Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH2:12][OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:48][N:49](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:13][CH2:12][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:48]#[N:49])[N:3]=1
Reactant: OCc1nc(Cl)cc2ccccc12
Reactant: CN(C)C=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: N#Cc1cc2ccccc2c(CO)n1
Temperature: 150 °C
Yield: 34 %

Procedure:
A suspension of (3-chloroisoquinolin-1-yl)methanol (1.0 g, 5.17 mmol), zinc cyanide (672 mg, 5.68 mmol), Pd2(dba)3 (190 mg, 0.21 mmol), XPhos (241 mg, 0.52 mmol) in DMF (15 mL) was heated at 150° C. for 1 hour under a nitrogen atmosphere in a microwave reactor. The reaction mixture was subsequently diluted with water and extracted with EtOAc. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography eluting with petroleum ether and EtOAc (4:1) to give the title compound as a yellow solid (330 mg, 34%). ESI-MS m/z [M+H]+ 185.1.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18].CCO.CCN(C(C)C)C(C)C>O>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:17]([CH2:13][CH2:14][OH:18])[C:16](=[O:15])[N:11]=1
Reactant: O=C1OCCC1Br
Reactant: NC(=S)N[C@H]1C[C@@H]2CC[C@H]1C2
Solvent: O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCO

Procedure:
1-((1S,2S,4R)-Bicyclo[2.2.1]heptan-2-yl)thiourea (887 mg, 5.25 mmol), 3-bromo-dihydrofuran-2(3 H)-one (1.65 g, 5 mmol), EtOH (10 mL) and DIEA (5.0 mL) were placed in a microwave reaction vessel. The mixture was placed in a microwave synthesizer and was irradiated at 150° C. for 30 min. The resulting mixture was poured into water and extracted with EtOAc and dried over MgSO4. After being filtered and concentrated in vacuo, the title compound was obtained a brown solid. MS (ES+): 255 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl>[Br:19][CH2:20][C:21]([C:8]1[CH:9]=[CH:10][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1)=[O:22]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)CBr)cc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (4.80 g, 32.0 mmol, 1.0 eq.) and 1-phenyloctane (6.84 g, 32.0 mmol) were dissolved in dry dichloromethane (10 mL) and cooled to −10° C. A solution of bromoacetyl bromide (3.14 mL, 32.0 mmol, 1.0 eq.) in dichloromethane (12 mL) was added dropwise and the mixture was allowed to return to r.t. while stirring overnight. The mixture was slowly poured into ice water (100 mL) and the aqueous phase was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The product was obtained as brown, highly viscous oil and was used in the next reaction without purification. Yield: 8.90 g (62%), purity: 69% (GC).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[C:28]([O:29][CH3:30])=[C:27](F)[CH:26]=[CH:25][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:27]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([F:17])[C:28]=3[O:29][CH3:30])[CH2:13]2)[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: CCOC(=O)c1ccc(F)c(OC)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)c(OC)c1F
Reaction time: 18 h
Yield: 76 %

