Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>CN(C)C=O.C(OCC)(=O)C>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([N:22]2[CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:1]2=[O:2])[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2N)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (8.73 g, 53.8 mmol) was added to a solution of tert-butyl 4-{[2-(2-aminophenyl)ethyl]amino}piperidine-1-carboxylate (17.2 g, 53.8 mmol) in dimethylformamide (200 mL), and stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate and extracted with water, then saturated brine. The crude product was purified by chromatography (silica gel, 0-30% ethyl acetate in methylene chloride gradient elution). The title compound was obtained as a dark solid (4.8 g).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:3])C.[CH2:19](SC1C=CC(B(O)O)=CC=1)CC>>[CH2:1]([S:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[CH:9][CH:10]=1)[CH2:3][CH3:19]
Reactant: CC(C)Sc1ccc(-c2csc(C(=O)O)c2)cc1
Reactant: CCCSc1ccc(B(O)O)cc1
Product: CCCSc1ccc(-c2csc(C(=O)O)c2)cc1

Procedure:
The title compound was prepared in a similar manner as described in the preparation of 4-(4-(isopropylthio)phenyl)thiophene-2-carboxylic acid (compound 73, example 12), except commercially available 4-(propylthio)phenylboronic acid was used in the place of 4-(isopropylthio)phenylboronic acid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Br)=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[NH2:21][C:22]([NH2:24])=[S:23].C(=O)(O)[O-].[Na+]>O>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:12][C:13]2[N:21]=[C:22]([NH2:24])[S:23][CH:15]=2)=[O:17])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nnc(NC(=O)Cc2csc(N)n2)s1
Yield: 96.1 %

Procedure:
A reaction mixture comprising 11.2 g (0.035 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, 200 ml of ethanol and 2.8 g (0.037 mole) of thiourea was refluxed for three hours. The reaction solution was cooled and added to 300 ml of water. With stirring, there was slowly added an excess of saturated aqueous sodium bicarbonate. The product was collected and dried. There was obtained 10 g (96.2%) of white solid, m.p. 226° (dec.). N.M.R. (dimethyl-d6 sulfoxide) ∂ 1.4 [C(CH3)3 ], 3.6 (CH2), 6.3 (hetero-aromatic), 6.9 (NH).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:25])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: CNCc1ccccc1
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(N(C)Cc1ccccc1)C2

Procedure:
Starting from 2.03 g (0.01 mol) of 5-acetylamino-2-tetralone and 4.37 g (0.03 mol) of N-benzyl-methylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 2.0 g (58.1% of theory) and with a melting point of 243° C. which does not change after recrystallisation from methanol/ether.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[NH2:17][C:18]1[C:19]2[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])[S:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1>O1CCCC1>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[S:30][C:20]=3[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: CN(NC(=O)c1cc2c(N)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(NC(=O)c1cc2c(NC(=O)c3ccc(Br)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Temperature: 25 °C
Yield: 10 %

