Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12](OCC)OCC)=[CH:6][CH:5]=1.C([SiH](CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH2:37][CH2:38][N:39]1[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]1=[O:49])=[CH:31]2.FC(F)(F)C(O)=O>ClCCl.CO.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][C:31]2[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=3)[NH:33][C:32]=2[CH2:37][CH2:38][N:39]2[C:40](=[O:49])[C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:47]2=[O:48])=[CH:8][CH:9]=1
Reactant: CCOC(COc1ccc(C(=O)OC)cc1)OCC
Reactant: O=C1c2ccccc2C(=O)N1CCc1cc2cc(Cl)ccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)c1ccc(OCCc2c(CCN3C(=O)c4ccccc4C3=O)[nH]c3ccc(Cl)cc23)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution 4-(2,2-diethoxy-ethoxy)-benzoic acid methyl ester (495 g, 1.84 mol), triethylsilane ((536 g, 4.62 mol) and 2-[2-(5-chloro-1 H-indol-2-yl)-ethyl]-isoindole-1,3-dione (500 g, 1.54 mol) in dichloromethane (3.5 L) was added trifloroacetic acid (878 g, 7.7 mol) during a period of 1 hour. Then, the reaction mixture was cooled to 0-10° C. A mixture of triethyl amine (787 g) and methanol (4 L) was added during a period of 45 min. The reaction mixture was stirred for 1 h at 0-10° C. and filtered. The crude product was washed with methanol (2×1000 mL) and dried to give a white solid (483 g) in 62% yields and 88.1% area purity. 1H NMR (CDCl3): δ6.9-8.6 (m, Ph, CHPh2), 4.13 (t, 2H, J=6.6 Hz), 4.04 (t, 2H, J=7.2 Hz), 4.13 (t, 2H, J=6.6 Hz), 3.87 (S, 3H), 3.23 (t, 2H, J=7.2 Hz), 3.16 (t, 2H, J=6.6 Hz).
Reaction SMILES: C(O[CH:4]=[C:5]([C:15]#[N:16])[C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])C.[C:17]1([NH:23][N:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC>[CH:25](=[N:24][N:23]([CH:4]=[C:5]([C:15]#[N:16])[C:6]([O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C(=NNc1ccccc1)c1ccccc1
Reactant: CCOC=C(C#N)C(=O)OCC[Si](C)(C)C
Solvent: CCCCCC
Product: C[Si](C)(C)CCOC(=O)C(C#N)=CN(N=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
2-(Trimethylsilyl)ethyl 2-ethoxymethylenecyanoacetate (10.0 g, 41.4 mmol) and benzaldehyde-phenylhydrazone (8.13 g, 41.4 mmol) were combined in 50 mL xylenes under N2 and heated at reflux for 5 h, cooled to room temperature, then treated with hexane (50 mL) and allowed to stir overnight. The precipitate was filtered off, washed with hexane and dried to afford 5.46 g of crude product. Purification by chromatography afforded 2.69 g (16%) of 2-(trimethylsilyl)ethyl 3-(N′-benzylidene-N-phenylhydrazino)-2-cyanoacrylate, as a white solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])[CH:10]=[C:11]([F:13])[CH:12]=1.CN(CCN(C)C)C.CN(C)[CH:31]=[O:32]>C1COCC1>[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:20])[O:16][CH:17]([CH3:18])[CH3:19])[CH:10]=[C:11]([F:13])[C:12]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: CC(C)OC(=O)Nc1cc(F)cc(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1cc(F)c(C=O)c(F)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M in hexane, 112 mL, 0.279 mol) was added dropwise at −78° C. to a solution of isopropyl 3,5-difluoro-phenylcarbamate (20 g, 0.093 mol) and N,N,N,N-tetramethylethylenediamine (32 mL, 0.214 mol) in 93 mL of THF, and stirred for 30 min. Dimethylformamide (10.8 mL, 0.140 mol) was then added dropwise at −78° C., stirred for 1 h, and allowed to warm to −20° C. The reaction was then quenched with saturated aqueous ammonium chloride (100 mL). The reaction mixture was extracted with ethyl acetate, the extracts washed with brine, dried (MgSO4), and concentrated. The crude product was triturated with hexane to provide the title compound. The combined hexane washings were concentrated and purified by flash column chromatography (30% ethyl acetate/hexane) to provide additional product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C@H:7]([C:19]([OH:21])=[O:20])[C:6]=2[CH:22]=1.Cl.[CH3:24]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@H:9]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:8][C@H:7]([C:19]([O:21][CH3:24])=[O:20])[C:6]=2[CH:22]=1
Reactant: O=C(O)[C@H]1C[C@H](CCc2ccccc2)Oc2ccc(F)cc21
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1C[C@H](CCc2ccccc2)Oc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Cis and trans 2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-carboxylic acid (2.9 gm) was dissolved in methanol, cooled to 0° C., and the mixture saturated with gaseous HCl. After 24 hours, the mixture was concentrated in vacuo, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (2:1 hexane/diethyl ether, SiO2) to yield the title compound (1.9 gm, Rf=0.3,2:1 hexane/diethyl ether, SiO2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:39]=[CH:38][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:36][CH3:37])=[C:21]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[NH:1]([C:9]1[CH:39]=[CH:38][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:36][CH3:37])=[C:21]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(Br)cc3)c2cc1C(=O)NCCCN1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(Nc4ccccc4)cc3)c2cc1C(=O)NCCCN1CCOCC1
Temperature: 100 °C

