:35][CH2:36][C:37]([N:39]2[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[CH2:41][CH2:40]2)=[O:38])[CH2:24]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[CH2:58]([O:57][C:56](=[O:65])[CH2:55][C:23]1([CH2:22][C:21](=[O:66])[O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:27][N:26]=[C:25]([C:28]2[CH:33]=[C:32]([O:34][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:31]=[CH:30][C:29]=2[CH2:35][CH2:36][C:37]([N:39]2[CH2:44][CH2:43][CH:42]([C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:46])[CH2:41][CH2:40]2)=[O:38])[CH2:24]1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(CC1(CC(=O)OCc2ccccc2)CC(c2cc(O)ccc2CCC(=O)N2CCC(C(=O)OCc3ccccc3)CC2)=NO1)OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(CC1(CC(=O)OCc2ccccc2)CC(c2cc(OC(=O)c3ccc([N+](=O)[O-])cc3)ccc2CCC(=O)N2CCC(C(=O)OCc3ccccc3)CC2)=NO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.5 %

Procedure:
4-Nitrobenzoyl chloride (405 mg) was added in small portions to a solution of benzyl 1-(3-(2-(5,5-bis(2-(benzyloxy)-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoyl)piperidine-4-carboxylate (800 mg) in pyridine (4 mL) at 0 C. The obtained mixture was stirred at room temperature for 45 minutes. To the reaction mixture, ethyl acetate and 1 M hydrochloric acid were added 0 C, followed by extraction with ethyl acetate. Combined organic layers were washed with diluted aqueous ammonia ((28% aqueous ammonia (0.5 mL)/water (25 mL))×2), 1 M hydrochloric acid, and brine and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (939 mg).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].IC.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1O)([O-:11])=[O:10]>C(O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[C:13]([O:4][CH3:1])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COc1cc(F)ccc1[N+](=O)[O-]
Yield: 10.1 %

Procedure:
Potassium carbonate(14.5 g, 105.1 mol) and iodomethane(7.1 ml, 114.6 mmol) were added to a solution of 2-nitro-5-fluorophenol(15 g, 95.5 mmol) in ethanol (100 ml), which was then refluxed for 12 hours. The resulting solid was filtered, washed with ethanol, and concentrated. The resulting oily residue was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/hexane=1/3) to give 1.65 g of the titled compound. (Yield 9.7%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[Cl:33]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:29]3[CH:30]=[CH:31][C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Clc1ccc([Mg]Br)cc1Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)c(Cl)c1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 3,4-dichlorophenylmagnesium bromide. Yield: 64 mg of a white solid. LC-MSD, m/z for C22H13BrCl2N2O2 [M+H]+=487.0, 489.0, 491.0; HPLC retention time: 2.9 min.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=O)=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+]>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)N1CC2CC2(c2ccccc2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Product: Fc1ccc(CN2CC3CC3(c3ccccc3)C2)cc1

Procedure:
In a similar manner, 3-(p-fluorobenzoyl)-1-phenyl-3-azabicyclo[3.1.0]hexane is reduced by Vitride® to give 3-(p-fluorobenzyl)-1-phenyl-3-azabicyclo[3.1.0]hexane.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].[C:26](Cl)(Cl)=[S:27]>O.C(O)CC>[I:13][C:10]1[CH:11]=[CH:12][C:3]([N:2]=[C:26]=[S:27])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(I)ccc1N
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCO
Product: COC(=O)c1cc(I)ccc1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 20 g (0.064 mol) of methyl 2-amino-5-iodobenzoate hydrochloride was added 720 mL of toluene, 180 mL of water, 49 g (0.593 mol) of sodium bicarbonate, and 13.2 mL (0.181 mol) of thiophosgene. The biphasic mixture was stirred at room temperature overnight, diluted with 400 mL of water, and the phases were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to deliver 21.43 g of the title compound, which was used without further purification, 1H NMR (300 MHz, CDCl3): δ3.97 (s,3H); 7.02 (d,1H); 7.81 (dd,1H); 8.30 (d,1H). An analytical sample was prepared by treating 0.30 g of the crude material with 5 mL of n-propanol, followed by the dropwise addition of water. The ensuing precipitate was filtered to deliver 259 mgs of purified methyl 5-iodo-2-isothiocyanatobenzoate, m.p. 60-62° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[CH2:12](OS(C1C=CC(C)=CC=1)(=O)=O)C>CN(C)C=O.O.CCCCCC>[CH3:3][O:4][C:5](=[O:11])[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH3:12]
Reactant: COC(=O)C(C)(C)CO
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
1 mol of sodium hydride was added to the solvent dimethylformamide, and 1 mol of hydroxypivalic acid methyl ester was added thereto while the temperature of the solution did not exceed 30° C. The solution was stirred at room temperature for 90 minutes. Then, 1.2 mol of p-toluenesulfonic acid ethyl ester was added to the solution while the temperature of the solution did not exceed 30° C. Then, a water/hexane mixture having the same mass as that of the dimethylformamide was added to and mixed with the solution, after which water was removed therefrom. The resulting organic material was concentrated, and the residue was fractionated under reduced pressure 76-79° C., thereby obtaining the intermediate 3-methoxy-2,2-dimethylpropionic acid methyl ester at a yield of 47%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[OH-].[NH4+:17].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 60 %