Procedure:
169 mg (1.22 mmol) of potassium carbonate, followed by 191 mg (0.87 mmol) of 4-bromobenzoyl chloride, are added to a solution of 0.27 g (0.70 mmol) of tert-butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 20 mL of tetrahydrofuran under argon. The reaction mixture is stirred at reflux for 2 hours. The reaction mixture is then cooled to a temperature in the region of 25° C. and treated with 40 mL of ice-cold water. The mixture is extracted successively with 60 mL and then with twice 40 mL of ethyl acetate. The organic phases are combined, washed twice with 40 mL of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 35° C. The residue is purified by chromatography on a cartridge of 25 g of silica gel (0.015-0.040 mm), eluting successively with dichloromethane/methanol mixtures (99/1 by volume, and then 98/2) at a flow rate of 13 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 0.04 g of tert-butyl 3-(4-bromobenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate is thus obtained in the form of a white solid melting at 192° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH2:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C>[CH2:31]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH2:19])=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][C:9]1=2)[CH:30]=[CH2:29]
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)sc2c1C1CCCCC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2sc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a 0.1M solution of methyl 6-cyclohexyl-5-(2-vinylphenyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate in dry DMF, 60% NaH (1.2 eq.) in mineral oil was added; when gas evolution had ceased, allyl bromide (1.3 eq.) was added, and the suspension was stirred at RT for 1 h. All volatiles were evaporated and the title compound was isolated by chromatography (PE/Et2O 20:1). Yield: 98%. 1H-NMR (400 MHz, CDCl3, 300K, δ) 7.73 (d, 1H, J 7.6), 7.70 (s, 1H), 7.47 (t, 1H, J 7.6), 7.36 (t, 1H, J 7.6), 7.25 (d, 1H, J 7.6), 6.48 (dd, 1H, J 17.8, 11.4), 5.72 (d, 1H, J 17.8), 5.80-5.69 (m, 1H), 5.20 (d, 1H, J 11.4), 5.09 (dd, 1H, J 10.3, 1.1), 4.97 (dd, 1H, J 17.1, 1.1), 4.36 (dd, 1H, J 16.2, 5.6), 4.23 (dd, 1H, J 16.2, 5.6), 3.92 (s, 3H), 2.35-2.24 (m, 1H), 1.75-1.16 (m, 10H).
Reaction SMILES: [H-].[Na+].[C@H:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[OH-].[Na+]>CN(C=O)C.O>[C@H:3]1([O:10][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[O:9][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: O[C@H]1CCCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(O[C@H]2CCCC[C@@H]2Oc2ccc(C#N)cc2)cc1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
Sodium hydride (7.1 g, 0.3 mol) was dispersed in 200 ml DMF and added with (1S,2S)-cyclohexane-1,2-diol (11.42 g, 98.3 mmol) while cooling with ice. The mixture after being cooled with ice for another one hour was reacted at room temperature for 2 hours and cooled again, followed by addition of p-fluorobenzonitrile (25 g, 206 mmol). After the reaction was continued overnight, the mixture was added carefully with 5 ml water to inactivate excess sodium hydroxide, followed by distillation of DMF in pressure. The residue was added with 200 ml water and then extracted with ethyl acetate, followed by washing with a saturated solution of sodium chloride thereby obtaining a coarse crystalline product. The crystalline product was then recrystallized from 200 ml isopropanol thereby obtaining the intended product (26.2 g, 82.3 mmol, 84%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OC)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:14][CH2:13]1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-methyl 4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (9.0 g, 35 mmol) in THF (70 mL) was added slowly a 2.0 M solution of LiAH4 in THF (20 mL, mmol) at −78° C. The reaction was warmed slowly to room temperature (over 4 h), and quenched by dropwise addition of water (5 mL), followed by addition of NaOH (5 mL) and Na2SO4. The mixture was stirred for 20 min and filtered. The filtrate was dried (Na2SO4), and concentrated. The crude mixture was purified by Isco to provide tert-butyl trans-4-(hydroxymethyl)cyclohexylcarbamate (5.5 g, 69%) as a white solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:34])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH3:29])[CH:22]=3)=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:30])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([C:17]2[CH:16]=[C:15]3[C:20]([C:12](=[CH:11][C:10]4[NH:9][CH:8]=[C:7]([CH3:34])[C:6]=4[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:30])[NH:14]3)=[CH:19][CH:18]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:29]
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(C)c2CCC(=O)O)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 44.2 %

Procedure:
4-(2-Carboxyethyl)-5-[6-(3-ethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid (350 mg) suspended in ethylene glycol (5 mL) was held in a sealed tube in a pre-heated oil bath at 200° C. for 2.5 hours. The reaction mixture was cooled to 100° C. and potassium hydroxide (4 pellets) was added. It was then stirred at 100° C. for 2 hours. The reaction mixture was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight. The crude solid was purified on a silica gel column using 33:66:1 ethyl acetate:hexanes:glacial acetic acid to give 140 mg (44%) of 3-{2-[6-(3-ethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4-methyl-1H-pyrrol-3-yl}-propionic acid as a brown solid.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([CH:8]1[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:7].ClCCl.[OH-].[Na+]>O>[CH2:6]([C:8]1([CH:10]([CH3:9])[C:11]#[N:12])[CH:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1)[CH3:7]
Reactant: CCC1CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCC1(C(C)C#N)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
10.0 g (28.5 mmoles) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolizinium perchlorate are dissolved in 100 ml. of dichloromethane, and 75 ml. of distilled water and 20 ml. of a 2 n aqueous sodium hydroxide solution are added to the stirred soltion under argon atmosphere. The reaction mixture is stirred for 10 minutes, thereafter the separated organic phase is isolated and dried over anhydrous potassium carbonate. The drying agent is filtered off, 10 ml. of freshly distilled acrylonitrile are added to the filtrate, the mixture is flushed with argon, and it is allowed to stand at room temperature. The colour of the mixture turns deeper. After 2 days of standing the mixture is evaporated in vacuo at a bath temperature of maximum 40° to 50° C under argon atmosphere, and the dark red, oily residue is triturated with 5 ml. of methanol. The obtained orange red crystals, weighing 8.10 g., are filtered off, and recrystallized from 15-fold volume of methanol. 7.30 g. (79.4%) of (1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizin-1-yl)-propionitrile are obtained: m.p.: 122°-123° C.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:3][CH:2]=1.C([O-])(=O)C.[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40](I)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40]([C:14]4[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:4]5[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=5)(=[O:10])=[O:9])=[CH:12][CH:13]=4)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)Nc5ccc(C)cc5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 45.1 %

