Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([O:18][CH2:19][CH3:20])=[C:6]([CH:12]2[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[Cl:10][C:8]1[C:7]([F:11])=[C:6]([CH:12]2[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[C:5]([O:18][CH2:19][CH3:20])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1C1COC(=O)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)O)cc(Cl)c(F)c1C1COC(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Acetyl-5-chloro-2-ethoxy-6-fluorophenyl)-1,3-oxazolidin-2-one (175 mg, 0.58 mmol) was stirred in methanol (10 mL) at 0° C. and sodium tetrahydroborate (33 mg, 0.87 mmol) was added. The mixture was stirred at rt for 1 hour and evaporated. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give an approximate 1:1 mixture of diastereomers, 175 mg, 99%. LCMS calculated for C13H15ClFNO4Na (M+Na)+: m/z=326.1; found: 326.1.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][NH:8][C:9]([C:11]1[C:23](=[O:24])[N:22]([CH3:25])[C:14]2[N:15]=[N:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:13]=2[C:12]=1[OH:26])=[O:10])(C)(C)C.ClC1N=NC2N(C)C(=O)C(C(NCC(OC(C)(C)C)=O)=O)=C(O)C=2C=1>[Pd]>[C:6]([CH2:7][NH:8][C:9]([C:11]1[C:23](=[O:24])[N:22]([CH3:25])[C:14]2[N:15]=[N:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:13]=2[C:12]=1[OH:26])=[O:10])([OH:27])=[O:5]
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(C(=O)O)nnc21
Agent: [Pd]
Agent: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(Cl)nnc21
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(C(=O)O)nnc21

Procedure:
6-((2-tert-Butoxy-2-oxoethyl)carbamoyl)-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-3-carboxylic acid. The title compound is prepared by a palladium catalyzed carbonylation reaction of tert-butyl 2-(3-chloro-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxamido)acetate according to the procedure of Tsuji, J., Palladium Reagents and catalysts: Innovations in Organic Synthesis Publisher: (Wiley, Chichester, UK), 340-45 (1995).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.O=[CH:10][C:11](=[CH2:13])[CH3:12]>>[CH3:13][C:11]1[CH:10]=[N:1][C:2]2[C:7]([CH:12]=1)=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2
Reactant: C=C(C)C=O
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc2ncc(C)cc2c1
Yield: 70 %

Procedure:
The procedure described in Example 1 was followed, except that 107 g/hour of 4-toluidine and 84 g/hour of methacrolein were employed. The product was distilled off under 5 mbar until the bottom temperature reached 250° C., and 110 g (70% of theory) of 3,6-dimethylquinoline of melting point 50° C. were obtained by crystallization with xylene.
Reaction SMILES: [Br:1][CH:2]([CH2:10]Br)[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].COC1C=CC(O)=CC=1.[OH-].[K+]>>[Br:1][C:2](=[CH2:10])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CCCCOC(=O)C(Br)CBr
Agent: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: C=C(Br)C(=O)OCCCC
Temperature: 25 °C
Yield: 72 %

Procedure:
n-Butyl 2,3-dibromopropionate (144 g, 0.5 mole) containing p-methoxyphenol (0.5 g) was stirred vigorously under nitrogen and at room temperature, whilst 20% w/v aqueous caustic potash solution was slowly added. The course of the dehydrobromination was constantly monitored by gas-liquid chromatography. From time to time the reaction mixture was allowed to separate and the almost neutral aqueous phase discarded, in order to maintain that effective concentration of the added base. When more than 95% of the starting material had been consumed, the reaction was stopped and the lower organic layer run off and washed with water. After drying (Na2SO4), the crude product was distilled to give a main fraction which was n-butyl 2-bromoacrylate (yield 72%), bp 92°/17 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](CO)N2C(=O)OC(C)(C)C)ccc1OC
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](C=O)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Using SO3/pyridine complex: A solution of 4.7 g of alcohol 6 in 58 ml of methylene chloride is treated with 33 mL of dimethylsulphoxide and 5.67 g of triethylamine is added. The mixture is cooled to 0° C. and a solution of 6.84 g of the SO3/pyridine complex dissolved in 46 mL of dimethyl sulphoxide is added dropwise within 20 minutes. The reaction is stirred at 0° C. for 2 hours and quenched with 105 mL of water and 105 mL of heptane. The organic layer is separated and washed with 25 mL of 10% aqueous sodium hydrogen sulphate solution. The organic phase is then washed with 110 mL of water followed by 25 mL of saturated aqueous sodium hydrogen carbonate solution. Finally the organic phase is washed with water until the pH of the aqueous solution is 7. The solvent is then removed to give the aldehyde 7 as an oil. A negative [a]d is found at c=1, CHCl3. 1H-NMR (d6-DMSO, 300K) 9.75 (1H), 6.90-6.80 (3H), 4.63-4.30 (3H), 4.00 (2H), 3.75 (3H), 3.50 (3H), 3.23 (3H), 2.10-1.90 (4H), 1.85 (1H), 1.60 (1H), 1.05 (9H), 0.85 (6H).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#N)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:37]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:37])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C#N)cc3)cc2)CC1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Temperature: -35 °C
Reaction time: 2 h