Procedure:
Aniline (0.03 ml) was added to a stirred mixture of 4-(4-bromophenoxy)-7-methoxy-N-(3-morpholinopropyl)quinoline-6-carboxamide (0.132 g), caesium carbonate (0.23 g), palladium acetate (0.01 g), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.055 g) and toluene (5 ml) and the reaction mixture was stirred and heated to stirred and heated to 100° C. for 16 hours. The mixture was evaporated and the resultant residue was partitioned between ethyl acetate and water. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulphate. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.103 g); NMR Spectrum: (CDCl3) 1.86 (m, 2H), 2.49 (m, 6H), 3.6 (q, 2H), 3.7 (m, 4H), 4.1 (s, 3H), 5.77 (s, 1H), 6.5 (d, 1H), 6.96 (t, 1H), 7.04-7.17 (m, 6H), 7.3 (m, 2H), 7.5 (s, 1H), 8.02 (m, 1H), 8.63 (d, 1H), 9.19 (s, 1H); Mass Spectrum: M+H+ 513.
Reaction SMILES: Br[CH2:2]/[C:3](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)\[CH2:5]Br.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.O>C(Cl)Cl>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[CH2:5][C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:2]2)=[CH:22][CH:21]=1
Reactant: BrC/C(=C(\CBr)c1ccccc1)c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(N2CC(c3ccccc3)=C(c3ccccc3)C2)cc1
Reaction time: 4 h

