Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>C(O)C>[OH:25][CH2:24][CH2:26][NH:27][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: NCCO
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCO)ncc2c(=O)[nH]1
Reaction time: 16 h

Procedure:
A stirred mixture of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and ethanolamine (0.25 ml) in ethanol (20 ml) was heated under reflux for 19 hours. More ethanolamine (0.75 ml) was added and stirring under reflux continued for 16 hours. A white crystalline solid which precipitated from the cooled reaction mixture was collected, washed with cold ethanol and recrystallized from ethanol to yield the title compound, 0.38 g, m.p. 204-205.5° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33](O)=[O:34]>>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[OH:20])[CH2:11]2)[CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3]1)=[O:34]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Product: CCCN(CCN1CCN(C(=O)c2cc3ccccc3o2)CC1)C1CCc2c(O)cccc2C1
Yield: 34.7 %

Procedure:
Compound 40h was prepared following Procedure G using 39b (214 mg, 0.674 mmol) and benzofuran-2-carboxylic acid (131 mg, 0.809 mmol) to give 40h (108 mg, 35%) after column chromatography. 1H NMR (400 MHz, CD3OD) δ 0.94-0.98 (t, 3H, J=7.2 Hz), 1.60-1.68 (m, 3H), 2.14-2.65 (m, 8H), 2.77-3.03 (m, 8H), 3.87 (bs, 4H), 6.55-6.60 (m 2H), 6.89-6.93 (t, 1H, J=7.2 Hz), 7.29-7.33 (t, 1H, J=6.4 Hz), 7.36 (s, 1H), 7.42-7.45 (t, 1H, J=7.2 Hz), 7.56-7.58 (d, 1H, J=8.8 Hz), 7.70-7.72 (d, 1H, J=7.2 Hz). The free base of 40h was converted in to its HCl salt. m.p. decomp at 140° C. Anal. [C28H35N3O.2HCl.1.5H2O] C, H, N.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].O1CCCC1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[C:13]=1[CH3:19]>O>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:2]([O:4][CH3:5])=[O:3])[C:13]=1[CH3:19]
Reactant: Cc1c(N)cccc1Cl
Reactant: COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(Cl)c1C
Temperature: 25 °C