Procedure:
A solution of 10.0 g of 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarbonitrile in 150 ml of methylene chloride was placed at -35° C. in a sulphonation flast while gassing with argon and treated within 8 minutes with 40 ml of an about 1.5N solution of diisobutylaluminium hydride in toluene. After completion of the addition, the mixture was stirred for 2 hours at -35° C. and then for a further 1.5 hours with gradual warming to 0° C., before it was treated cautiously with 100 ml of 1N sulphuric acid and extracted three times with 150 ml of diethyl ether each time. The organic phases were washed with 100 ml of 1N sulphuric acid, twice with 100 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. There were obtained 9.5 g (95%) of 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxaldehyde as a colourless, crystalline mass (m.p. 115°-116° C.) which was used in the following step without further purification. Rf value [toluene/ethyl acetate (19:1)]: educt 0.65, product 0.52.
Reaction SMILES: [I:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8](O)=[O:9].C(C1NC=CN=1)(C1NC=CN=1)=O.[BH4-].[Na+].CO>O1CCCC1>[I:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH2:8][OH:9]
Reactant: Cn1ncc(I)c1C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(I)c1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.4 %

Procedure:
To a solution of 4-iodo-2-methyl-2H-pyrazole-3-carboxylic acid (1.0 g, 3.96 mmol) in tetrahydrofuran (10 mL), under an atmosphere of nitrogen, was added carbonyl diimidazole (0.78 g, 4.36 mmol, 1.1 eq.). The resulting mixture was stirred at room temperature for 1.5 hr before adding sodium borohydride (0.75 g, 19.8 mmol, 3.0 eq.) followed by a solution of methanol in tetrahydrofuran (5 mL), dropwise over a period of 10 min. The resulting mixture was stirred for 3 hr before quenching with 2M aqueous hydrochloric acid (30 mL). This mixture was partition with ethyl acetate (50 mL). The organic phase was washed with 1M aqueous sodium hydrogen carbonate (20 mL), saturated brine (20 mL) and dried over sodium sulphate. The resulting mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a brown oil (0.56 g, 60%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[C:19]1([CH2:25][SH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH2:25]([S:26][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 133.2 %

Procedure:
To a solution of 2-chloro-5-nitrobenzonitrile (50 g, 0.15 mol) in MeCN (1000 mL) was added K2CO3 (45.5 g, 0.33 mol) and phenylmethanethiol (34 g, 0.27 mol). The mixture was stirred at room temperature overnight. The mixture was filtered through the celite pad and the filtrate was concentrated in vacuo to give 2-(benzylthio)-5-nitrobenzonitrile (54 g, 73%) as a yellow solid. 1H NMR CDCl3 400 MHz δ 8.43 (s, 1H), 8.27-8.25 (m, 1H), 7.44-7.31 (m, 6H), 4.35 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:25]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Yield: 83 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using ethylamine instead of methylamine, to the title compound (90 mg, 83%) which was obtained as a white solid. MS: m/e=338.4 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C-:16]#[N:17].[Na+]>CS(C)=O.O>[C:16]([CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1)#[N:17]
Reactant: [C-]#N
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c2c(c1C)OC(C)(CC#N)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
2-Bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (6.5 g, 18.6 mmol) was dissolved in dimethylsulfoxide (30 ml). Sodium cyanide (1.43 g, 88 mmol) was added and the resulting mixture was stirred at 80° C. for 18 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 2:1). The crude crystals obtained were recrystallized from methanol to obtain the desired compound (4.1 g, yield: 79.7%), m.p. 58°-59° C.
Reaction SMILES: NC1N=CC2C(=O)CC(C3C=CC=CC=3Br)CC=2N=1.[NH2:20][C:21]1[N:30]=[CH:29][C:28]2[C:27](=[O:31])[CH2:26][CH:25]([C:32]3[CH:37]=[CH:36][C:35](F)=[CH:34][C:33]=3[C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)[CH2:24][C:23]=2[N:22]=1>>[NH2:20][C:21]1[N:30]=[CH:29][C:28]2[C:27](=[O:31])[CH2:26][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)[CH2:24][C:23]=2[N:22]=1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1-c1cccnc1)CC2=O
Agent: Nc1ncc2c(n1)CC(c1ccccc1Br)CC2=O
Product: Nc1ncc2c(n1)CC(c1ccccc1-c1cccnc1)CC2=O