Procedure:
(3R)-3-(1-Tert-butoxycarbonylaminocyclopropyl)-pyrrolidine (4.75 g, 85% content) was dissolved in dimethylsulfoxide (30 mL). After adding thereto ethyl 2,4-difluoro-3-methoxybenzoate (3.2 g) and triethylamine (3.1 mL), the mixture was stirred at 75° C. After 18 hours, the mixture was allowed to cool, incorporated with 10% aqueous citric acid solution, and extracted with AcOEt. An organic layer was dried with anhydrous sodium sulfate and filtered, and then the solvent was distilled away. The resulting residual crystals (6.22 g) (2-position:4-position=17:83) were subjected to chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound as white crystals (4.75 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17](C)[C:18](OCC(Cl)(Cl)Cl)=O)[C:14]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.O1CCCC1.C(O)(=O)C>CO.[Zn]>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH3:18])[C:14]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CN(C(=O)OCC(Cl)(Cl)Cl)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To 17.3 g (30 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-(N-methyl-N-(2,2,2-trichloroethoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 115) dissolved in 50 ml of methanol and 50 ml of tetrahydrofuran was added 14 g (233 mmole) of acetic acid and 3.95 g (60 mmole) of zinc dust. After stirring for 1 hour the reaction mixture was filtered, concentrated in vacuo, dissolved in diethyl ether, washed with water, 5% aqueous sodium bicarbonate, and brine and dried over anhydrous magnesium sulfate. Concentration in vacuo and chromatography over silica gel using diethyl ether, hexanes, and ethyl acetate yielded 7.3 g of the compound, of Example 116, a white solid, mp 148°-149° C.
Reaction SMILES: CC1O[C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[N:3]=1.O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.CCOCC>[NH2:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:8]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COc1ccc2nc(C)oc(=O)c2c1
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(N)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-6-(methyloxy)-4H-3,1-benzoxazin-4-one (for a preparation see Reference compound A) (40.0 g, 0.21 mol) in a toluene/ether (2/1) mixture (760 mL) at 0° C. was added dropwise a solution of 4-chlorophenylmagnesium bromide (170 mL, 1M in Et2O, 0.17 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h before being quenched with 1N HCl (200 mL). The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was then dissolved in EtOH (400 mL) and 6N HCl (160 mL) was added. The reaction mixture was refluxed for 2 h before being concentrated to one-third in volume. The resulting solid was filtered and washed twice with ether before being suspended in EtOAc and neutralised with 1N NaOH. The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organics were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow solid (39 g, 88% yield); LC/MS (Method D): m/z 262 [M+H]+, Rt 2.57 min.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[S:14][C:8]=2[C:7]=1[OH:23])=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[S:14][C:8]3[C:7]([OH:23])=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[N:11]=[CH:10][C:9]=3[N:12]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: CCOC(=O)c1ncc2nc(-c3ccc(F)c(Cl)c3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3ccc(F)c(Cl)c3)sc2c1O
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A mixture of 2-(3-chloro-4-fluoro-phenyl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (101 mg, 0.29 mmole) and glycine (429 mg, 5.72 mmole) in 0.5 M sodium methoxide/methanol (10.9 ml, 5.43 mmole) was refluxed for 4 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (100 ml) and extracted with dichloromethane (3×50 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl (6.5 ml). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a brown solid (58 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.50 (br s, 1H), 8.89 (s, 1H), 8.36 (m, 1H), 8.16 (m, 1H), 7.65 (t, 1H), 4.03 (d, 2H, J=5.8 Hz); MS: (+) m/z 382.19 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:27]2[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]2)[CH:10]=[CH:9][C:8]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]
Reactant: O=C(c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C(F)(F)F)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A mixture of 1-(2-(3,5-dichlorobenzylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (0.78 g, 2.1 mmol), t-butyl piperazine-1-carboxylate (0.41 g, 2.2 mmol), N,N-diisopropylethylamine (0.8 mL, 4.4 mmol) and acetonitrile (10 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (0.31 g, 28%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1H), 7.67 (d, 1H), 7.31 (s, 1H), 7.21 (s, 2H), 6.13 (dd, 1H), 5.70 (d, 1H), 4.42 (d, 2H), 3.54 (m, 4H), 3.38 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z: Calculated: 531; Observed: 532 (M+H+).
Reaction SMILES: CS([O:5][CH:6]([CH2:9][CH3:10])[C:7]#[N:8])(=O)=O.[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1O.C(=O)([O-])[O-].[K+].[K+].C(OC)(C)(C)C>C(#N)C.O>[Cl:11][C:12]1[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:15]=[CH:14][C:13]=1[O:5][CH:6]([CH2:9][CH3:10])[C:7]#[N:8]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Reactant: CCC(C#N)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: O
Product: CCC(C#N)Oc1cccc(C(F)(F)F)c1Cl
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(methanesulfonyloxy)-butyronitrile (204 mg, 1.25 mmol) (prepared following Marco et. al., Tetrahedron, 2000, 56, 2525-31) 2-chloro-3-trifluoromethylphenol (196 mg, 1.0 mmol) and potassium carbonate (172 mg, 1.25 mmol) in acetonitrile (5 ml) was stirred for 1 hour at 95° C. The mixture was shaken between tBuOMe and water and the ethereal phase dried with Na2SO4, filtered over a silicagel pad and evaporated to give as yellowish oil 2-(2-chloro-3-trifluoromethyl-phenoxy)-butyronitrile; 1H-NMR (CDCl3): 1.27 t, 3H, 2.20 m, 2H, 2.40 s, 3H, 4.78 t, 1H, 7.34, d, 1H; 7.39, t, 1H, 7.48 d, 1H.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:21]=[CH2:22]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2ccccc2c(Cl)c1OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2ccccc2c1Cl
Temperature: 50 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 1-chloro-3-methyl-naphthalen-2-yl ester (14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59 mL, 49.97 mmol) and lithium chloride (5.78 g, 136.29 mmol) was added dichlorobis(triphenylphosphine) palladium(II) under argon. The reaction mixture was heated at 50° C. for 20 h, then heated at 90° C. for 8 h. The reaction mixture was than cooled to room temperature, diluted with ethyl acetate, washed with 5% lithium chloride solution (3×), brine and dried (MgSO4), filtered and then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1-chloro-3-methyl-2-vinyl-naphthalene contaminated by organotin. The residue was dissolved in dichloromethane and stirred with 10% KF solution overnight. The resulting white mixture was filtered through a pad of Celite and extracted with dichloromethane (2×). The organic layer was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1-chloro-3-methyl-2-vinyl-naphthalene. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.59-7.48 (m, 2H), 6.90 (dd, J=18.0, 11.8 Hz, 1H), 5.73 (d, J=11.8 Hz, 1H), 5.53 (d, J=18.0 Hz, 1H), 2.50 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[OH:11].C(O)(=O)[CH:13]([CH2:15][C:16](O)=O)[OH:14]>>[CH2:6]1[C:5]2[CH:9]=[C:10]3[C:2](=[C:3]([OH:11])[C:4]=2[O:8][CH2:7]1)[O:1][C:13](=[O:14])[CH:15]=[CH:16]3
Reactant: Oc1ccc2c(c1O)OCC2
Reactant: O=C(O)CC(O)C(=O)O
Product: O=c1ccc2cc3c(c(O)c2o1)OCC3

