Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH2:32])[N:24]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[N:24]=[C:25]([NH2:32])[C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine (12.3 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [C:1]1([C:7]#C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([CH2:12][CH2:13][CH2:14]CCN1C=CC=C(OCC2C=CC=CC=2)C1=O)=[N+:10]=[N-:11].[C:32]1([N:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C:46]3N=NN[CH:50]=3)=[C:40]([O:51]C)[C:39]2=[O:53])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:32]1([N:38]2[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][CH2:50][CH2:14][C:13]3[N:11]=[N:10][NH:9][CH:12]=3)=[C:40]([O:51][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:39]2=[O:53])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Reactant: [N-]=[N+]=NCCCCCn1cccc(OCc2ccccc2)c1=O
Reactant: C#Cc1ccccc1
Product: O=c1c(OCc2ccccc2)c(CCCCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 72 %

Procedure:
Reaction of phenylacetylene (0.04 g, 0.32 mmol) and 157d (0.10 g, 0.32 mmol) within 4 h as described for synthesis of 158a gave compound 158d (0.092 g, 72%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (m, 3H), 7.30 (m, 8H), 6.79 (d, J=6.8 Hz, 1H), 6.57 (d, J=7.3 Hz, 1H), 5.94 (t, J=7.1 Hz, 1H), 5.02 (s, 2H), 4.31 (t, J=7.0 Hz, 2H), 3.87 (t, J=7.2 Hz, 2H), 1.91 (m, 2H), 1.74 (m, 2H), 1.30 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.80, 148.57, 147.39, 136.02, 130.44, 128.64, 128.56, 128.27, 127.81, 127.71, 127.05, 125.40, 119.57, 115.12, 104.49, 70.40, 49.71, 49.06, 29.42, 28.03, 23.05.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:35](I)[CH3:36].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[CH:7]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:35][CH3:36])=[CH:29][CH:30]=1)[N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)C(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOc1ccc(CC(C(=O)OC(C)(C)C)N(CC(=O)OC(C)(C)C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
13.2 g (30 mmol) of N-benzyl-2-(4-hydroxybenzyl)-3-azaglutaric acid-di-tert-butyl ester (Example j) is dissolved in 50 ml of anhydrous N,N-dimethylformamide and mixed at 0° C. under argon with 1.31 g (33 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 15 minutes, then 8.05 g (51.7 mmol) of ethyl iodide is added, the reaction temperature is allowed to increase to room temperature and it is stirred for another three hours. For working-up, the batch is taken up in toluene and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine. The product fractions are concentrated by evaporation in a vacuum and dried.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].C(O)(=O)C>CN(C)C=O>[N:27]([CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:7][CH2:8]1)=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CN=[N+]=[N-])CC3)c(F)c2)C(=O)O1
Yield: 72 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with sodium azide (2.06 mmol) and glacial acetic acid (7.1 mmol) in dimethylformamide (15 ml) at a temperature 40° C. for 14 hours and by purifying the compound by silica gel column chromatography in 72% yield.
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]([F:17])([O:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])[CH:6]([F:8])[F:7].Cl.[N+:19]([O-:22])([O-:21])=[O:20].[NH4+]>C(O)C>[N+:19]([O-:22])([OH:21])=[O:20].[F:4][C:5]([F:17])([O:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]([NH2:3])=[NH:1])[CH:14]=[CH:15][CH:16]=1)[CH:6]([F:7])[F:8]
Reactant: O=[N+]([O-])[O-]
Reactant: N#CN
Reactant: Nc1cccc(OC(F)(F)C(F)F)c1
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Product: O=[N+]([O-])O
Temperature: 25 °C