Procedure:
Under cooling, to a mixture of methyl chloroformate 30 mL and tetrahydrofuran 50 mL was added dropwise 1-chloro-2-methyl-3-aminobenzene 5.00 g and the mixtures were stirred at 25° C. for a half hour. To the reaction mixtures was added water and the resulting mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The mixtures were concentrated under reduced pressure to give 1-chloro-2-methyl-3-methoxycarbonylaminobenzene 5.80 g.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:45][C:33]1[N:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:26][CH:27]=2)[C:40]2[C:35]([C:34]=1[CH3:44])=[CH:36][C:37]([C:41](=[O:42])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:38][CH:39]=2
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H]3C[C@H]3c3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (1R,2S)-2-phenylcyclopropanamine hydrochloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 515 [M+H]+.
Reaction SMILES: O[CH:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:3]1=[O:21].[H-].[Na+].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl>[C:24]([CH:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:3]1=[O:21])(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: COc1ccc(N2C(=O)C(O)C2c2ccccc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)C1C(=O)N(c2ccc(OC)cc2)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a solution of C3-hydroxy β-lactam 24 (5.80 g, 19.1 mmol) in 30 ml of freshly distilled CH2Cl2 was added NaH (60% suspension in mineral oil, 0.83 g, 21.0 mmol), and the mixture was stirred for 15 min at room temperature. Acryloyl chloride (2.59 g, 28.64 mmol) was then added dropwise and the resultant mixture was stirred until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and extracted (3×20 ml) with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 4.92 g (72%) of 25 as a white solid, mp 99-100° C. 1H NMR (250 MHz) δ 7.33 (d, J=7.9 Hz, 1H), 7.23-7.10 (m, 5H), 6.75 (d, J=8.9 Hz, 2H), 6.17 (d, J=5.0 Hz, 1H), 5.98 (dd, J=16.9, 1.00 Hz, 1H), 5.74 (dd, J=16.9, 10.4 Hz, 1H), 5.69 (d, J=5.0 Hz, 1H), 5.59 (d, J=10.4, 1.0 Hz, 1H), 3.66 (s, 3H). 13C NMR (63 MHz) δ 163.6, 161.2, 156.6, 133.7, 132.3, 130.3, 130.1, 129.8, 128.5, 126.8, 126.5, 118.6, 114.4, 75.3, 61.3, 58.2, 55.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12](Cl)[N:11]=[C:10]([CH:15]2[CH2:17][CH2:16]2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[Cl:7][C:8]1[N:9]=[C:10]([CH:15]2[CH2:17][CH2:16]2)[N:11]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: Clc1nc(Cl)nc(C2CC2)n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1nc(C2CC2)nc(N2CCOCC2)n1
Temperature: 5 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A solution of 2.61 g (0.03 mole) of morpholine in 20 ml of chloroform is added in the course of 30 minutes to a solution of 5.7 g (0.03 mole) of 2,4-dichloro-6-cyclopropyl-1,3,5-triazine in 50 ml of chloroform, cooled to between 3° and 5° C. The temperature of the mixture is allowed to return to about 10° C., then the mixture is cooled again to 5° C. and a solution of 4.14 g (0.03 mole) of potassium carbonate in 15 ml of water is added dropwise. The mixture is then stirred at room temperature for two hours. 30 ml of water are added and the organic phase is separated off. The solution is washed with water and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica (eluent: 96.5:3.5 (v/v) dichloromethane-ethylacetate) and then recrystallized from hexane. 5.5 g of 2-chloro-4-cyclopropyl-6-morpholino-1,3,5-triazine are thus obtained. Yield: 76.2%. M.P.: 99°-100° C.
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=O.Cl.[NH2:27][OH:28].C(OCC)(=O)C.O>CN(C)C=O>[OH:28][N:27]=[CH:1][C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc2occ(C=NO)c(=O)c2cc1Oc1ccccc1
Reaction time: 1 h
Yield: 72 %

Procedure:
4 g of 3-formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 20 ml of N,N-dimethylformamide. Thereto was added 850 mg of hydroxylamine hydrochloride. The mixture was stirred for 1 hour at 20°-25° C. The reaction mixture was mixed with 50 ml of ethyl acetate and 100 ml of water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from ethanol to obtain 3.0 g (yield: 72.3%) of 3-hydroxyiminomethyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 199°-200° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([Cl:18])[C:10]=1[Cl:19])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2]>[Pt]>[CH2:1]([N:3]([CH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Cl:18])[C:10]=1[Cl:19])[CH2:4][C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN(CC(=O)O)Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Agent: [Pt]
Product: CCN(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl

Procedure:
Ethyl N-(2,3-dichloro-6-nitrobenzyl)glycine (compound VI) may also be catalytically hydrogenated using a sulfided platinum on carbon catalyst under hydrogen pressure. The catalyst is then removed by filtration and the filtrate concentrated, diluted with water and an organic solvent and basified using an alkali to a pH of about 9-10. The organic phase is separated and concentrated and the crude material purified by low temperature recrystallization to give ethyl-(6-amino-2,3-dichlorobenzyl)glycine (compound I).
Reaction SMILES: Br[C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:2]3[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[N:7]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1ncc(NCCO)nc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ncc(NCCO)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 82c, 3-bromo-5-(2-hydroxy-ethyl-amino)-pyrazine-2-carbonitrile was treated with 1-(4-fluorophenyl)piperazine in the presence of potassium carbonate in N,N-dimethylformamide between room temperature and 80° C. to yield 4-(4-fluoro-phenyl)-6′-(2-hydroxy-ethylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as light yellow solid; m.p. 149-151° C.; MS: 343 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[N:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:40]>O1CCCC1>[Cl:40][C:21]1[N:16]2[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[N:23]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]=3)=[C:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: c1ccn2nc(-c3ccnc(NC4CCCC4)n3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccnc(NC4CCCC4)n3)nn12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
N-Cyclopentyl-N-(4-{2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)amine (140 mg, 0.32 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). The resulting solution was cooled to −78° C., then n-butyllithium (0.99 mL, 1.6 mmol, 1.6 M in hexane) was added dropwise. The resulting dark solution was stirred at −78° C. for 20 minutes, then carbon tetrachloride (2 mL) was added. The reaction was stirred for additional 20 minutes and then quenched by the addition of water and allowed to warm to room temperature. The phases were separated and the aqueous phase extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate:hexane) gave 80 mg (53%) of N-(4-{7-chloro-2-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinyl)-N-cyclopentylamine as a foam. 1H NMR (CDCl3): δ 8.37 (d, 1H), 8.27 (d, 1H), 8.16 (d, 1H), 7.26 (t, 1H), 7.06 (d, 1H), 7.04 (m, 1H), 6.62 (d, 1H), 5.21 (d, 1H), 5.15 (d, 1H), 4.32 (m, 1H), 4.10 (m, 1H), 1.4–2.1 (m, 16H); MS m/z 475 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[C:7]([Cl:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=1>O1CCCC1>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=2)=[O:13])=[C:7]([Cl:16])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)c(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)c(Cl)c1
Yield: 7.2 %