Procedure:
reacting 6,7-dihydroxy-2,3-dihydrobenzofuran with malic acid to form 2,3-dihydroxanthotoxol,
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][C:54]=1[C:63]1[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=1>CN(C=O)C>[CH:53]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55][C:54]=1[C:63]1[CH:64]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:66]=[CH:67][CH:68]=1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3ccccc3c2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 74.2 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.068 mmol) and HATU (0.029 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-naphthalen-2-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 63% yield: LCMS (ESI) m/z 476 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([N:20]([CH3:19])[CH:21]3[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]3)[N:7]=[CH:6][N:5]=2)=[O:9])=[C:12]([CH3:18])[CH:13]=1
Reactant: CNC1CCC(C)CC1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Product: Cc1cc(O)ccc1NC(=O)c1cc(N(C)C2CCC(C)CC2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and N,4-dimethylcyclohexanamine (Enamine), the title compound was obtained as a mixture of cis-trans stereoisomers, as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C=CC=C.S([O-])([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=O)=O.[Na+]>>[CH2:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: C=CC=C
Agent: [Na+]
Product: CCCCCCCCCCCCO

Procedure:
The surfactant properties of sodium lauryl sulfate and sodium ethoxylated-lauryl sulfate produced from n-lauryl alcohol which is a derivative of butadiene trimer compare very favorably with those of sodium lauryl sulfate and sodium ethoxylated-lauryl sulfate produced from natural lauryl alcohol. On the other hand, surfactant properties of sodium iso-lauryl sulfate are inferior to those of others. Sodium ethoxylated-iso-lauryl sulfate might be used equally to sodium ethoxylated-lauryl sulfate produced from natural alcohol. Products from iso-lauryl alcohol have foam breaking characteristic. Therefore, it is expected to be used as industrial surfactant such as fiber treating agent (to remove fat from fiber).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[C:11]([C:12]([OH:14])=O)=[CH:10][NH:9][N:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]([N:18](C(C)C)CC)([CH3:17])[CH3:16].C(N)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH:15]([NH:18][C:12]([C:11]1[C:7]([CH2:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:8][NH:9][CH:10]=1)=[O:14])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OCc1n[nH]cc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1c[nH]nc1COC(C)(C)C
Temperature: 70 °C

