Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([O:27][CH3:28])([CH3:26])[CH3:25])=[O:20].FC(F)(F)S(O[C:35]1[C:46]([CH3:47])=[N:45][C:38]2[N:39]=[C:40]([NH:43][CH3:44])[N:41]=[CH:42][C:37]=2[CH:36]=1)(=O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:35]2[C:46]([CH3:47])=[N:45][C:38]3[N:39]=[C:40]([NH:43][CH3:44])[N:41]=[CH:42][C:37]=3[CH:36]=2)=[CH:4][C:3]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([O:27][CH3:28])([CH3:25])[CH3:26])=[O:20]
Reactant: COC(C)(C)CCNC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1F
Reactant: CNc1ncc2cc(OS(=O)(=O)C(F)(F)F)c(C)nc2n1
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: O
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)OC)c(F)cc3C)c(C)nc2n1
Temperature: 55 °C
Yield: 21.1 %

Procedure:
Combine 1-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(3-methoxy-3-methylbutyl)urea (0.17 g, 0.431 mmol), 7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (0.139 g, 0.431 mmol) and NaHCO3 (0.109 g, 1.293 mmol) in dioxane (6 mL) and H2O (1.5 mL). Sparge the mixture with argon. Treat with tetrakis(triphenylphosphine)palladium (0.025 g, 0.022 mmol), sparge again with argon and heat at 55° C. overnight. Add an additional portion of tetrakis(triphenylphosphine)palladium (25 mg, 0.022 mmol) and heat at 65° C. overnight. Cool the mixture to RT, remove solids by filtration, and wash solids with dioxane. Combine filtrates, dilute with EtOAc, wash with saturated NaHCO3 and brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex). Dissolve in DCM, wash with saturated NaHCO3 and brine, dry over Na2SO4, concentrate to dryness. Treat with 1:1 MeCN/H2O, freeze in −78° C. bath and lyophilize to obtain the title compound (40 mg, 21% yield) as a pale yellow solid. MS (ESI) m/z: 441.2 (M+1).
Reaction SMILES: [NH:1]1[C:10](=S)[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[NH:4][C:2]1=[S:3].C([NH2:14])C.C>O>[NH:1]1[C:10]([NH2:14])=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[N:4][C:2]1=[S:3]
Reactant: S=c1[nH]c(=S)c2[nH]cnc2[nH]1
Reactant: CCN
Solvent: O
Product: Nc1[nH]c(=S)nc2nc[nH]c12
Yield: 97.4 %

Procedure:
6.67 g (16 mmoles) of dithioxanthine and 52 ml of 70% ethylamine in water were heated to 150° C. in a pressure reactor (250 psi) for 12 hours under nitrogen. The solution was treated with charcoal (5%), filtered, and evaporated in vacuo to dryness. The residue was suspended in water, acidified with 1N HCl to pH 4 and neutralized to pH 8 with sodium bicarbonate. The solid was collected, washed and dried to give 6.66 g (97.4%) of crude thioisoguanine.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[Li+].[OH-].Cl>O1CCCC1.CO>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][C:11]([NH:10][C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=2)=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cscc1NC(=O)CCCCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCc1ccccc1)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 4-(5-phenyl-pentanoylamino)-thiophene-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) in tetrahydrofuran/methanol 2/1 (1.5 ml) was added a 1 N aqueous LiOH solution (0.95 ml, 0.95 mmol). The reaction mixture was stirred at room temperature for 2 h, acidified with 1 N HCl and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by thin layer chromatography (SiO2, dichloromethane) to give the title compound as colorless oil (20 mg, 0.07 mmol, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:36]=[CH:35][C:22]([O:23][C:24]4[CH:25]=[CH:26][N:27]=[C:28]5[C:33]=4[NH:32][C:31](=[O:34])[CH:30]=[CH:29]5)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:40]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]([CH3:40])[C:19]3[CH:20]=[CH:21][C:22]([O:23][C:24]4[CH:25]=[CH:26][N:27]=[C:28]5[C:33]=4[NH:32][C:31](=[O:34])[CH:30]=[CH:29]5)=[CH:35][CH:36]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=c1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc(Oc2ccnc3ccc(=O)[nH]c23)cc1)c1nnc(-c2ccc(Cl)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 20 mL sealed tube, was dissolved 8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-2(1H)-one (0.25 g, 0.508 mmol) in THF (2.2 mL), and the mixture was cooled to 0° C. Sodium Hydride, 60% in mineral oil (0.045 g, 1.12 mmol), was added and the mixture was stirred at 0° C. for 1 hour. Iodomethane (0.070 mL, 1. 