Procedure:
A mixture of (4-tert-butyl-2-chlorophenoxy)acetic acid (121 mg, 0.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (90 mg, 0.55 mmol), triethylamine (0.30 ml), tetrahydrofuran (3.0 ml) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (127 mg, 0.5 mmol) was treated in the same procedure described in Example 2(b) to give 16 mg (7% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:13][CH:14]=1)[O:7][CH2:8][CH2:9][C:10]2=[O:12]
Reactant: COc1ccc(OCCC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclisation is carried out on the acid chloride generated starting from the acid. Heating the acid obtained in Step B (500 mg:2.55 mmol) at reflux of toluene (20 ml) for 3 hours in the presence of thionyl chloride (0.56 ml:7.65 mmol:3 eq.) allows easy access to the acid is chloride. The solvent and also the excess reagent are removed by concentrating the resulting yellow solution under reduced pressure. The dry residue is then taken up in 20 ml of anhydrous dichloromethane; aluminium chloride (465.9 mg:3.49 mmol:1.5 eq.) is then introduced cautiously. The reaction mixture is hydrolysed in the cold state after 1 hour of stirring at ambient temperature. The product is extracted, washed with water and then purified on a silica column (AcOEt/PE 3/7).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[N:25][OH:26])[CH2:9][N:10]([CH2:14][CH:15]=[CH2:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: C=CCN(CC=C)CC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC=C)CC(=NO)c1cccc(Br)c1
Temperature: 50 °C
Yield: 119.3 %

Procedure:
A solution of 1-(3-bromophenyl)-2-(diallylamino)ethanone (60 g, 204.7 mmol) in ethanol (720 mL) and pyridine (24.8 mL, 307 mmol) is stirred 15 minutes at 22° C. Hydroxylamine hydrochloride (17 g, 246 mmol) is added in portions to the solution over 1 hour. The reaction is warmed to 50° C. for 2 hours and then heated to 70° C. for 16 hours. The solvent is evaporated and the residue partitioned in water (300 mL) and methyl tert-butyl ether (300 mL). The organic layer is separated and washed with water (100 mL, 2×) and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated to dryness to give the title compound (75.5 g, 79%). ES/MS (m/e): 309 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[C:4]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:3]=1.[O-]CC.[Na+]>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C@H:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[C:4]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cc(OCc2ccccc2)nc(C)c1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc(OCc2ccccc2)nc(C)c1C
Temperature: 55 °C

Procedure:
To an ethanol solution (0.1 M) of cis-1-(1,1-dimethylethyl) 3-ethyl 4-{2,3-dimethyl-6-[(phenylmethyl)oxy]-4-pyridinyl}-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added freshly prepared sodium ethoxide (1.2 eq.). The resulting yellow-orange solution was heated at 55° C. for 16 h. The volatiles were then removed in vacuo and the residue was partitioned between EtOAc and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 90:10 (v/v) Hex:EtOAc→1:1 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].[C:8]1([C:14]([C:31]([F:34])([F:33])[F:32])=[C:15]([C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:27]1[CH:28]=[CH:29][C:24]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:31]([F:32])([F:33])[F:34])=[CH:25][CH:26]=1
Reactant: CN(C)CCO
Reactant: COc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(F)cc2)cc1
Agent: [Na]
Product: COc1ccc(C(=C(c2ccccc2)C(F)(F)F)c2ccc(OCCN(C)C)cc2)cc1
Yield: 89.5 %