Procedure:
A solution of 3-bromo-4-fluorobenzenesulfonyl chloride (1 g, 3.3 mmol, 90% pure) stirred at 0° C. in THF (15 ml) and DCM (5 ml) was treated with aqueous ammonium hydroxide (28%) by dropwise addition over 15 min. After stirring at 0° C. for 210 min, the mixture was acidified (pH=1) by addition of 1 N HCl (aq). After the mixture was concentrated in vacuo to near dryness, it was treated with water (50 ml), sonicated for 3 min and filtered. After the filter cake was washed sequentially with water (50 ml) and hexanes (100 ml), it was dried in vacuo to afford the title compound (503 mg, 60%) as a white solid which was carried forward without purification. LCMS (M−H)−=253.
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.[C:57](OC(=O)C)(=[O:59])[CH3:58]>>[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:32]7[C@:33]([CH2:48][CH3:49])([C@@H:37]([O:47][C:57]([CH3:58])=[O:59])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:50][CH3:51])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:9]=3[CH2:10][CH2:11]2)[CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: 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
Product: CC[C@]1(O)C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reaction time: 1 h

Procedure:
0.29 g of deacetyl-vinblastine is dissolved in 3 ml of acetic anhydride and the solution is allowed to stand for one hour at room temperature. The thus obtained vinblastine is isolated from the reaction mixture in the usual way and then converted into the sulfate salt. 0.28 g of vinblastine sulfate is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[S:34]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.77 (d, 1H), 8.04 (m, 1H), 7.87 (d, 1H), 7.68 (d, 1H), 7.54 (m, 2H), 7.42 (m, 1H), 7.14 (m, 3H), 7.07 (m, 1H), 6.88 (d, 1H), 6.83 (s, 1H), 6.44 (dd, 1H), 4.36 (s, 2H), 4.32 (s, 2H), 3.62 (s, 3H), 2.79 (t, 2H), 2.49 (t, 2H); MS 491 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)O)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(O)c3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COc1ccc2c(Cc3ccc(N)cc3)ccnc2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of (7-methoxyquinolin-4-yl)(4-nitrophenyl)methanol (0.187 g, 0.603 mmol) and tin(II) chloride dihydrate (0.823 g, 3.62 mmol) in MeOH (10 mL) was heated to 60° C. After 1 hr an additional 5 eq of tin(II) chloride dihydrate was added. After 3 hrs, the mixture was concentrated in vacuo and diluted with EtOAc and water. Saturated NaHCO3 was added until the aqueous layer was basic. The resulting suspension was filtered and the solids washed with EtOAc. The organic fraction was washed with water, brine, and dried with Na2SO4. After concentrating in vacuo, the crude, yellow solid, 4-((7-methoxyquinolin-4-yl)methyl)benzenamine was advanced without further purification. MS found: M+H+=265.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[C:17]#[N:18])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:17][NH2:18])=[CH:10][CH:9]=1
Reactant: N#CC(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(CCc1ccc(Cl)cc1)(Cn1cncn1)c1ccccc1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A slurry of 18 g (0.45 mole) of lithium aluminum hydride in 1000 mL of dry tetrahydrofuran was cooled to 5° C. while stirring under nitrogen. To the slurry was added alpha-(2-(4-chlorophenyl)ethyl)-alpha-phenyl-1H-1,2,4-triazole-1-propanenitrile in 2000 mL of dry tetrahydrofuran over 3 hours. The reaction was kept at 5°-10° C. during the addition then allowed to warm to room temperature and stirred overnight. The reaction was cooled in an ice bath and quenched with the slow addition of sodium sulfate. The solvent was removed and the residue was extracted with ethyl acetate and washed with 1000 mL water and 1000 mL brine. After drying, and removal of the solvent, 137 g (89.5% yield) of a very viscous oil resulted.
Reaction SMILES: [N+]1([O-])C=CC=CC=1.Br[C:9]1[C:10]([C:15]#[N:16])=[N:11][CH:12]=[CH:13][CH:14]=1.C[Si](C#N)(C)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(#N)C.C(N(CC)CC)C>[C:15]([C:10]1[C:9]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:16]
Reactant: N#Cc1ncccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: C[Si](C)(C)C#N
Agent: [O-][n+]1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cccnc2C#N)cc1

Procedure:
Synthetic Scheme XXVIII shows the 4-step preparation of the alkylating reagent 2-cyano-3-(4-bromomethylphenyl)pyridine (75) from 3-bromopyridine (76) (Aldrich). In step 1, the pyridine 76 was reacted with hydrogen peroxide in acetic acid at reflux to give the pyridine N-oxide 77. In step 2, the N-oxide 77 was converted to 3-bromo-2-cyanopyridine (78) by reaction with trimethysilylcyanide and triethylamine in acetonitrile at reflux. In step 3, the nitrile 78 was coupled with 4-methylphenylboronic acid (52) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 2-cyano-3-(4-methylphenyl)pyridine (79). In step 4, 79 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 75. ##STR82##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1B(O)O
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(NN(C)C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Yield: 26.7 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 300 mg, 2.05 mmol), 2-isopropylphenylboronic acid (Lancaster; 330 mg, 2.01 mmol), copper(II) acetate (373 mg, 2.05 mmol) and triethylamine (287 μL, 2.05 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5% ethyl acetate/hexanes, to give N′-(3-isopropyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (142 mg, 26%) as an oil.