Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([N:21]([CH3:34])[C:22]3[N:27]=[C:26]([S:28][C:29]#[N:30])[C:25]([N+:31]([O-])=O)=[CH:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].CN1CCCC1=O.Cl.[OH-].[Na+]>C(O)C>[NH2:30][C:29]1[S:28][C:26]2[N:27]=[C:22]([N:21]([CH3:34])[C:17]3[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:20]=[CH:19][CH:18]=3)[N:23]=[CH:24][C:25]=2[N:31]=1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a suspension of the above-mentioned crude product of 2-{[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenyl](methyl)amino}-5-nitropyrimidin-4-yl thiocyanate and reduced iron (368 mg, 6.59 mmol) in ethanol (8 mL)/1-methylpyrrolidin-2-one (2 mL) was added 1N hydrochloric acid (2 mL), and the mixture was stirred at 100° C. for 30 min. The reaction mixture was neutralized with 2N aqueous sodium hydroxide solution (1.5 mL), the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL, 2×20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/70→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (211 mg, 36%) as pale-purple crystals.
Reaction SMILES: O.NN.[Cl-:4].[NH4+].[N+:6]([NH:9][C:10]1[NH:11][CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][N:15]=1)([O-])=O>C(O)CC>[ClH:4].[NH:9]([C:10]1[NH:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][N:11]=1)[NH2:6]
Reactant: [Cl-]
Reactant: CC1(C)CN=C(N[N+](=O)[O-])NC1
Agent: NN
Agent: [NH4+]
Solvent: O
Solvent: CCCO
Product: CC1(C)CN=C(NN)NC1
Product: Cl
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Hydrazine hydrate (1.98 grams; 0.0396 mole) is added to a mixture of 1-propanol (50 mls), ammonium chloride (1.56 grams; 0.028 mole), and 2-nitroamino5,5-dimethyl-1,3-diazacyclohex-2-ene (5.0 grams; 0.029 mole). The resulting mixture is heated to 95° C. over a period of 20 minutes, and stirred thereat for 2 hours. Additional hydrazine hydrate (0.94 gram; 0.0187 mole) is then added to the reaction mixture, and heating at 95° C. is continued for an additional 24 hours. The slurry is then cooled to room temperature and the precipitate is isolated by filtration, washed with 1-propanol (20 mls) and dried under a vacuum at 50° C. to obtain 3.55 grams (68.5% of theoretical) of the desired product. Evaporation of the filtrate affords a second crop (1.5 grams) of the same compound. The total yield in two crops is 96.5% of theoretical. The infrared absorption spectra of the two crops are identical with that of 2-hydrazino-5,5-dimethyl-1,3-diazacyclohex-2ene monohydrochloride.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1.[BrH:15]>O>[Br:15][C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1nnc(Br)s1
Yield: 87 %

Procedure:
A solution of 69 g (1.0 mole) of sodium nitrite in 150 ml of water was added dropwise over the course of 1.5 hours, while stirring, to a solution, cooled to +5° C, of 84.5 g (0.5 mole) of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole in a mixture of 400 ml of hydrogen bromide (48% strength) and 100 ml of water. Thereafter, the evolution of the nitrous gases and of the nitrogen was completed by stirring at 25° C (1 hour). The product separated out as a dark brown, heavy liquid and was abstracted from the reaction mixture by repeated extraction with a total of 500 ml of methylene chloride. After washing with 2 × 100 ml of water, drying over sodium sulfate and careful distillation of the solvent, the residue was fractionated in vacuo through a short column. 101 g (87% of theory) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole of boiling point 55° C/10 mm Hg were obtained. ##STR80##
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].C([NH:29][CH2:30][C:31](O)=[O:32])(OC(C)(C)C)=O>>[Cl:19][CH:18]([Cl:20])[C:16]([NH:15][CH:12]([CH2:13][F:14])[CH:11]([O:21][C:31](=[O:32])[CH2:30][NH2:29])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)=[O:17]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CS(=O)(=O)c1ccc(C(OC(=O)CN)C(CF)NC(=O)C(Cl)Cl)cc1
Yield: 80 %