Procedure:
After dissolving compound 20 (300 mg, 0.819 mmol) and 4-chloroaniline (105 mg, 0.819 mmol) in DCM (10 ml), TEA (457 l, 3.28 mmol) was added thereto and the reflux was conducted for 4 hours. After the termination of the reaction, the temperature was reduced to room temperature and water was added thereto. The organic layer was washed with water and water was removed by using anhydrous Na2SO4. After the distillation under the reduced pressure was carried out for the removal of the solvent, column chromatography was conducted to obtain compound 21.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]([CH:22]1[CH:31]([OH:32])[C:30]2[C:25](=[CH:26][C:27]([C:33](=[N:35]O)[NH2:34])=[CH:28][CH:29]=2)[O:24][CH2:23]1)=[N+:20]=[N-:21].CCN(C(C)C)C(C)C>C(#N)C>[N:19]([CH:22]1[CH:31]([OH:32])[C:30]2[C:25](=[CH:26][C:27]([C:33]3[N:35]=[C:16]([C:10]4[O:9][N:8]=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:11]=4[C:12]([F:15])([F:14])[F:13])[O:17][N:34]=3)=[CH:28][CH:29]=2)[O:24][CH2:23]1)=[N+:20]=[N-:21]
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: [N-]=[N+]=NC1COc2cc(C(N)=NO)ccc2C1O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2C1O
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride Int-1-G (273 mg, 1.05 mmol) in ACN (6.7 mL) was added racemic (3R*,4S*,E/Z)-3-azido-N′,4-dihydroxychroman-7-carboximidamide (250 mg, 1.0 mmol) and Hunig's Base (210 μL, 1.2 mmol). The resulting solution was stirred overnight. Next, the solvent was evaporated. The resulting residue was purified by column chromatography (ISCO Combiflash Companion, 12 g silica gel, 10% ethyl acetate-hexane for 5 min then ramp to 50% ethyl acetate-hexane over 7 min then 50% ethyl acetate-hexane for 3 more min, product came out 8-10 min) to give racemic (3R*,4S*)-3-azido-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-4-ol (280 mg, 0.59 mmol, 59.3% yield): LCMS=470.98 [M+H]+, 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (1H, dd, J=8.03, 1.65 Hz), 7.66-7.72 (3H, m), 7.52-7.62 (4H, m), 4.96-5.02 (1H, m), 4.43-4.51 (1H, m), 4.32-4.38 (1H, m), 4.08-4.17 (1H, m).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5]([NH2:17])=[N:4][CH:3]=1.C[C@H](N)C1C=CC=CC=1.NC1C(Br)=NC(Br)=CN=1.CCC[CH2:39][OH:40]>>[C:11]1([C@@H:9]([N:8]2[C:6]3=[N:7][CH:2]=[CH:3][N:4]=[C:5]3[NH:17][C:39]2=[O:40])[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([NH2:17])=[N:4][CH:3]=1
Reactant: CCCCO
Agent: C[C@H](N)c1ccccc1
Agent: C[C@H](Nc1nc(Br)cnc1N)c1ccccc1
Agent: Nc1ncc(Br)nc1Br
Product: C[C@@H](c1ccccc1)n1c(=O)[nH]c2nccnc21

Procedure:
(S)-6-Bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine. The title compound was prepared using (S)-α-methylbenzylamine (2.28 mL, 17.93 mmol), 2-amino-3,5-dibromo-pyrazine (3.00 g, 11.96 mmol), and n-BuOH (30 mL) as described in General Procedure A. The crude molecule was purified via silica gel chromatography (20-30% EtOAc in hexanes). Clean fractions were combined and condensed, and subsequently triturated from methanol with water while sonicating to afford 1.52 g (5.18 mmol, 43%) of (S)-6-bromo-N2-(1-phenylethyl)pyrazine-2,3-diamine. MS (ESI) m/z 294.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH2:8][CH2:7]2.CCO.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(c(Cl)c2CC1)NC(=O)CC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(c(Cl)c2CC1)NCCC3
Reaction time: 3 h
Yield: 118 %

Procedure:
To a solution of 1.772 g of t-butyl 11-chloro-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 10 ml of THF was added 10.1 ml of a 1 M solution of a borane-THF complex in THF under ice-cooling, followed by elevating to room temperature and stirring for 3 hours. To the reaction mixture was added dropwise 10 ml of EtOH, and subsequently 10 ml of a 1 M aqueous sodium hydroxide solution was added dropwise thereto, followed by stirring. The mixed solution was diluted with water, followed by extraction with EtOAc. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 2.007 g of t-butyl 11-chloro-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless viscous substance.
Reaction SMILES: Cl.C(N[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][N:13]=[C:14]([CH3:27])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:10][CH:9]=1)=[O:7])(=O)C.S(=O)(=O)(O)[OH:29]>O>[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][N:13]=[C:14]([CH3:27])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:10][CH:9]=1)([OH:7])=[O:29]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)NC(=O)c1ccc2c(c1)N(Cc1ccc(Cl)cc1Cl)C(C)=NC2
Agent: Cl
Solvent: O
Product: CC1=NCc2ccc(C(=O)O)cc2N1Cc1ccc(Cl)cc1Cl
Temperature: 70 °C
Yield: 38.5 %