Procedure:
A mixture of 0.489 g of N-p-tolyl-4-bromo-benzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 6.5 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25-15:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate/acetonitril (1:1) gives 0.22 g of the title compound as a solid of m.p. 219-220° C. The mass spectrum shows the molecular peak MH+ at 500.3 Da.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](O)(=O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[OH:13][CH2:12][C:11]1[NH:1][C:2]2=[N:3][C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[C:7]2[N:8]=1
Reactant: O=C(O)CO
Reactant: Cc1cc(C)c(N)c(N)n1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2nc(CO)[nH]c2n1
Yield: 15.2 %

Procedure:
A mixture of 13.72 g of 2,3-diamino-4,6-dimethylpyridine and 25 g of glycolic acid in 200 ml of toluene was heated under reflux for 3.5 hours, whilst distilling off azeotropically the water formed in the course of the reaction. At the end of this time, the reaction mixture was freed from the toluene by decantation and the oily residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethanol and ethyl acetate in ratios ranging from 2:3 to 1:1 by volume as a eluent, to give 2.7 g of the title compound, melting at 244°-246° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([S:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:11]([CH3:22])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[OH-].[Na+].Cl>C(O)C>[F:24][C:2]([F:1])([F:23])[C:3]([C:9]1[CH:10]=[C:11]([CH3:22])[C:12]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[C:13]([CH3:15])[CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: COC(=O)CSc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1SCC(=O)O

Procedure:
Combine methyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenylthio]acetate with 30 ml ethanol and 5 ml 1.0 N sodium hydroxide. Reflux 4 hours, add 5 ml 1.0 N HCl, and extract with ether. Dry, concentrate and recrystallize from ether-hexane to obtain 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenylthio]acetic acid, m.p. 133°-135° C.
Reaction SMILES: [O:1]1[C@H:3]2[C:4]3[C:5]([O:17][C:18]([CH3:20])([CH3:19])[C@:2]12O)=[CH:6][C:7]1[C:8]([CH3:16])=[CH:9][C:10]([CH2:14][OH:15])=[N:11][C:12]=1[CH:13]=3.[C:22]1([CH2:28][CH2:29][NH2:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)CC>[OH:15][CH2:14][C:10]1[CH:9]=[C:8]([CH3:16])[C:7]2[CH:6]=[C:5]3[O:17][C:18]([CH3:19])([CH3:20])[C@H:2]([OH:1])[C@@H:3]([NH:30][CH2:29][CH2:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:4]3=[CH:13][C:12]=2[N:11]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cc(CO)nc2cc3c(cc12)OC(C)(C)[C@]1(O)O[C@@H]31
Solvent: CCCO
Product: Cc1cc(CO)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3NCCc1ccccc1
Yield: 125.8 %

Procedure:
To a liquid mixture of 7.98 g (29.4 mmol) of the obtained (3R,4S)-3,4-epoxy-7-hydroxymethyl-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol and 16.07 g of 1-propanol, 4.30 g (35.5 mmol, 1.2 equivalent) of 2-phenylethylamine was added and the resultant mixture was heated and refluxed for 5 hours. The solvent was distilled off to produce 14.52 g of (3R,4S)-7-hydroxymethyl-2,2,9-trimethyl-4-(phenethylamino)-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol as a brown oily substance.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33]O)[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.C([O-])(=O)C.[NH4+].CP(C)C.O1CCCC1>O1CCCC1.O>[NH2:51][CH2:33][C:31]1[S:30][CH:29]=[C:28]([CH:27]=[C:26]([CH:10]2[O:11][C:12](=[O:13])[CH2:14][CH:15]([OH:25])[C:16]([CH3:24])([CH3:23])[C:17](=[O:18])[CH:19]([CH3:22])[CH:20]([OH:21])[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]3([CH3:36])[CH:7]([O:8]3)[CH2:9]2)[CH3:35])[N:32]=1
Reactant: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CP(C)C
Agent: [NH4+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(=Cc1csc(CN)n1)C1CC2OC2(C)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1
Temperature: 32.5 °C
Reaction time: 5 h

