Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:43]=[CH:42][C:26]([CH2:27][NH:28][C:29](=[O:41])[O:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[NH2:8][C:9]1[C:10]([NH:20][C:21]([C:23]2[CH:43]=[CH:42][C:26]([CH2:27][NH:28][C:29](=[O:41])[O:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=3)=[CH:25][CH:24]=2)=[O:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)Oc2ccc3ccccc3c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)Oc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-naphthyl {4-[({4-[(tert-butoxycarbonyl)amino]-1-phenyl-1H-pyrazol-3-yl}amino)carbonyl]benzyl}carbamate (approximately 5 mg) in ethyl acetate (1 mL) was added 4M HCl in dioxane (1 mL). The reaction was stirred at ambient temperature for 16 hours. Evaporation in vacuo gave the title compound as a white solid. 1H NMR (600 MHz, CD3OD) δ 8.44 (s, 1H), 8.07 (d, J=8.2 Hz, 2H), 7.87 (t, J=8.5 Hz, 2H), 7.82 (d, J=7.9 Hz, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.52 (m, 7H), 7.37 (t, J=7.3 Hz, 1H), 7.28 (dd, J=8.8, 2.1 Hz, 1H), 4.50 (s, 2H); ESIMS calcd 478.2 (M++H), found 478.1 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:13](Cl)(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([S:13]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1sccc1N
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1N1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(N2CCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.1 %

Procedure:
To a solution of 121(1.5 g; 5.5 mmol) in dichloromethane (14 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.86 g; 5.5 mmol) was added followed by pyridine (0.87 g; 11.0 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (20 mL) and extracted with water. The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to give the title product as a light red solid (86 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23]([NH:25][NH2:26])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[C:18]([O:22][C:23]([NH:25][NH:26][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Benzyl 4-oxo-1-piperidinecarboxylate (10.0 g, 42.9 mmol), tert-butyl-1-hydrazinecarboxylate (5.70 g, 42.9 mmol) and sodium triacetoxyborohydride (13.6 g, 64.1 mmol) were stirred together for 4 hours at room temperature in dichloromethane/acetic acid (40 ml, 10% solution). The solvents were evaporated under reduced pressure. The residue was basified with saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic solutions were dried (MgSO4), filtered and evaporated under reduced pressure to yield the title compound as a colourless gum, 14.2 g.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3N)[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2].C[Si]([Br:33])(C)C.C(ON=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(Br)Br.C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[Br:33])[O:7][C@@H:6]1[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: BrCBr
Product: CC(=O)O[C@H]1C[C@H](n2cnc3c(Br)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
To a solution of (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-({[tert-butyl-(dimethyl)silyl]oxy}methyl)tetrahydrofuran-3-yl acetate (2.00 g, 4.91 mmol) in CH2Br2 (98.2 mL) was added TMSBr (0.717 mL, 5.55 mmol) and t-butylnitrite (3.98 mL, 33.4 mmol). The reaction mixture was stirred at r.t. for 3 hours then slowly poured into 50 mL of a 1:1 mixture of saturated aq NaHCO3:CH2Cl2. The organic layer was washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 30% EtOAc/hexanes) to obtain the title compound as a yellow oil (1.26 g, 55%).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:17]=[CH:16][C:9]([CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O>[C:25]([NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:17][CH:16]=1)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)OCc1ccccc1
Yield: 99.5 %