Procedure:
10.1 g (240 mmol) of cyanamide (50% in water) are added to a suspension of 25.2 g (120 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-aniline in 125 ml of ethanol. 16.3 ml of hydrochloric acid (conc., 192 mmol) are then added to the brown solution and the reaction mixture is heated under reflux for 19 h. After cooling to RT, the reaction mixture is concentrated under reduced pressure and the residue is dissolved in 80 ml of water. After the addition of 19.2 g (240 mmol) of ammonium nitrate, the product is isolated by filtration, then washed with water and dried at 60° under I-HV. 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate is obtained; m.p. 132°-14133°.
Reaction SMILES: B.CSC.[F:5][C:6]([F:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([NH2:9])=O.CO.Cl>C1COCC1>[F:5][C:6]([F:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:7][NH2:9]
Reactant: NC(=O)C(F)(F)c1ccccc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: NCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
Borane·dimethylsulfide (1.5 ml; 15.4 mmol) was added dropwise over 30 minutes to a solution of the title compound of Step (B) (1 g; 5.84 mmol) in 6 ml of THF at room temperature. After stirring 18 hr at room temperature and 2 hr at reflux, the reaction mixture was cooled to 0° C. and 3 ml of methanol were added carefully over 15 minutes. The solution was saturated with HCl (g) and the cloudy mixture was stirred 6 hr at room temperature, 30 minutes at reflux and 60 hr at room temperature. After removing the volatiles in vacuo, the residue was partitioned between ether (50 ml) and 1N HCl (30 ml). The ether layer was extracted with 1N HCl (10 ml) and the combined aqueous was backwashed with ether (50 ml). After adjusting the pH to 8 with solid NaHCO3, 1N NaOH (1 ml) was added and the aqueous layer was extracted with ether (50 ml). After washing with saturated NaHCO3 solution (25 ml), water (25 ml) and brine (25 ml), the ether layer was dried (MgSO4) and concentrated to afford 355 mg (39%) of the title compound of this step as a colorless liquid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:45])[NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)=[O:45])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 99 (120 mg, 0.18 mmol) in DCM (20 mL) was added TFA (5.6 mL). The reaction mixture was stirred at RT overnight, concentrated, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 20/80 over 20 CV), to afford the title compound 100 (90 mg, 0.13 mmol, 72% yield, TFA salt) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) δ 8.74 (s, 1H), 8.60 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 7.20 (d, J=10.0 Hz, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.61 (s, 1H), 3.84 (s, 2H), 3.35-3.25 (m, 2H), 3.05 (s, 3H), 3.02-2.90 (m, 2H), 2.59-2.50 (m, 1H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 556.5 (M+H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH:31]=O.N1CCCCC1>C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH:31]=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20]
Reactant: O=CCCc1ccccc1Cl
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1SC(=CCCc2ccccc2Cl)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 738 mg (4.4 mmol) of 3-(2-chlorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.37 g (96.5%, yellow oily substance) of the desired product.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[C:17]([O:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][C:15]=2[N+:32]([O-:34])=[O:33])=[CH:10][CH:9]=1)=[O:7].C1COCC1.Cl>CO.O>[N+:32]([C:15]1[CH:16]=[C:17]([O:23][C@H:24]([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:18]([N:20]([CH3:21])[CH3:22])=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)([O-:34])=[O:33]
Reactant: CCCCCC[C@@H](C)Oc1cc([N+](=O)[O-])c(-c2ccc(C(=O)OC)cc2)cc1N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)Oc1cc([N+](=O)[O-])c(-c2ccc(C(=O)O)cc2)cc1N(C)C
Yield: 103.1 %

Procedure:
Lithium hydroxide monohydrate (96 mg, 2.28 mmol) was added to a stirred solution of compound 64 (49 mg, 0.11 mmol), THF (2 ml), water (3 ml), and methanol (10 ml). The reaction mixture was refluxed overnight and then was acidified with concentrated HCl. The reaction mixture was extracted twice with dichloromethane, the combined organic layers were washed with brine and dried over MgSO4. Evaporation of solvent yielded 47 mg (100%) of a yellow solid. The crude product was carried on without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:17]=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.B(O[O-])=[O:20].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([OH:20])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=BO[O-]
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
4′-Chloro-3-(1,1-dichloromethyl)-4-nitrobiphenyl (0.4 g, 1.26 mmol) was dissolved in methanolic sodium methoxide (15 mL; 0.5 M). The mixture was refluxed for 12 hours under argon. The solvent was evaporated and the residue diluted in 1,4-dioxane (15 ml) and water (1 ml), then a few drops of concentrated HCl were added. The reaction mixture was stirred at 100° C. for 4 hours. The solvent was then evaporated and the crude mixture purified by flash chromatography on silica gel (eluting with dichloromethane in petroleum ether) to yield the 4′-chloro-4-nitrobiphenyl-3-carbaldehyde (0.32 g, 1.26 mmol); m/z (APCI−) 260 (40%, [M−H]−), 231 (100%). This aldehyde (0.32 g, 1.26 mmol) was dissolved in acetic acid (5 mL) and sodium perborate (0.23 g, 1.5 mmol) was added. The resulting mixture was stirred at 50° C. for 16 h. The mixture was cooled, the solvent was evaporated, ethyl acetate was added and the organic layer washed with water, dried over MgSO4 and evaporated to yield the 4′-chloro-4-nitrobiphenyl-3-carboxylic acid (0.14 g, 41%); m/z [APCI−] 276 (100%, [M−H−], 247 (60%).
Reaction SMILES: Br[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Br)[CH:10]=[C:11]([Br:17])[CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=[C:4]([Br:20])[CH:3]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[C:24]([CH3:30])[CH:23]=1.[C:31]([O-])(=O)[CH3:32].[Na+]>C([O-])(=O)C.[Cu+]>[C:24]1([CH3:30])[CH:23]=[C:22]([CH3:21])[CH:27]=[C:26]([CH3:28])[C:25]=1[NH:29][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH:29][C:25]4[C:24]([CH3:30])=[CH:23][C:22]([CH3:27])=[CH:21][C:31]=4[CH3:32])[CH:10]=[C:11]([Br:17])[CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=[C:4]([Br:20])[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=C1c2cc(Br)cc(Br)c2C(=O)c2cc(Br)cc(Br)c21
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: [Cu+]
Agent: [Na+]
Product: Cc1cc(C)c(Nc2cc(Br)cc3c2C(=O)c2cc(Br)cc(Nc4c(C)cc(C)cc4C)c2C3=O)c(C)c1
Temperature: 170 °C
Reaction time: 7 h