Procedure:
To a suspension of epothilone F (5.0 g, 9.55 mmol, 86.2% potency) and diphenylphosphoryl azide (2.27 ml, 10.5 mmol, 1.1 eq) in tetrahydrofuran (40 ml) was added gradually 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.71 ml, 11.46 mmol, 1.2 eq) and the reaction subsequently stirred at 25-40° C. for 4-6 hrs. To the reaction mixture was then added a 6.0 M solution of ammonium acetate (7.96 ml, 47.7 mmol, 5 eq) followed by 1.0 M trimethylphosphine/tetrahydrofuran solution (1.5 eq). The reaction mixture was diluted with water and the aqueous phase extracted with three portions of ethyl acetate (40 ml each). The organic phase was then washed with three portions of diluted ammonium hydroxide (40 ml each). The combined aqueous washes are then extracted with two portions of ethyl acetate (40 ml each). The combined ethyl acetate phases are washed with two portions of water (20 ml each) then concentrated and azeotropically dried under reduced pressure to a final volume of 60 ml. The resulting solution was heated at 65-75° C. and 70 ml n-heptane was added slowly. The mixture was allowed to cool slowly and stirred at a final temperature of 15-20° C. The resulting solid (3.34 g, 78% corrected for input potency) was isolated by filtration followed by vacuum drying to afford crystalline product.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][S:13][C:4]1[N:3]=[C:2]([NH:26][CH2:25][CH2:23][OH:24])[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=1
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Reactant: NCCO
Product: O=c1cnc2c(NCCO)nc(SCc3cccc(F)c3F)nc2[nH]1

Procedure:
The titled compound (52 mg) was prepared from the product of Example 3 step (b) (150 mg) and ethanolamine (35 ul) using the method of Example 2 step (f).
Reaction SMILES: [CH2:1]1[CH2:19][CH2:18][C:17]2[C:12](=[C:13]([OH:21])[CH:14]=[C:15]([OH:20])[CH:16]=2)[C:10](=[O:11])[O:9][CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]([OH:22])[CH2:3][CH2:2]1.[C:23](#N)C.C>O>[CH3:23][C@@H:8]1[O:9][C:10](=[O:11])[C:12]2[C:17](=[CH:16][C:15]([OH:20])=[CH:14][C:13]=2[OH:21])[CH2:18][CH2:19][CH2:1][CH2:2][CH2:3][C@@H:4]([OH:22])[CH2:5][CH2:6][CH2:7]1
Reactant: O=C1OCCCC[C@@H](O)CCCCCc2cc(O)cc(O)c21
Reactant: CC#N
Solvent: O
Product: C[C@H]1CCC[C@H](O)CCCCCc2cc(O)cc(O)c2C(=O)O1
Reaction time: 8 h
Yield: 38.99 %

Procedure:
3 59 kg of an α, β-zeranol mixture (55:45), acetonitrile with 0.5% water (80 1) and active charcoal (0.05 kg) were placed into a 150 1 crystallizer. The mixture was refluxed for 30 min., warm filtered and the filtrate was refluxed again. The obtained clear solution was cooled adjusting the fall in temperature to about 8°-10° C./hour, under strong mechanic stirring, so as to obtain a controlled crystallization. Crystal withdrawals were carried out at 42° C., 36° C. and 30° C. on which crystals HPLC analysis was effected a described in Example 1: content in α-zeranol proved to be extremely constant (9I.9%, 92.3% and 9I.8%, respectively, at the above cited temperatures). Stirring was continued overnight and for I2 hours more at 30 C; then the product was filtered and dried to obtain 1.40 kg (38.99%) of an α-zeranol with a 93.5% titre. This product was dissolved in 42 1 of acetonitrile with 1% of water and crystallized following the same procedure as above. 1.01 kg of final product was obtained, with a 98.6% titre (HPLC), m.p.=181°-182° C., [α]D20 =46.2 (c =1.0; methanol).