Procedure:
Sodium hydroxide (10 g, 0.25 m) is dissolved in water (300 ml). To this solution 4-nitrophenylalanine (50.3 g, 0.22 m) is added and stirred until complete dissolution. To the resulting solution the sodium carbonate (28.8 g, 0.26 m) is added and stirred suspension is cooled in an ice bath to +8° C. Benzyl chloroformate (44.7 g, 0.26 m) is added dropwise with vigorous stirring, maintaining internal temperature in +6° to +9° C. range. The mixture is stirred at +6° C. for additional 1 hr, transferred to the separatory funnel and washed with ether (2×150 ml). Aqueous phase is placed in a large Erlenmeyer flask (2L) and is cautiously acidified with dil. aq. HCl to pH=2 and extracted with ethyl acetate (4×500 ml). The combined extracts are washed with water and dried with MgSO4. The solution is filtered and filtrate evaporated, residue is dissolved in ethyl acetate (150 ml) and diluted with hexane (500 ml). Crystalline material is filtered off and rinsed with cold solvent, air dried to give Cbz-4-nitrophenylalanine, 75 g (99.5% yield). 1H-NMR, DMSO-d6, (δ): 12.85 (bs, 1H), 8.12 (d, 2H, J=9 Hz), 7.52 (d, 2H, J=9 Hz), 7.30 (m, 5H), 4.95 (s, 2H), 4.28 (m, 1H), 3.32 (bs, 1H), 3.10 (m, 2H).13C-NMR (δ): 173.1, 156.3, 146.6, 137.3, 130.8, 128.5, 128.0, 127.8, 123.5, 65.6, 55.1, 36.6. MS (m/z): 367.1 [M+23].
Reaction SMILES: [C:1]([CH:3]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[CH2:4]1)#[N:2].[H-].[Na+].Br[CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>CN(C)C=O>[C:1]([CH:3]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:10][C:5]=2[CH2:4]1)#[N:2]
Reactant: N#CC1Cc2cc(O)ccc21
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc2c(c1)CC2C#N)OCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 16.5 g of 1-cyano-4-hydroxybenzocyclobutane in 205 ml of dimethylformamide is poured into a suspension of 67.8 mmol of sodium hydride in 160 ml of dimethylformamide. The reaction mixture is stirred for 30 minutes and then a solution of 10.2 ml of 1-bromo-2,2-diethoxyethane in 40 ml is added over the course of 15 minutes and the temperature is then maintained at 60° C. for 6 hours. The mixture is stirred for a further 12 hours, the dimethylformamide is removed by evaporation, and the residue is taken up in water, extracted with dichloromethane, dried and concentrated in vacuo. The residue is chromatographed over silica gel (CH2Cl2/AcOEt: 95/5), enabling the expected product to be isolated.
Reaction SMILES: [N:1]1(C2CCCCCCC2)[CH2:8]CCCCCN1.Cl[C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.[C-]#N.[Na+]>CS(C)=O.O>[CH:24]1([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:8]#[N:1])[N:23]=2)[CH2:26][CH2:25]1
Reactant: C1CCCC(N2CCCCCCN2)CCC1
Reactant: Clc1nccc(C2CC2)n1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1nccc(C2CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 803.7 %

Procedure:
To a solution of diazabicyclooctane (0.013 g, 0.12 mmol) in dimethylsulfoxide and water was added a solution of 2-chloro-4-cyclopropylpyrimidine (0.2 g, 1.2 mmol) in dimethylsulfoxide followed by sodium cyanide (0.066 g, 1.3 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was then poured into water and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified via flash chromatography (10% ethyl acetate in petroleum ether) to afford 4-cyclopropylpyrimidine-2-carbonitrile (0.14 g, 77%). MS (ES+APCI) (M+H) 146.1; LCMS retention time 3.054 min (Method J).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:15](N(CC)CC)C>O1CCOCC1>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccnc1Cl
Yield: 85.4 %

Procedure:
To a mixture of 2-chloronicotinic acid (Aldrich, 100.0 g, 0.63 mol) in 1,4-dioxane (500 mL) was added thionyl chloride (70 mL, 0.96 mol). The suspension was heated under reflux for 22 h with a gas trap to absorb hydrogen chloride gas. After evaporation of the solvent, the residue was dissolved in methanol (300 mL). To the solution was added dropwise triethylamine (TEA, 120 mL, 1.26 mol) at 0° C. over 2 h. The solvents were evaporated and the residue was suspended in ethyl acetate. The precipitate was removed by filtration. The filtrate was concentrated to afford the ester 18 (92.3 g, 86%) as an oil:
Reaction SMILES: [CH3:1][C:2]([CH3:5])=[C:3]=[O:4].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N:18]=[N:19][NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]#[N:32])#[N:7]>C(OCC)(=O)C.CCOCC>[C:3]([N:18]([C:9]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=1[C:6]#[N:7])[N:19]=[N:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]#[N:32])(=[O:4])[CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)=C=O
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)C(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 12 h

