Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:4]3[CH2:5][N:6]([C:15](=[O:17])[CH3:16])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.Cl.Cl.[N:20]1([C@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C)C=O>[N:20]1([CH:26]2[CH2:27][CH2:28][CH:29]([NH:32][C:2]3[C:3]4[C:4]5[CH2:5][N:6]([C:15](=[O:17])[CH3:16])[CH2:7][CH2:8][C:9]=5[S:10][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:30][CH2:31]2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Reactant: CC(=O)N1CCc2sc3ncnc(Cl)c3c2C1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of 1-[3-chloro-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-one (100 mg, 0.37 mmol, 1.00 equiv) and trans-4-(morpholin-4-yl)cyclohexan-1-amine dihydrochloride (412 mg, 1.61 mol, 4.32 equiv) in 10 mL of N,N-dimethylformamide was added TEA (200 mg, 1.98 mmol, 5.29 equiv) and the resulting solution was stirred for 12 h at 50° C. under nitrogen. After concentration in vacuo, the crude product was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (10% CH3CN up to 35% in 11 min, up to 95% in 1.5 min, down to 10% in 1.5 min); detector: UV 254/220 nm. The product-containing fractions were collected and partially evaporated under reduced pressure and lyophilized overnight to give 76.9 mg (50%) of 1-(3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl)ethan-1-one as a white solid. MS (ES): m/z 416 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 1.40-1.60 (m, 4H), 2.08 (d, 2H), 2.20-2.45 (m, 6H), 2.60-2.70 (m, 4H), 2.92, 3.02 (t, t, 2H), 3.70-3.80 (m, 4H), 3.89, 3.95 (t, t, 2H), 4.05-4.22 (m, 1H), 4.96, 5.00 (s, s, 2H), 8.29, 8.30 (s, s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[N:18]([O-])=O.[Na+]>Cl.O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[NH2:18])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1ccc(N(N)C(=O)c2ccc(F)cc2)cc1
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a stirred suspension of 5.0 gm (23.9 mMol) N-(4-fluorobenzoyl)-4-aminoaniline in 42 mL concentrated hydrochloric acid at 0° C. was added dropwise a solution of 1.65 gm (23.9 mMol) sodium nitrite in 30 mL water. The mixture was stirred for 10 minutes after the addition was complete and was then added dropwise to a solution of 19.6 gm (86.87 mMol) stannous chloride dihydrate in 40 mL concentrated hydrochloric acid at 0° C. The resultant white paste was stirred vigorously for 1 hour and was then filtered under vacuum. The solid which formed was then partitioned between ethyl acetate and 5N sodium hydroxide, the phases separated and the aqueous phase was extracted again with dichloromethane. The combined organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to give 3.8 gm (72%) of the title compound as a brown solid which is suitable for use in subsequent reactions without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J17) (347 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as a light red foam (550 mg, 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[O:12][CH2:13][C:14](=O)[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:15]2[C:16](=[O:18])[O:17][CH2:13][C:14]=2[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1=C(Nc2cccc([N+](=O)[O-])c2)OCC1=O
Reactant: Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Product: O=C(Nc1cccc([N+](=O)[O-])c1)C1=C(Nc2ccccc2)COC1=O

Procedure:
The title derivative was prepared by a procedure similar to that described in Example 8 starting with 2-[(m-nitrophenyl)amino]-4-oxo-3-furoic acid (7.4 grams, 0.028 mol), BOP-Cl (7.13 grams, 0.028 mol) and aniline (2.58 ml, 0.025 mol) dissolved in 90 ml methylene chloride. Yield: 6.71 g, mp 194°-195° C. (R2 =C6H4NO2 --m).
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:13](Cl)(=O)[C:14]([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[C:14]([C:17]1[O:12][C:11]2[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=2)[N:2]=1)([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1nc2c(C(=O)O)cccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.30 g, 1.28 mmol) and pivaloyl chloride (0.16 mL, 1.28 mmol) in dichloromethane (10 mL) was added triethylamine (0.72 mL, 5.12 mmol) dropwise, then the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (240 mg, 1.26 mmol). The reaction mixture was then heated to reflux for 1.5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated then washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford 2-tert-butylbenzoxazole-4-carboxylic acid (0.15 g, 53%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.71 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 1.45 (s, 9H); MS (ESI+) m/z 220 (M+H).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: BrC1CCCCCC1
Product: CCOC(=O)/C(=N\OC1CCCCCC1)C(C)=O
Yield: 80 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (5.Og) was treated with cycloheptyl bromide as described in Example 13a to give the title compound as a colourless liquid (6.36 g, 80%). (Found: M+ +H, 256.1547, C13H21NO4 requires M+H 256.1550), νmax (film) 2940, 1750, 1690 cm-1 ; δH (CDCl3): 1.31 (3H, t) 1.4-2.0 (12H, m), 2.35 (3H, s) 4.32 (3H, q+m).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[C:18]1([C:24](=[N:31][C:32]2[CH:33]=[N:34][CH:35]=[C:36]([CH:39]=2)[CH:37]=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.CCCCCC>[Cl:1][C:2]1[C:3]2[C:10]([CH:37]([C:36]3[CH:35]=[N:34][CH:33]=[C:32]([N:31]=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:39]=3)[OH:38])=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1cc(C(O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2c(Cl)ncnc21
Reaction time: 0.83 h
Yield: 48 %