12 mmol), was added and the mixture was warmed to 60° C., and stirred for 3 hours. A mixture of products was revealed by LC/MS. The mixture was cooled to RT, quenched with water, extracted into ethyl acetate, washed 1× water, 1× NaCl, dried with Na2SO4, filtered through fritted funnel, and filtrate was concentrated. The crude concentrate was purified by reverse phase chromatography. The product containing fractions were extracted into DCM, washed 1× sodium carbonate, 1×H2O, dried with Na2SO4, filtered through fritted funnel, and the filtrate was concentrated down to a light yellow solid containing two methylated products. The solids were suspended in methanol, filtered, rinsed with methanol, and air dried to yield 8-(4-((4-(4-chlorophenyl)phthalazin-1-yl)(methyl)amino)phenoxy)-1,5-naphthyridin-2(1H)-one. MS: [M+H]=506.0; Calc'd 505.9 for C29H20ClN5O2.
Reaction SMILES: C[Al](C)C.[NH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([O:14][C:15]([C:17]1[C:21]([NH2:22])=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[N:18]=1)=O)C>C(Cl)(Cl)Cl>[N:6]1([NH:5][C:15]([C:17]2[C:21]([NH2:22])=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[N:18]=2)=[O:14])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Reactant: NN1CCOCC1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Product: Nc1c(C(=O)NN2CCOCC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (2M solution in toluene, 625 microliters, 1.25 mmol) is added to a solution of 4-aminomorpholine (121 microliters, 1.25 mmol) in CHCl3 (3 ml) at room temperature. The reaction mixture was stirred for 1 h, then 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (I-2A-1a, 188 mg, 0.5 mmol) was added in one portion. The reaction mixture was stirred at 45° C. for 4 h, cooled to room temperature, and quenched with 1 M HCl (1 ml) (CAREFUL: gas evolution). The pH of the solution was adjusted to ˜13 using 25% KOH, at which point all solids went into solution. The aqueous solution was extracted with EtOAc (2×) and the combined organic solution was washed with saturated aqueous brine, dried, and concentrated under vacuum to give the product I-10A-1a as an amorphous solid (208 mg): MS 432.0 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 7.44-7.32 (m, 4H), 7.28-7.23 (m, 2H), 7.13-7.09 (m, 2H), 3.86 (m, 4H), 2.95 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[S:7]1[CH2:10][CH:9]([OH:11])[CH2:8]1.CN(C)C1C=CC=CC=1.S(=O)(=O)(O)O>>[C:1]([O:11][CH:9]1[CH2:10][S:7][CH2:8]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OC1CSC1
Reactant: C=C(C)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: CN(C)c1ccccc1
Product: C=C(C)C(=O)OC1CSC1
Temperature: 0 °C
Reaction time: 192 h
Yield: 26.9 %

Procedure:
22.99 g of methacryloyl chloride (0.22 mole) are slowly poured (20 mins), with stirring, into a solution of 18 g of 3-thietanol (0.2 mole) in dimethylaniline (80 g, i.e. 0.66 mole). Stirring is then continued at ambient temperature for 8 days. After this time, the reaction mixture is poured on to the following mixture: 270 g of ice-27 cm3 (47.5 g) of concentrated sulphuric acid. The solution is stirred for 2 hours, then theorganic phase is extracted with ether. It is then washed with demineralisedwater until neutral and dried over sodium sulphate. The ether is eliminatedand then the remaining product is distilled in the presence of hydroquinone. The distillation temperature is 44° C. under a pressure of 0.1 mm of Hg. 8.5 g of 3-thietanyl methacrylate are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:6][CH:5]=[CH:4][C:3]3[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=3[CH3:1])[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Cc1ccccc1C=CCCl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C=CCN1CCc2nc(N)sc2CC1