Procedure:
The title compound was prepared from 2-amino-7-(2-bromo-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/h stage 2), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 4/a stage 1).
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.Cl[C:25]([O:27][C:28]([CH3:30])=[CH2:29])=[O:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:29]=[C:28]([O:27][C:25]([NH: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)=[O:26])[CH3:30]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)OC(=O)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1 g, 5 mmol) and DIEA (1.76 ml) in DCM (10 ml) at 0° C. was added isopropenyl chloroformate dropwise. After the addition, the reaction mixture was allowed to warm up to room temperature and was stirred for 30 minutes. Saturated sodium bicarbonate solution (10 ml) was added and the organic layer was collected, washed with water and dried over sodium sulfate. After removal of solvent, the crude product (1.8 g) was used directly for the next step reaction.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[CH:24]=[O:25])([O-:14])=[O:13].[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)[N:19]=[C:18]2[CH:24]=[O:25])([O-:14])=[O:13]
Reactant: O=Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
p-Toluenesulfonic acid (30 mg, 0.158 mmol) was added to a solution of 5-nitro-indazole-3-carbaldehyde (300 mg, 1.569 mmol) and 3,4-dihydro-2H-pyran (265 mg, 3.150 mmol) in a mixture of THF/CH2Cl2 (1:1, 8 mL). The reaction mixture was stirred for 12 h at room temperature and then the solvent was removed in vacuo. The residue was taken in CH2Cl2 (50 mL) and poured in water (20 mL). The organic layer was separated, the aqueous layer was extracted with CH2Cl2 (50 mL), the combined organic layers were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and concentrated. Purification by flash chromatography (CH2Cl2) afforded title compound 215 mg (50% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 9.23 (d, 1H, J=2.0 Hz), 8.35 (dd, 1H, J=2.0 and 9.2 Hz), 7.80 (d, 1H, J=9.2 Hz), 5.89 (dd, 1H, J=2.8 and 8.8 Hz), 3.98 (m, 1H), 3.80 (m, 1H), 2.53 (m, 1H), 2.19 (m, 2H), 1.76 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][C:17]([Cl:22])=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Product: CC(Cc1cc(F)cc2cc(Cl)oc12)NC(=O)OC(C)(C)C
Yield: 42.7 %

Procedure:
Beginning with 0.29 gm (1.0 mMol) N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane and 0.16 gm (1.20 mMol) N-chlorosuccinimide, 0.14 gm (43%) of the desired compound were prepared essentially as described in EXAMPLE 16.
Reaction SMILES: [Br:1][C:2]1([O:13][CH3:14])[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH2:3]1>C(O)(=O)C.C(O)C.[Fe]>[Br:1][C:2]1([O:13][CH3:14])[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH3:12])[CH2:3]1
Reactant: COC1=C([N+](=O)[O-])C=CC(Br)(OC)C1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COC1=C(N)C=CC(Br)(OC)C1
Temperature: 120 °C

Procedure:
A suspension of 4-bromo-2,4-dimethoxy-nitrobenzene (0.48 g) and iron powder (0.42 g) in acetic acid (10 mL) and ethanol (10 mL) is heated to 120° C. for approximately 5 hours. The mixture is then cooled, filtered, and concentrated under reduced pressure. Water is added and the mixture is cooled in an ice bath and neutralized with solid potassium carbonate and then extracted with dichloromethane. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then chromatographed over silica gel (20% ethyl acetate in hexanes is used as the eluant) to provide the desired compound as an amber oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[N:19][OH:20])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a suspension of 4-(4-fluoro-benzyloxy)-benzaldehyde (21.9 g, 95.2 mmol) and hydroxylamine hydrochloride (7.3 g, 105 mmol) in 400 mL water/ethanol 9:1 was added a solution of NaOH (9.5 g in 100 mL of water) dropwise over 15 min. The now yellow solution was stirred for 2 h at rt after which the reaction was adjusted to pH 5-6 with acetic acid. The resulting white precipitate was collected by filtration and washed with water. The wet filter cake was dissolved in ethyl acetate and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(4-fluoro-benzyloxy)-benzaldehyde oxime (23.5 g, 95.8 mmol) as a yellowish crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:42]([C:52]([F:55])([F:54])[F:53])[CH:41]=1)=[NH:39]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:4]([C:5]2[O:7][N:39]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[C:42]([C:52]([F:53])([F:54])[F:55])[CH:41]=3)[N:37]=2)=[CH:8][CH:9]=[C:10]([O:12][CH3:13])[N:11]=1
Reactant: N=C(NO)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Reactant: COc1ccc(C(=O)O)c(OC)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)no2)c(OC)n1
Reaction time: 16 h