Procedure:
To stirred solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 226, 6.6 g, 22.7 mmol) in THF (130 mL) was added n-BuLi (18.2 mL of a 2.5M solution in hexane, 45 mmol) at −75° C. under N2, and the mixture was stirred for 50 min. A solution of 5-((diphenylmethylene)amino)nicotinaldehyde (Preparation 106, 6.5 g, 22.7 mmol) in dry THF (50 mL) was added and the mixture was stirred at −70° C. for 80 min. The mixture was quenched with sat. aq. NH4Cl solution and extracted with EtOAc (300 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown solid in 48% yield, 5.2 g.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.Cl.[NH2:15][NH:16][C:17]([NH2:19])=[O:18]>C(O)C.O>[Cl:1][CH2:2][C:3](=[N:15][NH:16][C:17]([NH2:19])=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1
Reactant: NNC(N)=O
Reactant: O=C(CCl)COc1ccc(Cl)cn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=O)NN=C(CCl)COc1ccc(Cl)cn1

Procedure:
1-Chloro-3-(5-chloropyrid-2-yloxy)propan-2-one (400 mg.) was dissolved in ethanol (4 ml.) with warming, and stirred while a solution of semicarbazide hydrochloride (223 mg.) in water (2 ml.) was added. The mixture was cooled in ice for 11/2 hours and filtered, and the filter cake was washed with a 1:1 v/v mixture of ethanol and water (1 ml.), then with water (3 × 1 ml.). The product was dried in a desiccator over silica gel to give 1-chloro-3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropane, RF = 0.72 (5% v/v methanol in ethyl acetate), m.p. 115°-117° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]2[CH:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:10]2[CH:47]([CH2:49][CH:50]=[CH2:51])[OH:48])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:59](Cl)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:59]([O:48][CH:47]([CH2:49][CH:50]=[CH2:51])[CH:10]1[CH:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:11]1[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)(=[O:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCC(O)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCC(OC(=O)c1ccccc1)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of Compound (XIII) (3.00 g; 4.40 mmoles) and triethyl amine (2.4 mL; 17.6 mmoles) in methylene chloride (25 mL), cooled at 0° C., was added benzoyl chloride (1.6 mL; 13.2 mmoles). The reaction was kept at room temperature for 16 hours, then water (5 mL) and saturated aqueous sodium bicarbonate solution (40 mL) were added. The phases were separated, and the aqueous phase was extracted with methylene chloride (30 mL). The combined organic solution was dried over sodium sulfate and the solvent evaporated under reduced pressure. The crude oil was purified via flash chromatography (silica gel; 1:4 ethyl acetate:hexane) to yield 3,4,5-tris(phenylmethoxy)-6-[(phenylmethoxy) methyl]-1-(phenylmethyl)-α-(2-propenyl)-2-piperidinemethanol benzoate (ester) (XIV) (1.92 g; 56%) as a clear, colorless oil and recovered Compound (XIII) (0.60 g; 0.88 mmoles). IR (neat) 1719 cm-1 (C=0); MS (FAB-MNBA) 788 (MH+), 680 (MH + --PhCH2OH); 1H nmr (CDCl3) δ 2.4 (m, 1H), 2.9 (dt, 1H), 3.5-4.0 (m, 8H), 4.1 (d, 1H), 4.4 (s, 2H), 4.5-4.9 (m, 9H), 5.4-5.6 (m, 1H), 7.1-7.4 (m, 27H), 7.5 (m, 1H), 8.1 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH2:22])=[N:18][CH:19]=1.C(N(CC)CC)C.[O:30]1[C:39]2[CH:38]=[C:37]([CH:40]=O)[N:36]=[CH:35][C:34]=2[O:33][CH2:32][CH2:31]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[O:30]1[C:39]2[CH:38]=[C:37]([CH2:40][NH:22][CH2:21][CH2:20][C:17]3[CH:16]=[CH:15][C:14]([C:7]4[C:6]5[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[N:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:19][N:18]=3)[N:36]=[CH:35][C:34]=2[O:33][CH2:32][CH2:31]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1ccc2nccc(-c3ccc(CCN)nc3)c2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(-c3ccc(CCNCc4cc5c(cn4)OCCO5)nc3)c2n1
Reaction time: 24 h
Yield: 168.7 %