Procedure:
By following the general procedures II and III using 12.9 g of florfenicol and 6.9 g of N-Boc glycine, the prodrug (13.2 g, 80% yield) was obtained as white powder after the crude solids were dried under reduced pressure at 50° C. for 6 days; H1-NMR (DMSO-d6), δ=3.2 ppm (m, 3H), 3.9 ppm (s, 2H), 4.3-4.7 ppm (m, 3H), 6.1 ppm (s, 1H), 6.8 ppm (s, 1H), 7.7 ppm (d, 2H), 7.9 ppm (d, 2H), 8.6 ppm (br, 3H), 9.4 ppm (d, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)=[O:9].C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[CH3:7][C:4]1[S:3][C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:8]=[O:9])=[N:6][N:5]=1
Reactant: Cc1nnc(Br)s1
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccccc2C=O)s1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (150 mg, 0.84 mmol) in 1,2-dimethoxyethane (5 mL) are added 2-formylphenylboronic acid (190 mg, 1.26 mmol), Pd(PPh3)4 (97 mg, 0.08 mmol) and Na2CO3 (sat., 0.10 mL) at room temperature. The solution is heated to 100° C. for 18 hours then cooled and poured into water and EtOAc. Layers are separated and the aqueous phase extracted with EtOAc (1×10 mL). The combined organics are dried (MgSO4), filtered and concentrated to give the crude product which is purified via flash chromatography (12 g silica gel, 5-60% EtOAc/hexanes). The product-containing fractions are combined and concentrated to give 2-(5-methyl-1,3,4-thiadiazol-2-yl)-benzaldehyde (100 mg, 58%) which is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:7][OH:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C.[Br:24][CH2:25][CH2:26]Br>CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:26][CH2:25][Br:24])[CH2:7][OH:8])[CH3:2]
Reactant: CCOc1cc(CO)ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCOc1cc(CO)ccc1OCCBr
Yield: 79.5 %

Procedure:
While stirring a mixture of 30 g of 3-ethoxy-4-hydroxybenzyl alcohol, 125 g of anhydrous potassium carbonate, and 600 ml of methyl ethyl ketone, 168 g of 1,2-dibromoethane was added to the mixture, and the resultant mixture was refluxed for 48 hours with stirring. After cooling, the reaction mixture was filtered under suction and the filtrate was distilled under reduced pressure to provide a pale-yellow oily matter. The product was dissolved in 300 ml of ether and the solution was washed twice each with 50 ml of an aqueous 5% sodium hydroxide solution and then with 50 ml of water, dried with anhydrous sodium sulfate, and distilled under reduced pressure to provide a yellow oily matter. To the product was added 100 ml of a mixture of ether and petroleum ether of 1:1 by volume ratio to form crystals, which were recovered by filtration under suction to provide 39 g of 3-ethoxy-4-(2-bromoethoxy)benzyl alcohol having a melting point of 51°-53° C.
Reaction SMILES: N[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:19]([NH:21][C:22]3[CH:23]=[C:24](/[CH:29]=[CH:30]/[C:31]([O:33]CC)=[O:32])[CH:25]=[CH:26][C:27]=3[F:28])=[O:20])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=1.C(OC(=O)C)(=[O:38])C.N1C=CC=CC=1.[C:49](#[N:51])[CH3:50]>>[C:49]([NH:51][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:19]([NH:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][C:31]([OH:33])=[O:32])[CH:25]=[CH:26][C:27]=3[F:28])=[O:20])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=1)(=[O:38])[CH3:50]
Reactant: CC#N
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3cccc(CN)c3)cc3ccccc23)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc(-c2cc(C(=O)Nc3cc(C=CC(=O)O)ccc3F)c3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound 16d (600 mg crude) was dissolved in acetonitrile (15 mL), acetic anhydride (1 mL) and pyridine (1 mL) were added to the reaction mixture and stirred at rt for 16 h. The reaction mixture was evaporated to dryness. To the crude was added THF/water (1:1, 50 mL) followed by lithium hydroxide 1.5 g and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated under vacuum to dryness. The resulting residue was adjusted to pH 5 with dilute HCl and the resulting suspension was stirred for some time following which the solid formed was filtered, dried under vacuum and purified by reverse phase HPLC.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:23][NH2:24]>C(O)C>[NH2:6][C:5]1[NH:24][N:23]=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:4]=1[C:7]#[N:8]
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.8 %