Procedure:
2,6-Dimethoxy-nicotinic acid (1 eq) is dissolved in dioxane and EDC.HCl (1.3 eq) and HOBt (1.1 eq) are added. After 30 minutes at room temperature N-hydroxy-2-trifluoromethyl-biphenyl-4-carboxamidine (1 eq) is added and the reaction mixture is kept at 900 degrees Celsius for 16 hours. After removal of the solvent the residue is dissolved in ethyl acetate and extracted with saturated NaHCO3 solution. Title compound is obtained after drying of the organic phase over Na2SO4 on silica gel using c-hexane/ethyl acetate→c-hexane/ethyl acetate 100→70/30 as mobile phase.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[N+:28]([C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[S:42])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29].C(OCC)(=O)C>CO.ClCCl>[CH3:14][S:11]([O:10][C@H:8]1[CH2:7][N:6]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:5]([C:3]2[N:43]=[C:41]([CH2:40][NH:39][C:37]([O:36][CH2:35][C:34]3[CH:44]=[CH:45][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)=[O:38])[S:42][CH:2]=2)[CH2:9]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)CBr)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: NC(=S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of (2S,4R)-2-bromoacetyl-4-methanesulfonyloxy- 1-(4-nitrobenzyloxycarbonyl)pyrrolidine (840 mg) in a mixture of methanol (30 ml) and dichloromethane (20 ml) was added 2-(4-nitrobenzyloxycarbonylamino)thioacetamide (700 mg) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into ethyl acetate and washed with saturated aqueous sodium bicarbonate and bring successively. The dried organic layer was evaporated and the resulting oil was subjected to column chromatography on silica gel (30 g) eluting with ethyl acetate to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-{N-(4-nitrobenzyloxycarbonyl)aminomethyl}thiazol-4-yl]pyrrolidine (540 mg).
Reaction SMILES: CC(C[C@@H]1NC(=O)[C@H:34]2[N:30]([CH2:31][CH2:32][CH2:33]2)[C:28](=O)[C@H:27]([CH:38](C)C)NC(=O)C2=CSC(=N2)CNC(=O)C2=CSC(=N2)[C@H](CCC(N)=O)NC1=O)C.[NH:46]1CCC[C@H:47]1[C:48](OC)=O.FC(F)(F)C(O)=O.[OH-].[Na+].C1CCC(N=C=NC2CCCCC2)CC1.FC1C(O)=C(F)C(F)=C(F)C=1F>O1CCOCC1.COCCOC.CO.C(O)C.C(OCC)C.C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[N:30]1([C:28]2[CH:27]=[CH:38][N:46]=[CH:47][CH:48]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC(C)C[C@@H]1NC(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)c2csc(n2)CNC(=O)c2csc(n2)[C@H](CCC(N)=O)NC1=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: c1cc(N2CCCC2)ccn1
Yield: 76 %

Procedure:
Synthesis of dolastatin 3 is accomplished by one L-amino acid unit additions from L-Pro-OMe employing diethyl phosphorocyanidate (DEPC)-triethylamine for peptide bond formation and N-Boc-protection (trifluoroacetic acid cleavage). The thiazole amino acid components used herein were prepared as described by Schmidt et al (Synthesis, 1987, 233-236; Schmidt et al, Synthesis, 1986, 992-998; Kelly et al, J. Org. Chem., 1986, 51, 4590-4594; Houssin et al, J. Org. Chem., 1985, 50, 2787-2788; and Holzapfel et al, J. Org. Chem., 1985, 50, 2323-2327). By these means, Boc-L-Leu--L-(gln)Thz-(gly)Thz-L-Val-L-Pro-OMe, mp 125°-126° from ethyl acetate-hexane, [α]D25.8 -74.9 (c=3.73, CHCl3) was obtained in 71% overall yield. After successive hydrolysis [1N NaOH, dioxane 3N HCl→mp 168°-170° from ethanol-diethyl ether, [α]D22 -37.7 (c=1.64, CH3OH), conversion (DCCI, DME, pentafluorophenol) to the OPfp active ester, Boc cleavage, and cyclization in dioxane containing 4% t-butanol and 4 -pyrrolidinopyridine (at 95° C., 76% yield), synthetic (-)-dolastatin 3, a colorless amorphous solid from ethanol-ethyl acetate, mp 170°-173°, [α]D25 -53.3 (c=0.94 in CHCl3), 1H- and 13C-NMR was realized in 41% overall yield.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:7]([C:6]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:21][CH2:20]1
Reactant: OC1CCNCC1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Yield: 70 %

Procedure:
Prepared in analogy to Example 1 from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 4-hydroxypiperidine. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as an amorphous yellow solid (yield 70%). MS (m/e): 342.3 (M+H+, 100%).