Procedure:
To a solution of 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid [1.520 g, Reference Example 17(d)], hydroxybenzatriazole (3.110 g) and diisopropyl ethylamine (4.010 ml) in dimethyl formamide (130 ml) was added isopropylamine (1.960 ml) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.420 g). The mixture was heated at 70° C. for 2.5 hours, then diluted with ethyl acetate, then washed with water, then with brine, then dried over magnesium sulfate and then evaporated. The residue was triturated with a mixture of ethyl acetate and petrol to yield 3-tert-butyloxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide (652 mg) as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[N:24]1([C:19]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)c2cccnc2N2CCCCC2)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccnc1N1CCCCC1
Reaction time: 62 h
Yield: 97.7 %

Procedure:
A 100 mL round bottom flask which contains 2-[(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-3′-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (343, 330 mg, 0.84 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (89 mg, 2.12 mmol). After 62 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction flask. The reaction is capped and allowed to stir at ambient temperature. After 38 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides 0.3 g of a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH2:24]Br>>[F:21][C:22]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=1[CH2:24][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)ccc2F)c1
Yield: 41.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (165 mg, yield: 41.2%).
Reaction SMILES: CC1(C)C2C=C(O)C=CC=2C[C@H]2[C@@H]1CCCN2.C1(C(Cl)=O)CCCC1.[CH:26]1([C:31]([N:33]2[C@@H:42]3[C@@H:37]([C:38]([CH3:56])([CH3:55])[C:39]4[CH:46]=[C:45]([O:47]C(C5CCCC5)=O)[CH:44]=[CH:43][C:40]=4[CH2:41]3)[CH2:36][CH2:35][CH2:34]2)=O)[CH2:30][CH2:29][CH2:28][CH2:27]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.N1C=CC=CC=1>[CH:26]1([CH2:31][N:33]2[C@@H:42]3[C@@H:37]([C:38]([CH3:56])([CH3:55])[C:39]4[CH:46]=[C:45]([OH:47])[CH:44]=[CH:43][C:40]=4[CH2:41]3)[CH2:36][CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC1(C)c2cc(OC(=O)C3CCCC3)ccc2C[C@H]2[C@@H]1CCCN2C(=O)C1CCCC1
Agent: CC1(C)c2cc(O)ccc2C[C@@H]2NCCC[C@@H]21
Agent: O=C(Cl)C1CCCC1
Agent: [Al+3]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1(C)c2cc(O)ccc2C[C@H]2[C@@H]1CCCN2CC1CCCC1

Procedure:
To a stirred solution of 6.92 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-5,5-dimethylbenzo[g]quinolin-7-ol in 120 ml. of warm pyridine there was added dropwise 8.78 g. of cyclopentanecarbonyl chloride and the resulting reaction mixture was stirred for five and one-half hours. The reaction mixture was worked up, using partitioning between water and diethyl ether, in a manner similar to that described in Example 13 to yield approximately 12 g. of crude cis-1,2,3,4,4a,5,10,10a-octahydro-1-cyclopentanecarbonyl-5,5-dimethyl-7-cyclopentanecarbonyloxybenzo[g]quinoline in which some solvent remained. This product in 75 ml. of tetrahydrofuran was added dropwise to 1.25 g. of lithium aluminum hydride in 25 ml. of tetrahydrofuran. After this addition was completed, the reaction mixture was stirred and refluxed for 3 hours. The reaction mixture was then worked up to yield crude cis-1,2,3,4,4a,5,10,10a-octahydro-1-(cyclopentylmethyl)-5,5-dimethylbenzo[g]quinolin-7-ol which was converted to the p-toluenesulfonate salt, and off-white solid melting at 220°-222°C.
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.B#B.[OH-].[Na+]>O1CCCC1>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7][CH2:2][CH2:3]1
Reactant: O=C1COc2ccccc2N1
Agent: B#B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCO2

Procedure:
3,4-Dihydro-3-oxo-1,4(2H)-benzoxazine was refluxed for several hours in one equivalent of diborane in tetrahydrofuran. Excess sodium hydroxide solution was added, the product was extracted with ether and the solvent was evaporated to give the title compound as an oil.