Procedure:
To a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (80 g, 290 mmol) in ethanol (200 mL) was added hydrazine hydrate (20 mL). The mixture was stirred at RT for 16 hr then was concentrated to give the crude product and washed with MeOH (30 mL) to afford 55 g (68.8%) of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a off-white solid. 1H NMR (DMSO-d6) δ 12.11 (br s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.46-7.39 (m, 2H), 7.18 (t, J=7.6 Hz, 1H), 7.12-7.04 (m, 4H), 6.43 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C@H:11]2[O:12][C@H:10]2[C:9]2[CH:8]=[C:7]([CH2:13][C:14]([NH:16][CH:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:6]=[CH:5][C:4]=2[O:3]1.[NH3:28]>>[NH2:28][C@@H:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][C:14]([NH:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[O:15])[CH:8]=2)[O:3][C:2]([CH3:27])([CH3:1])[C@H:11]1[OH:12]
Reactant: CC1(C)Oc2ccc(CC(=O)NC3CCCc4ccccc43)cc2[C@@H]2O[C@@H]21
Reactant: N
Product: CC1(C)Oc2ccc(CC(=O)N[C@@H]3CCCc4ccccc43)cc2[C@@H](N)[C@@H]1O

Procedure:
40 g of the 2-[(1aS,7bS)-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl]-N-1,2,3,4-tetrahydronaphth-1-yl acetamide obtained above and 250 ml of a 25%-strength aqueous ammonia solution were reacted in a manner corresponding to the procedure of Example 1E). Chromatography of the crude product on silica gel (mobile phase: dichloromethane/methanol/25%-strength aqueous ammonia solution (75:50:2 v/v/v)) yielded 13.2 g 2-[(3S,4R)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl]-N-[(1R)-1,2,3,4-tetrahydronaphth-1-yl]acetamide as oil, which was used without further purification for the subsequent reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:21]1[CH:33]=[CH:32][C:24]2[C:25]([C:29]([OH:31])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=2[CH:22]=1.[C:34]([O-:37])([O-])=O.[Cs+].[Cs+].O>CS(C)=O.CC(O)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:34]([O:37][C:32]3[C:24]4[C:25]([C:29]([OH:31])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=4[CH:22]=[CH:21][CH:33]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc2cc(O)ccc2c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: Clc1ccnc2cc(OCc3ccccc3)ccc12
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1oc2cccc(Oc3ccnc4cc(OCc5ccccc5)ccc34)c2c1C(=O)O
Temperature: 130 °C
Yield: 189.9 %

Procedure:
7-(benzyloxy)-4-chloroquinoline 90-B was prepared (see general synthesis Scheme I) from the commercially available compound 90-A (from Aldrich). A mixture of 90-B (2.8 g, 10.4 mmol), 6-hydroxy-2-methyl-1-benzofuran-3-carboxylic acid 90-C (2 g, 10.4 mmol) and Cs2CO3 (10.1 g, 31.4 mmol) in DMSO (70 ml) was heated to 130° C. for 2 hours. The solution was poured into water, neutralized with AcOH and extracted with EtOAc. The concentrated residue was purified by silica gel chromatography using 2-5% MeOH in CH2Cl2 to give 6-{([7-(benzyloxy)quinolin-4-yl]oxy}-2-methyl-1-benzofuran-3-carboxylic acid 90-D (4.2 g, 94% yield) as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20]N(CC)CC2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.[CH2:44]([N:46]1[CH2:51][CH2:50]C(C(C)CO)[CH2:48][CH2:47]1)[CH3:45]>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:21][CH:20]2[CH2:48][CH2:47][N:46]([CH2:51][CH3:50])[CH2:44][CH2:45]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Reactant: CCN1CCC(C(C)CO)CC1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 19 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine and 2-(1-ethyl-4-piperidinyl)-1-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1.[CH:16](OCC)(OCC)OCC.[N-:26]=[N+:27]=[N-:28].[Na+]>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]3[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]3=[N:6][CH:7]=2)[CH:16]=[N:28][N:27]=[N:26]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C1CCc2cc(N)cnc21
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2cc(-n3cnnn3)cnc21
Temperature: 100 °C