Yield: 52 %

Procedure:
Prepared from 2-methyl-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 52% of theory, Melting point: 112°-115° C. (ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][C:21]1[O:25][C:24]([CH3:26])=[N:23][CH:22]=1>CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:20][C:21]2[O:25][C:24]([CH3:26])=[N:23][CH:22]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: Cc1ncc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NCc2cnc(C)o2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
To a solution of 33.63 parts of 1-amino-4-methoxy-2-nitrobenzene in 282 parts of N,N-dimethylformamide there were added 21.2 parts of sodium carbonate and a solution of 35.2 parts of 5-bromomethyl-2-methyloxazole in 94 parts of N,N-dimethylformamide. The whole was stirred for 20 hours at 70° C. and was then evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2C2 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from petroleum ether. The product was filtered off and dried, yielding 30 parts (57.0%) of N-(4-methoxy-2-nitrophenyl)-2-methyl-5-oxazolemethanamine (interm. 14).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][C:13]=1[O:26][CH3:27].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=1[O:26][CH3:27]
Reactant: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1OC
Yield: 81.5 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methoxylphenyl-acetate (2.01 g, 5.20 mmol) in CH2Cl2 (15 ml) was added trifluoroacetic acid (10 ml), and the resulting mixture was heated under reflux for 30 min. The mixture was concentrated in vacuo. Water was added to the residue to give precipitate, which was collected by filtration. The crude solid was recrystallized from EtOH/hexane to give 4-[N′-(2-methoxyphenyl)ureido]-3-methoxy phenylacetic acid as white powder (1.40 g, 82%). mp 182–185° C.; 1H-NMR (CD3OD) δ 3.55 (s, 2 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 6.80–6.99 (m, 5 H), 7.94 (d, J=8.4 Hz, 1 H), 8.00 (d, J=7.2 Hz, 1 H); MS (ESI) m/z 330 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[CH2:23][CH2:22][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15](OC(C)(C)C)=[O:16])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.FC(F)(F)C(O)=O.[F:32][C:33]1[CH:41]=[CH:40][C:36](C(Cl)=O)=[CH:35][CH:34]=1>>[CH3:1][N:2]([CH3:24])[CH:3]1[CH2:23][CH2:22][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:16])[C:36]4[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=4)=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: CN(C)C1CCc2oc3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
A mixture of 0.090 gm (0.273 mMol) of (+)-N,N-dimethyl-8-(tert-butoxycarbonyl)amino-1,2,3,4-tetrahydro-2-dibenzofuranamine and 1 mL of trifluoro-acetic acid was stirred at room temperature for 20 minutes. The excess trifluoroacetic acid was then removed under reduced pressure. The residue was dissolved in 5 mL of tetrahydrofuran and to this solution were added 1.5 mL of triethylamine followed by 0.05 mL (0.42 mMol) of 4-fluorobenzoyl chloride. After stirring for 1 hour the volatiles were removed under reduced pressure. The residue was taken up in 5 mL of dichloromethane and stirred with dilute aqueous sodium carbonate. After stirring for 16 hours the dichloromethane layer was separated and the aqueous layer extracted with fresh dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 5% methanol (containing 5% ammonium hydroxide) in chloroform. Fractions containing product were combined and concentrated under reduced pressure. The resulting residue was crystallized from toluene/hexane to provide 0.058 gm (60%) of the title compound as a crystalline solid in two crops.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:9][CH:6]([CH:7]=[CH:8]1)[CH2:5][CH:4]2[CH2:10][OH:11].[F:12][C:13]([F:22])([F:21])[C:14]1([C:17]([F:20])([F:19])[F:18])[O:16][CH2:15]1>CN(C=O)C>[CH:3]12[CH2:9][CH:6]([CH:7]=[CH:8]1)[CH2:5][CH:4]2[CH2:10][O:11][CH2:15][C:14]([C:13]([F:12])([F:21])[F:22])([OH:16])[C:17]([F:20])([F:19])[F:18]