Procedure:
A solution of 3.5 g. (0.05 mol.) of dimethylketene in ethyl acetate is added dropwise under a nitrogen atmosphere to a cooled (0°) solution of 18.6 g. (0.05 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in ether. The reaction mixture is stirred for 12 hours then concentrated at reduced pressure. Crystallization of the residue from ether gives 3-isobutyryl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=O)[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:28]>O1CCOCC1>[Cl:28][C:7]1[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[N:6]=1
Reactant: CC(=O)Nc1nc2ccc(Cl)nc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a suspension of 2-acetamido-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (2.38 g, 10 mmol) and DIEA (5.2 mL, 30 mmol) in dioxane (120 mL) was added POCl3 (2.8 mL, 30 mmol). The mixture was heated to 80° C. for 2 hours. After removal of solvent, the residue was stirred with crashed ice for 10 minutes, then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness providing the pure title compound as a brown solid (2.01 g, yield 78%) which was characterised as follows: MS (m/z) 256.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([OH:25])=O)=O.Cl.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23](=[O:25])[C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc2[nH]cc(CCC(=O)Nc3ccccc3C(=O)O)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(CCc3nc4ccccc4c(=O)n3-c3ccccc3)c2c1
Yield: 39.9 %

Procedure:
To a solution of 3-(5-methoxyindol-3-yl)-N-(2-carboxyphenyl)propionamide (4.0 g, 11.8 mmol) in 50 ml of THF at room temperature was added 1,1-carbonyldiimidazole (1.92 g, 11.8 mmol). The reaction mixture was stirred for one hour after which aniline hydrochloride (3.06 g, 23.6 mmol) and 25 ml of dimethylformamide were added. The reaction mixture was stirred at reflux under a drying tube for two days, allowed to cool, and concentrated in vacuo to dryness. The residue was partitioned between lN hydrochloric acid and ethyl acetate. The organic layer was washed (water, lN sodium hydroxide, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. Crystallization of the product from ethyl acetate/trace methanol provided 1.86 g of 2-[2-(5-methoxyindol-3-yl)-ethyl]-3-phenyl-4-(3H)quinazolinone as a white powder: mp 220°-221° C.; EIMS: 395 (M+)
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:17]=O)[C:12]([CH:15]=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[NH2:24][CH2:25][C:26]#[N:27].C(N(CC)CC)C>CN(C=O)C>[O:16]=[C:15]1[C:12]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:19]=[CH:20][C:3]([C:2]([F:22])([F:21])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=2)[CH2:17][N:27]1[CH2:26][C:25]#[N:24]
Reactant: N#CCN
Reactant: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1Cc2cc(OCc3ccc(C(F)(F)F)cc3)ccc2C1=O
Temperature: 25 °C
Yield: 7 %

Procedure:
To a cooled (0° C.) solution of 4-(4-trifluoromethyl-benzyloxy)-benzene-1,2-dicarbaldehyde (250.0 mg, 0.81 mmol) in DMF (7 mL) was added aminoacetonitrile HCl (150.1 mg, 1.62 mmol) and triethylamine (164.1 mg, 1.62 mmol) and the resulting mixture was warmed up to RT over 1 h and then heated at 50° C. for 1 h. After cooling to RT, the mixture was evaporated and the residue partioned between ethyl acetate and hydrochloric acid (1 N). The organic layer was then dried over sodium sulfate, filtered and evaporated to leave a clear oil which was purified by chromatography (SiO2, DCM:MeOH 9:1) to afford the title product (19.6 mg, 7%) as a light brown solid. MS m/e 345.2 (M−H−).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].OC([N:11]1[C:20]2[C:15](=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH2:12]1)CO.[C:24](OCC)(=[O:26])C>O1CCCC1.O>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][C:12]([CH:24]=[O:26])=[N:11]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc2c1C=CCN2C(O)CO
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c([N+](=O)[O-])cccc2n1
Reaction time: 20 h