Procedure:
To a solution of ethyl 3-amino-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (3.0 g, 14.6 mmol) and triethyl orthoformate (6.5 g, 43.6 mmol) in 50 mL of acetic acid was added sodium azide (1.0 g, 16.0 mmol). The mixture was heated to 100° C. for 3 hours. The reaction was complete by TLC. The reaction mixture was cooled to room temperature. The solvent was removed under vacuum. The residue was dissolved in EtOAc, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford the title compound
Reaction SMILES: C(N1C2C(=CC=C([Cl:13])C=2)C(O)=C1)(=O)C.P(Cl)(Cl)(Cl)=O.[OH-].[K+].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>O>[ClH:13].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1
Reactant: CC(=O)n1cc(O)c2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccc(N)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a 500 ml 3-neck flask with nitrogen purge, drying tube and stirrer is added 250 ml of dry pyridine. To this is added 10 g (0.0477 mole) of 1-acetyl-6-chloro-indol-3-ol. The flask is cooled to less than about 10° C. in a methanol/dry ice bath in a darkened hood. To the suspension is added 5.5 ml of phosphorous oxychloride. The temperature is allowed to come up to 0° C. and maintained for 4 hours. The reaction mixture turns a light red color. The reaction mixture is allowed to stir overnight. The solution is rotovaped to dryness (less than about 50° C.) using a cold trap and vacuum pump. The resulting residue is taken up in 100 ml of ice cold water and adjusted to pH of 9.0 with 10% KOH. The dark solution is rotovaped to dryness and traces of water removed by 3 evaporations of 100 ml portions of ethanol. The resulting solid residue is dissolved in 100 ml of dry methanol. To this dark solution is added a 20 ml portion of dry methanol containing 1.6 g of potassium metal. This mixture is stirred overnight on a stirring plate. The mixture is neutralized with a small portion of acetic acid to a pH between 5.5 and 6.0. This solution is rotovaped to dryness. The residue is dissolved in 100 ml of water and charcoal filtered. A solution of 6.9 g of p-toluidine hydrochloride is prepared in 100 ml of water. The p-toluidine solution is stirred into the reaction solution. The resulting precipitate is collected by vacuum filtration, washed with ethanol and vacuum dried.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]1[O:18][C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[O:11][CH2:10]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:15]2[CH2:16][CH2:17][C:12]3([O:18][CH2:9][CH2:10][O:11]3)[CH2:13][CH2:14]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nccc(N2CCC3(CC2)OCCO3)n1
Reaction time: 2.5 h

Procedure:
A solution of 18.5 g 2,4-dichloropyrimidine in 150 ml ethanol is added dropwise to a solution of 16 ml 4-piperidone-ethylene ketal and 17.5 ml triethylamine in 100 ml ethanol while cooling on ice. Subsequently the reaction mixture is stirred for a further 2.5 hours, the ethanol is then removed in a vacuum, the residue is admixed with 100 ml water and the aqueous mixture is extracted three times with 50 ml methylene chloride each time. After drying the combined organic phases over sodium sulfate and removing the solvent, the solid residue is recrystallized from ethyl acetate/isohexane. In this way 11 g 8-(2-chloro-pyrimidin-4-yl)-1,4-dioxa-8-aza-spiro[4.5]decane is obtained as a white powder. f.p.: 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[C:14]([F:25])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[C:14]([F:25])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)([OH:12])[C:28]([F:30])([F:29])[F:27]
Reactant: COc1ccc(C(C)C(=O)c2cc3c(cc2F)OCC(=O)N3C)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: COc1ccc(C(C)C(O)(c2cc3c(cc2F)OCC(=O)N3C)C(F)(F)F)c(Cl)c1

Procedure:
In analogy to Example 1, step 3, 6-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e)=448.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](O)([CH3:17])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:15][CH3:16])([CH3:14])[CH2:8]2.[H][H]>CO.S(=O)(=O)(O)O.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH3:17])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:15][CH3:16])([CH3:14])[CH2:8]2
Reactant: [H][H]
Reactant: CCC1(C)Cc2ccc(C(C)(O)C(=O)OC)cc2C1
Agent: O=[Pt]=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCC1(C)Cc2ccc(C(C)C(=O)OC)cc2C1

Procedure:
A solution of 8 g of 2-ethyl-α-hydroxy-2,α-dimethyl-5-indanacetic acid methyl ester in 100 cc of methanol and 8 cc of concentrated sulphuric acid is hydrogenated at 40° to 45° and a hydrogen pressure of 4 atmospheres with the addition of 0.8 g of platinum(IV) oxide. After the take up of the theoretic amount of hydrogen, the solution is filtered, diluted with a 5% sodium bicarbonate solution and extracted with ether. The extract is washed with water, dried over sodium sulphate and concentrated by evaporation. The resulting oily title compound is purified by distillation. B.P. 138°-140° at 0.3 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloro-2-fluorobenzaldehyde (2.36 g, 14.88 mmol) in THF (29.8 mL) was cooled down to −78° C. under argon. To the solution was added vinyl magnesium bromide (1 M in THF) (20 mL, 20.00 mmol) via syringe pump over 30 min, while stirring was continued at −78° C. After 2 h, the reaction mixture was warmed to 0° C., quenched with 1 N HCl and adjusted the pH to 4. The aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine and dried over MgSO4. The solids were filtered off and the filtrate was concentrated under vacuum to yield a yellow oil as the desired product. MS (ESI) m/z: 169.1 (M+H-H2O)+.