Procedure:
0.46 g (0.02 g.-atoms) of sodium are dissolved in 4.5 g (50 mmoles) of 2-dimethylamino-ethanol. 3.72 g (10 mmoles) of 2-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-1-(4-methoxyphenyl)-propene are added to the solution, the mixture is heated at 150°-155° C. for one hour, and then processed as described in Example 19. 3.95 g (89.6%) of 1-[4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-3,3,3-trifluoro-1-(4-methoxyphenyl)propene are obtained as a resinous substance; the product is a 9:1 mixture of the (Z) and (E) isomers.
Reaction SMILES: C(OC(=O)[CH:5]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)C.O.[Li+].[OH-]>CO>[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:7]=2)=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)c1ccnc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of the product prepared in Step 1 (440 mg, 1.24 mmol) in methanol (13 mL) containing a drop of water, was added powdered LiOH (36 mg, 1.5 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated to remove the methanol, diluted in dichloromethane, and washed with water. The combined organic extracts were dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography eluting with 10-25% ethyl acetate in hexanes to give 4-(4-nitrobenzyl)-2-(trifluoromethyl)pyridine as a light yellow solid (100 mg, 29%). 1H NMR (CHCl3-d) δ 8.65 (d, J=4.7 Hz, 1H), 8.21 (m, 2H), 7.49 (s, 1H), 7.35 (m, 2H), 7.28 (m, 1H), 4.18 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[CH:3]([OH:5])[CH3:4].[H][H]>[Pd].C(O)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1([CH3:15])[CH3:14])[CH:3]([OH:5])[CH3:4]
Reactant: CC1=CCC(CCC(C)C(C)O)C1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(O)C(C)CCC1CCC(C)C1(C)C
Yield: 97.3 %

Procedure:
A mixture of 105 g (0.5 mole) of 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol, 5.3 g of 5% palladium on carbon and 100 ml of ethanol was hydrogenated at 30°-45° C and 35-50 psi until the hydrogen uptake ceased. The mixture was filtered to remove the catalyst and the solvent was removed from the filtrate by distillation. The residual oil was fractionally distilled to yield 3-methyl-5-(2,2,3-trimethylcyclopentan-1-yl)pentan-2-ol: 93.2 g (97.3% yield); bp 105°-107° C (1.3 mm); mol wt 212 (ms);
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([OH:26])[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH:11]([O:26][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])=[CH:14][C:13]=1[Cl:25])[CH2:8]2
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(C(O)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl 4-(adamantan-2-yl(hydroxy)methyl)-3-chlorobenzoate (0.32 mg, 1.00 mmol) in anhydrous dimethylformamide (5 mL) was added sodium hydride (60% dispersion in mineral oil, 0.048 g, 1.2 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. Benzyl bromide (0.24 mL, 2.00 mmol) and tetrabutylammonium iodide (0.037 g, 0.10 mmol) was added and the reaction mixture was stirred for 16 hours at ambient temperature. After quenched with saturated ammonium chloride solution (10 mL), the mixture was diluted with ethyl acetate (150 mL). The organic phase was washed with water (3×10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-20% ethyl acetate in hexanes as eluent to afford the title compound as a colorless oil (0.437 g, quant.): 1H NMR (300 MHz, CDCl3) δ 7.97-7.95 (m, 1H), 7.90 (d, J=8.18 Hz, 1H), 7.60 (d, J=7.39 Hz, 1H), 7.46-7.18 (m, 5H), 5.18-5.11 (m, 1H), 4.30 (d, J=11.54 Hz, 1H), 4.18 (d, J=11.60 Hz, 1H), 2.41 (s, 1H), 2.12-1.30 (m, 22H), 1.13 (s, 1H).