Reactant: FC(F)(F)C1(C(F)(F)F)CO1
Reactant: OCC1CC2C=CC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(COCC1CC2C=CC1C2)(C(F)(F)F)C(F)(F)F
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A dry round bottom flask with mechanical stirrer and condenser was charged under nitrogen with 28.8 g (1.2 mol) of 95% sodium hydride and 400 ml of anhydrous DMF (N,N′-dimethylformamide). 5-Norbornene-2-methanol (108.6 g, 0.875 mol) was added dropwise at room temperature over 0.5 hr. The resulting mixture was stirred for 3 hr. 1,1-Bis(trifluoromethyl)ethylene oxide (1, Hexafluoroisobutylene epoxide) (173.2 g, 0.96 mol) from Example 1 was added dropwise over 2 hr. The resulting mixture was stirred for 72 hr at room temperature. DMF was evaporated on a rotary evaporator at 45° C. and 1 mm. The residue was diluted with 300 ml of ice water containing 30 ml of glacial acetic acid. A lower layer was separated and the aqueous layer was extracted with 2×25 ml of methylene chloride. The combined organic layers were washed with 3×100 ml of water, dried over anhydrous magnesium chloride, filtered and distilled under vacuum in a Kugelrohr apparatus at 65-87° C. and 0.1 mm. An NMR spectrum revealed that the product was contaminated with small amounts of DMF so it was dissolved in 100 ml of hexane, washed with 4×200 ml water, dried over anhydrous magnesium sulfate, filtered and distilled in a Kugelrohr apparatus at 70-80° C. and 0.1 mm giving 233.9 g (88%) of the title product (3-[(bicyclo[2.2.1]hept-5-en-2-yl)methoxy]-1,1,1-trifluoro-2-(trifluoromethyl)-2-propanol, comonomer 2). In another preparation, the product was distilled through a 12″ Vigreux column indicating a bp of 52-53° C. at 0.1 mm. 1H NMR (δ, CD2Cl2) 0.5 to 4.3 (complex multiplets, 12 H), 5.90, 6.19 and 6.26 (m, 2H). 19F NMR (δ, CD2Cl2) −77.4 (s).
Reaction SMILES: Cl/[C:2](/[CH2:16][CH3:17])=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[CH3:42][C:43]([OH:47])(C)[C:44]#C>[Cu]I.[Pd](Cl)Cl.O1CCCC1>[OH:47][C:43]([CH3:44])([CH3:42])[C:17]#[C:16]/[CH:2]=[CH:3]/[CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:6][CH3:7]
Reactant: CC/C(Cl)=C\CN(CC)Cc1cccc(O)c1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCN(C/C=C/C#CC(C)(C)O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
To 7.5 ml tetrahydrofuran were added 1.13 g (5 mmol) of (E)-N-(3-chloro-2-pentenyl)-N-ethyl-3hydroxybenzylamine, 4.76 mg (0.25 mmol) of copper (I) iodide, 18.0 mg (0.1 mmol) of palladium chloride and 52.5 mg (0.2 mmol) of triphenyiphosphine, and further, 0.99 ml (10 mmol) of n-butylamine and 0.58 ml (6 mmol) of 3-methyl-1-butyne-3-ol under ice cooling. The mixture stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate =3/2 ). The desired fractions were put together and concentrated under reduced pressure to obtain 1.07 g (yield: 78%) of the above identified compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH:16][CH3:17])[CH:10]=2)=[C:4]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:3]=1.[N:24]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:15]=[CH:14][C:12]3[N:13]=[N:24][N:16]([CH3:17])[C:11]=3[CH:10]=2)=[C:4]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH:3]=1
Reactant: CNc1cc(Sc2ccc(Cl)cc2Cn2cncn2)ccc1N
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cn1nnc2ccc(Sc3ccc(Cl)cc3Cn3cncn3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