Procedure:
To 7-(acetylcarbamoyl)-1-(2,4-dichlorobenzyl)-1,4-dihydro-2-methylquinazoline hydrochloride (0.46 g) were added water (1.2 g) and concentrated sulfuric acid (1.0 g) and the mixture was heated at 70° C. for 90 min. After cooling, ice was added and the precipitated solid was collected by filtration. The precipitate was washed with water and 2-propanol and dried to give the objective compound (0.145 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[C:26]([CH2:37][O:38][CH3:39])[CH:25]=3)[O:21][N:20]=2)[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].Cl>O1CCOCC1>[CH3:39][O:38][CH2:37][C:26]1[CH:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[CH:15][C:3]([CH2:4][N:5]([CH3:14])[CH2:6][C:7]([OH:9])=[O:8])=[C:2]([Cl:1])[CH:18]=3)[N:23]=2)[CH:29]=[CH:28][C:27]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36]
Reactant: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)OC(C)(C)C)c(Cl)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3ccc(CN(C)CC(=O)O)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To tert-butyl 2-((2-chloro-4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)(methyl)amino)acetate (0.192 g, 0.35 mmol) was added a 4N solution of HCl in dioxane (2 mL) and the reaction mixture stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by SCX-2 chromatography eluting with methanol followed by DCM and ammoniacal MeOH (7M) to afford the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.32 (1H, d, J=1.8 Hz), 8.17 (1H, dd, J=7.9, 1.9 Hz), 8.08-8.01 (2H, m), 7.84 (1H, d, J=7.9 Hz), 7.42 (1H, d, J=7.9 Hz), 7.38-7.33 (2H, m), 7.33-7.26 (1H, m), 7.15 (1H, d, J=7.4 Hz), 4.26-4.13 (2H, m), 3.84 (2H, s), 3.25 (3H, s), 2.94 (2H, s), 2.30 (3H, s), 2.04 (3H, s). LC/MS (Method A): 492 (M+H)+. HPLC (Method F) Rt 3.29 min (Purity: 98.0%).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:27])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:23]([C:18]1[CH:19]=[C:20]([NH:22][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:21]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:17]=1[OH:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(NC(=O)C=Cc2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)cinnamamide was prepared by adding a solution of 18.2 grams of cinnamoyl chloride in 50 milliliters of benzene to a solution of 2,6-di tert.butyl-4 -aminophenol prepared as described in Example 2 to which had been added 6 grams of sodium carbonate. The addition was accomplished in 30 minutes at 24° C. to 37° C. The mixture was stirred for 1 hour. The solid product was filtered, washed thoroughly with 2% hydrochloric acid, and dried. The yield was 17 grams of product which melted at 211° C. to 214° C.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([C:11]#[N:12])=[CH:6][CH:7]=[CH:8]2)=[N:3]1>CO.N.[Ni]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:11][NH2:12])=[CH:6][CH:7]=[CH:8]2)=[N:3]1
Reactant: Cn1cc2cccc(C#N)c2n1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cn1cc2cccc(CN)c2n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-methyl-2H-indazole-7-carbonitrile (1 equiv.) in methanol and aq. ammonia solution (9:1), catalytic amount of Raney Nickel was added. Reaction mass was stirred at room temperature under hydrogen pressure (balloon pressure) for 2-5 h. On completion of reaction, it was filtered through celite bed and filtrate was concentrated under reduce pressure to afford the title compound (quant. yield).
Reaction SMILES: F[C:2]1(F)[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([I:16])[CH:11]=2)=[O:9])[CH2:4]C1.IC1C=C(C=CC=1)C(O)=O.C1C2C(=CC=CC=2)CCN1>>[I:16][C:12]1[CH:11]=[C:10]([C:8]([N:5]2[CH2:4][CH2:2][CH2:7][CH2:6]2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1cccc(I)c1)N1CCC(F)(F)CC1
Agent: O=C(O)c1cccc(I)c1
Agent: c1ccc2c(c1)CCNC2
Product: O=C(c1cccc(I)c1)N1CCCC1