Procedure:
2.99 g (14.0 mmol) of sodium periodate is added to a solution that consists of 1.64 g (7.0 mmol) of 1-(1,2-dihydroxyethyl)-5-nitroquinoline in 42 ml of tetrahydrofuran and 7.0 ml of water. After 20 hours at room temperature, ethyl acetate is added, and the organic phase is washed with saturated sodium chloride solution. After the organic phase is dried on sodium sulfate, after the solvent is removed, and after purification on silica gel with hexane-ethyl acetate (0-100%), 1.40 g (99% of theory) of the product is obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:11]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([C:12]2[C:11]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:10]([CH2:9][N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[N:15]=[C:14]3[S:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=23)[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc(C)c(C)c2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
Sodium hydride (60% in oil, 0.171 g) was added to a solution of 1H-1,2,4-triazole (0.271 g) in N,N-dimethylformamide (DMF) (15 ml). The mixture was stirred for 15 minutes at room temperature, to which was added ethyl 6-chloromethyl-4-(3,4-dimethoxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.5 g). The mixture was stirred for 35 minutes at 80° C. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform-methanol (30:1, v/v), ethyl 4-(3,4-dimethoxyphenyl)-2,3-dimethyl-6-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate (1.0 g, 62%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.136°-137° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][C@@H:9]([CH3:11])[C@:8]([C:13]#[CH:14])(O)[C:7]([CH3:16])([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].O>CC1C=CC=CC=1C.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:4][C@H:5]1[CH2:6][C:7]([CH3:15])([CH3:16])[C:8]([C:13]#[CH:14])=[C:9]([CH3:11])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: C#C[C@]1(O)[C@H](C)C[C@@H](OC(C)=O)CC1(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: C#CC1=C(C)C[C@@H](OC(C)=O)CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
121.6 g of crude (1R,4S,5R)-4-ethynyl-4-hydroxy-3,3,5-trimethylcyclohexyl acetate (prepared according to Example 9) were dissolved in 1 l of o-xylene under argon in a sulphonation flask having a water separator. The mixture was treated with 7.9 g of copper(II)sulphate and boiled and stirred intensively for 2 hours under reflux and with the separation of water. The reaction mixture was subsequently cooled to room temperature and the insoluble copper sulphate was filtered off (rinsing with 400 ml of hexane). The filtrate was washed with 400 ml of water and with 400 ml of semi-saturated sodium bicarbonate solution The wash solutions were back-extracted twice with 300 ml of hexane each time. The organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated to a volume of about 200-300 ml in a rotary evaporator at 80 Torr and 40°-60° C. bath temperature. Distillation of the residual xylene solution in a high vacuum gave at about 83° C./0.19- 0.09 Torr 96.5 g of (R)-4-ethynyl-3,5,5-trimethyl-3-cyclohexen-1-yl acetate (purity 98.1%) as a colourless oil; boiling point 78-82° C./0.14 Torr. The chemical yield amounted to 93% based on (4R,6R)-4-hydroxy-2,2,6-trimethylcyclohexanone.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: CCCCN
Product: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1

Procedure:
The title compound, a colorless oil, is prepared from 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-one and butylamine according to the procedure given in Example 38.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[N:7]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30])[CH:23]=[CH:22]2>>[ClH:18].[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:35]3[CH2:34][CH2:33][N:32]([S:29]([C:24]4[CH:23]=[CH:22][C:21]5[C:26](=[CH:27][CH:28]=[C:19]([Cl:18])[CH:20]=5)[CH:25]=4)(=[O:31])=[O:30])[CH2:37][CH2:36]3)=[O:14])=[CH:15][CH:16]=2)[N:7]=1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)c[nH]1
Agent: Cl
Product: Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)c[nH]1

Procedure:
In a similar manner to Example 4 except for the use of 4-(2-aminoimidazol-4-yl)benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [C:1]([O:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23](C(OC(C)(C)C)=O)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][C:18]=1[F:38])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)CC#C.[C:44]([C:46]1[CH:50]=[CH:49][S:48][CH:47]=1)#[CH:45]>>[C:1]([O:8][C:9]1[CH:14]=[C:13]([C:45]#[C:44][C:46]2[CH:50]=[CH:49][S:48][CH:47]=2)[CH:12]=[CH:11][C:10]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:19][C:18]=1[F:38])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#Cc1ccsc1
Reactant: CC(C)(C)OC(=O)Oc1cc(Br)ccc1Oc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1F
Agent: C#CCCO
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C#Cc3ccsc3)cc2OC(=O)OC(C)(C)C)c(F)c1

Procedure:
According to the procedure of example 11(a) except substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by O,N,N-triBoc-2-(4-amino-2-fluorophenoxy)-5-bromophenol (0.62 mmol; 363 mg) and 3-butyn-1-ol by 3-ethynylthiophene (1.55 mmol; 153 μL), the title compound was obtained as a yellow solid (60%, 195 mg) after purification on silica gel (cyclohexane/ethyl acetate gradient).