Procedure:
37 g of 1,3,5,7-tetrabromoanthraquinone, 12.3 ml of mesidine, 17.3 g of sodium acetate and 0.5 g of copper(I) acetate are introduced into a laboratory reaction apparatus and stirred for 7 hours at 170° C. After cooling to RT, the crude product is precipitated by the addition of 1 liter of 2N HCl and recrystallised from ethanol. After filtration and drying 21 g (47%) of product are obtained.
Reaction SMILES: [B-](F)(F)(F)F.[N:6]#[O+].[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:21]3([CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[O:20][C:19]3[C:28]([CH3:34])=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[C:18]2=3)=[CH:13][CH:12]=1)([CH3:10])[CH3:9].[OH-].[Na+]>C(#N)C>[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:21]3([CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[O:20][C:19]3[C:28]([CH3:34])=[C:29]([CH3:33])[C:30]([NH2:6])=[C:31]([CH3:32])[C:18]2=3)=[CH:13][CH:12]=1)([CH3:10])[CH3:9]
Reactant: Cc1cc(C)c2c(c1C)OC1(CCN(C)CC1)C2c1ccc(C(C)C)cc1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.5 %

Procedure:
A solution of nitrosyl tetrafluoroborate (470.7 mg, 4.03 mmol) in acetonitrile (40 ml) was cooled to 0° C. To the solution was added a solution of 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine] (479.1 mg, 1.32 mmol) in acetonitrile (10 ml) and the mixture was stirred for 20 minutes. The reaction mixture was poured into ice water and basified with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was dissolved into ethanol (20 ml) and palladium-carbon (59.9 mg) was added into the solution, then the mixture was stirred at 60° C. for 18 hours under a hydrogen atmosphere. The reaction mixture was cooled down to room temperature, filtered to remove insoluble materials, and then concentrated under reduced pressure. The residue was subjected to column chromatography (on Chromatorex NHDM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.); hexane-ethyl acetate 3:1) to obtain 402.0 mg (83% yield) of the title compound. Melting point: 123-124° C. (Hexane).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][O:3]1.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[CH3:15]>CN(C=O)C>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:1][C:2]([CH3:5])([OH:3])[CH3:4])=[CH:9][C:8]=1[CH3:15]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC1(C)CO1
Solvent: CN(C)C=O
Product: Cc1cc(OCC(C)(C)O)cc(C)c1Br
Temperature: 25 °C

Procedure:
In a microwave vial 2.20 g (0.03 mmol) of 2,2-dimethyloxirane are added to a suspension of 6.00 g (0.03 mmol) of 4-bromo-3,5-dimethylphenol and 11.0 g (0.08 mmol) K2OC3 in 6.0 ml DMF. The vial is sealed and the mixture is heated for 48 hours to 120° C. After cooling to r.t., the mixture is partitioned between sat. aq. Na2CO3 solution and EtOAc. The aq. phase is extracted twice with EtOAc and the combined organic phases are dried and concentrated. The residue is chromatographed on silica gel (CH/EtOAc 100:050:50) to give the title compound. Yield: 2.9 g; LC (method 4): tR=1.76 min; Mass spectrum (ESI+): m/z=273 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH2:8])=[S:7])(=[O:3])[CH3:2].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=[O:12].C(=O)(O)[O-].[Na+]>ClCCCl>[ClH:9].[C:1]([O:4][CH2:5][C:6]1[S:7][CH2:13][C:11]([CH2:10][Cl:9])([OH:12])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(N)=S
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)OCC1=NC(O)(CCl)CS1
Product: Cl
Temperature: 40 °C
Yield: 60 %