The aniline derivative was dissolved in 10% H2SO4 (2 ml) under ice cooling, followed by addition of an aqueous solution (0.5 ml) of sodium nitrite (50 mg), and the temperature of the resulting solution was raised up to room temperature for subsequent stirring for 20 hours. The solution was neutralized with an aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (methylene chloride:methanol=99:1 to 98:2), to give the title compound (55 mg; 41%). The purity of the compound was 100 % by HPLC.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([OH:15])[CH2:12][CH:13]=[CH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1CC[CH2:17]1>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3([OH:15])[CH2:17][CH:14]=[CH:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: C=CCC(O)C1CCC2(CC1)OCCO2
Solvent: ClCCl
Product: OC1(C2CCC3(CC2)OCCO3)CC=CC1
Temperature: 40 °C

Procedure:
A solution of 1-(1,4-dioxaspiro[4.5]decan-8-yl)but-3-en-1-ol (840 mg, 3.33 mmol), prepared in the previous step, and the Grubbs Generation II catalyst (185 mg, 0.218 mmol) in DCM was degassed and heated to 40° C. under argon for 4 hours. After extraction with saturated NaHCO3 solution, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, ether) to afford the product.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].Br[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.O>CN(C)C=O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([O:4][CH2:3][CH:2]([NH2:1])[CH3:5])=[CH:10][CH:11]=1)#[N:14]
Reactant: CC(N)CO
Reactant: N#Cc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N)COc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
50.0 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 29.3 g of 60% sodium hydride and 300 mL of dimethylformamide at 0° C. After the reaction mixture was stirred for 30 minutes at 0° C. a solution containing 121.2 g of 4-bromobenzonitrile dissolved in N,N-dimethylformamide was added dropwise to the reaction mixture. The resultant mixture was stirred for 20 hours at room temperature. After completion of the reaction, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure. The residue was distilled under reduced pressure to obtain 48.0 g of the desired product (yield 41%). Boiling point: 132° C./0.26 mmHg.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH2:6][N:5]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:4]1.[C:27]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])#[N:28]>>[C:27]([C:29]1[CH:30]=[C:31]([C:32]([NH:2][CH:3]2[CH2:8][CH:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=3)[CH2:6][N:5]([C:19]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[O:20])[CH2:4]2)=[O:33])[CH:35]=[CH:36][CH:37]=1)#[N:28]
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: Cl
Product: N#Cc1cccc(C(=O)NC2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)c1

Procedure:
200 mg (0.508 mmol) of the amine from Example 57A [racemic cis isomer] and 112 mg (0.762 mmol) of 3-cyanobenzoic acid were reacted according to General Method 8. Yield: 206 mg (80% of theory)
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24](=[O:27])[NH:25][NH2:26]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24](=[O:27])[NH:25][N:26]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: NNC(=O)Nc1ccc(Cl)cc1Cl
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccc(Cl)cc1Cl

Procedure:
ninhydrin, 4-(2,4-dichlorophenyl)-semicarbazide hydrochloride
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25](O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25]=[CH:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1
Reactant: CCCCCC1CCC(C2CCC(CC(O)c3c(C)cc(OCC)c(F)c3F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(C2CCC(C=Cc3c(C)cc(OCC)c(F)c3F)CC2)CC1

Procedure:
0.16 g of p-toluenesulfonic acid monohydrate was added to the compound (9) having been dissolved in 60 mL of toluene, and the mixture was heated under stirring by using a Dean-Stork trap until completion of azeotrope of water. After terminating the reaction by adding water, the aqueous layer was extracted with toluene, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and then subjected to recrystallization to obtain 11.2 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-(4-pentylcyclohexyl)cyclohexyl)ethene (Compound 1-3-3-10) as colorless crystals.