Procedure:
According to Step 77-1 in the synthetic method for compound 77-1, 3-iodobenzoic acid 1 and pyrrolidine 2 were used to obtain compound 87-1.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([CH3:21])[N:8]=2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([CH3:21])[N:8]=[C:7]([C:5]3[S:6][C:2]([N:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:23]4[NH2:22])=[CH:3][CH:4]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Br)s2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(N3C=CC=CC3N)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example E.87) (0.25 g, 0.626 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.152 g, 0.689 mmol) according to the general procedure VI. Obtained as a light brown solid (0.055 g, 21%). MS (ISP) 412.1 [(M+H)+], 414.2 [(M+2+H)+] and 416.2 [(M+4+H)+]; mp 180° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8](Cl)=[O:9].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][C:21]=1[Cl:25])=[O:9]
Reactant: Clc1cccc(Cl)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1Cl)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 80 °C

Procedure:
6 g of aluminium chloride are added to 5 g of 2-chloro-5-nitrobenzoyl chloride in 60 ml of dichloromethane, and 30 ml of 1,3-dichlorobenzene are then added dropwise. The reaction medium is heated for 2 hours at 80° C. and then cooled, and poured onto crushed ice. After extracting with dichloromethane, washing with water and drying over sodium sulphate, the organic phase is evaporated to dryness under vacuum and the crystalline residue is recrystallized in cyclohexane (3.6 g).
Reaction SMILES: B.CSC.O=[C:6]1[NH:24][CH2:23][CH2:22][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:8][CH2:7]1>C1COCC1>[CH2:10]1[C:9]2([CH2:22][CH2:23][NH:24][CH2:6][CH2:7][O:8]2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC(=O)CO2)CC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCNCCO2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Borane-methyl sulfide complex (2M in THF, 2.88 mL) was added to a solution of tert-butyl 9-oxo-7-oxa-3,10-diazaspiro[5.6]dodecane-3-carboxylate (example 89, step d) (0.41 g) in dry THF (40 mL) and the reaction mixture then heated at 70° C. for 30 minutes under nitrogen. The mixture was cooled to room temperature and quenched with methanol. The solvents were removed under reduced pressure and the residue dissolved in methanol (100 mL). N1,N2-dimethylethane-1,2-diamine (1.0 g) was added and the mixture heated at reflux under nitrogen for 16 h. Further N1,N2-dimethylethane-1,2-diamine (1.0 g) was added and refluxing continued for 16 h. The solvents were evaporated under reduced pressure and the residue azeotroped with toluene. The crude product was purified by flash silica chromatography using 6% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.176 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@@H](CO)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@H](COS(C)(=O)=O)O1

Procedure:
The (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (Aldrich, 0.38 mL, 3.1 mmol), triethylamine (0.85 mL, 6.1 mmol), and methanesulfonyl chloride (0.31 mL, 4.1 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]([CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14].[H][H]>C(OCC)(=O)C.[Ni]>[NH2:9][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:12][C:13]([CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:14]
Reactant: [H][H]
Reactant: O=C(Nc1c(Cl)cc(O)cc1[N+](=O)[O-])C1CCOCC1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(O)cc(Cl)c1NC(=O)C1CCOCC1

Procedure:
0.60 g (2.00 mmol) N-(2-chloro-4-hydroxy-6-nitrophenyl)tetrahydro-2H-pyran-4-carboxamide were placed in 10 mL ethyl acetate and hydrogenated under a hydrogen atmosphere and with the addition of 0.20 g Raney nickel at RT and a hydrogen pressure of 3 bar until all the hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down i.vac.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:17][CH:16]=1
Reactant: CC(=O)C(Cl)=NNc1ccccc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C(=NNc1ccccc1)Sc1ccc(Cl)cc1
Yield: 23.5 %

Procedure:
The reaction of 951 mg (4.85 mmol) of 1-chloro-1-[(phenyl) hydrazono]-2-propanone with 864 mg of 4-chlorothiophenol and 840 ul of triethylamine in 15 ml of ethanol as Example 11 yielded 347 mg of 1-[(4-chlorophenyl)thio]-1-[(phenyl)hydrazono]-2-propanone, mp 111°-113° C.