Procedure:
A mixture of 5.33 g of 2-acetoxythioacetamide, prepared according to Example 2, 5.21 g of 1,3-dichloroacetone, 3.44 g of sodium bicarbonate and 20 ml of 1,2-dichloroethane was heated at 40° C. for 15 hours. The mixture was filtered to remove insoluble inorganics and concentrated under reduced pressure to an oil. The oil was taken up in 25 ml of isopropyl alcohol saturated with hydrogen chloride (5N) and 25 ml of isopropanol added to improve stirring. The slurry was stirred for 30 minutes at 0° C. and then filtered. The precipitate was washed with cold IPA and dried at room temperature under reduced pressure. The product 2-acetoxymethyl-4-chloromethyl-4-hydroxythiazoline hydrochloride was obtained in 60% yield (1.66 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>CCOC(C)=O.Cl>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 76 %

Procedure:
To a stirring mixture of morpholine (1.00 g) and triethylamine (1.6 mL) in EtOAc (10 mL) at 0° C. is added chloroacetyl chloride (1.83 mL) dropwise. The mixture is stirred at 0° C. for 35 min., diluted with 10% HCl (25 mL) and extracted with EtOAc (3×50 mL). The organic layer is dried over MgSO4, and the solvent removed. The residue is purified by SiO2 flash column chromatography (eluent 35% EtOAc/hexane) to afford 1.42 g (76%) of the title compound as a yellow liquid. Physical characteristics: 1H NMR (CDCl3) δ3.54, 3.64, 3.72, 4.07; IR (liq.) 2859, 1654, 1463, 1438, 1302, 1270, 1251, 1233, 1115, 1069, 1040, 965, 790, 657, 604 cm−1; MS (ESI+) m/z 164 (M+H)+. Anal. Found: C, 43.66; H, 6.17; N, 8.58.
Reaction SMILES: C1C2C(=CC=CC=2)CCC21CC[C:13](=[O:16])[CH2:12]C2.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[C:24]1([CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)[CH2:23]2)[CH3:18].Cl>CC(C)=O>[CH2:13]1[O:16][C:25]2([C:26]3[C:22](=[CH:21][C:20]([O:19][CH2:17][CH3:18])=[CH:28][CH:27]=3)[CH2:23][C:24]32[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]3)[O:29][CH2:12]1
Reactant: CCOc1ccc2c(c1)CC1(CCC(=O)CC1)C2=O
Reactant: O=C1CCC2(CC1)CCc1ccccc1C2
Agent: Cl
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)CC1(CCC(=O)CC1)C21OCCO1

Procedure:
A mixture of 1.86 g. (0.0072 mole) of 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one, ethylene ketal (8) (prepared in Example 7C) and 2 ml. of 2.5 N hydrochloric acid in 40 ml. of acetone is heated at reflux for about 17 hours. Most of the solvent is removed under vacuum and the residue dissolved in water and ether. The organic layer is washed with water and brine and then evaporated to dryness to give 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one (9).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=C.[O:12]=[O+][O-].[BH4-].[Na+].Cl>CO>[OH:11][C:5]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[CH2:1][CH2:2][OH:12]
Reactant: C=CCc1cc(C)ccc1O
Reactant: O=[O+][O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(O)c(CCO)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of 8.34 g (0.05 mol) of 2-allyl-4-methylphenol in 420 ml of CH3OH containing a few crystals of Sudan III indicator was cooled to -78° C. Ozone was passed through this solution until a color change of the Sudan III indicator showed that the ozonization reaction was complete. Solid sodium borohydride (6.4 g) was added in small portions to the cold solution. When this addition was complete, the solution was allowed to warm to room temperature overnight. The solution was made acid by the addition of 6N HCl, and then was concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and was washed with water, saturated NaHCO3 solution and brine. The solution was dried, filtered, and evaporated to give 7.3 g (96%) of 2-(2-hydroxy-5-methylphenyl)ethanol.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:12][CH:13]=2)[C:8]([NH2:19])=[N:7]1)=O)C>C(OC(OC(OCC)=O)=O)C>[NH2:19][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:17])([F:16])[F:18])[NH:6][N:7]=1
Reactant: CCOC(=O)n1nc(N)c2c(C(F)(F)F)cccc21
Agent: CCOC(=O)OC(=O)OCC
Product: Nc1n[nH]c2cccc(C(F)(F)F)c12

Procedure:
Analogously to Example 21, 0.06 mol of 3-amino-4-trifluoromethylindazole in 50 ml of pyrocarbonic acid diethyl ester gives 3-amino-4-trifluoromethylindazole-1-carboxylic acid ethyl ester (melting point: 185°-186° C; 68% of theory) in 2 hours at 75° C.