Procedure:
To a stirred solution of (2-{5-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-pyridinyl}ethyl)amine hydrochloride salt (0.69 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added triethylamine (0.29 mL, 2.07 mmole) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.12 g, 0.73 mmole). After 24 h, the reaction contents were concentrated and dried under high vacuum. To a stirred solution of the crude imine in dry EtOH (25 mL) at RT was added NaBH4 (0.03 g, 0.73 mmole). After 24 h, Silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.50 g, 72%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 9.52 (d, J=1.8 Hz, 1H), 9.22 (d, J=5.6 Hz, 1H), 9.02 (d, J=8.3 Hz; 1H), 8.57 (m, 2H), 8.48 (d, J=5.6 Hz, 1H), 8.19 (d, J=9.3 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J=9.3 Hz, 1H), 4.66 (m, 4H), 4.54 (s, 2H), 4.13 (s, 3H), 3.82 (m, 2H), 3.71 (s, 2H). LC-MS (ES) m/e 430 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([N:15]([CH2:17][CH2:18][OH:19])C)[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23].[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25].CCN(CC)CC>C1COCC1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([NH:15][CH2:17][CH2:18][O:19][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of 2-(4-bromo-3-formyl-phenoxy)-6-[(2-hydroxy-ethyl)-methyl-amino]-nicotinonitrile (7, 0.94 g, 2.59 mmol) in THF (anhydrous, 100 mL) were added tert-butyl chloro-dimethyl silane (0.86 g, 5.7 mmol), Et3N (0.8 mL, 5.7 mmol) and cat. amount of DMAP. The solution was stirred at room temperature overnight. The solution was filtered and concentrated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-50% EtOAc/hexanes gradient, to afford 1.1 g (89% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]([C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=O)[CH:8]=O)=[CH:4][CH:3]=1.Cl.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1.C[O-].[Na+]>CO>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:8]=[N:31][N:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:33])[F:32])=[CH:25][CH:26]=3)[C:10]=2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=CC(Cc1ccc(Br)cc1)C(=O)C1CCCCC1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)Oc1ccc(-n2ncc(Cc3ccc(Br)cc3)c2C2CCCCC2)cc1

Procedure:
To a solution of 3.17 g 2-(4-bromobenzyl)-3-cyclohexyl-3-oxopropanal from Step C above and 2.47 g 4-trifluoromethoxyphenylhydrazine hydrochloride in 100 mL methanol was added 21.6 mL 0.5 M sodium methoxide in methanol. The resulting mixture was refluxed under nitrogen for two days. The solvent was removed under reduced pressure. The resulting crude product was subjected to repeated chromatography on silica gel using 0˜10% MeCN in methylene chloride, 0˜2% MeCN in methylene chloride, or 7˜10% EtOAc in hexanes. Pure 4-(4-bromobenzyl)-5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole was obtained as the major product by recrystallization of chromatographic fractions from methanol. 1H NMR (CDCl3, 500 MHz) δ 7.64˜7.67 (m, 2H), 7.43˜7.46 (m, 2H), 7.44 (s, 1H), 7.23˜7.27 (m, 2H), 7.10˜7.13 (m, 2H), 3.82 (s, 2H), 2.63 (tt, J=3.3 & 11.8 Hz, 1H), 1.83˜1.89 (m, 4H), 1.72˜1.76 (m, 1H), 1.60˜1.69 (m, 2H), 1.27˜1.40 (m, 3H). LC-MS: 2.91 min. (M+H=479). Pure 4-(4-bromobenzyl)-3-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole was obtained as the minor product following preparative HPLC of the silica gel chromatography fractions. 1H NMR (CDCl3, 500 MHz) δ 7.59˜7.63 (m, 2H), 7.44˜7.47 (m, 2H), 7.41 (s, 1H), 7.25˜7.28 (m, 2H), 7.10˜7.13 (m, 2H), 3.82 (s, 2H), 2.64 (tt, J=3.2 & 12.1 Hz, 1H), 1.83˜1.89 (m, 4H), 1.72˜1.76 (m, 1H), 1.57˜1.66 (m, 2H), 1.27˜1.39 (m, 3H). LC-MS: 2.70 min. (M+H=479.1/481). The identity of the isomers were confirmed by NOE difference spectra.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][C:16](/[C:19](/[CH3:23])=[CH:20]/[CH2:21][OH:22])=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][C@@H:27]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:25]>>[CH2:24]([O:26][C@@H:27]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:22][CH2:21]/[CH:20]=[C:19](/[C:16]2[CH:15]=[CH:14][C:13]([C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][CH:10]=3)=[CH:18][CH:17]=2)\[CH3:23])=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:25]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(-c4ccccc4)c3)cc2)cc1)OCC
Yield: 78.7 %

Procedure:
The title compound (0.41 g, 80% yield) was prepared from (E)-3-[1,1′;3′,1″]terphenyl-4″-yl-but-2-en-1-ol (0.30 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52 c.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([OH:10])=[C:4]([F:11])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([O:10][CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[C:4]([F:11])[CH:3]=1
Reactant: CCc1cc(O)c(F)cc1Br
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 4-bromo-5-ethyl-2-fluoro-phenol (Preparation 3, 80 g, 365 mmol) in DCM (1 L) was added DIPEA (70 mL, 401 mmol) and SEM-Cl (71 mL, 401 mmol). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with water (1 L), dried over MgSO4 and concentrated in vacuo to yield the crude product. This material was purified by silica gel chromatography eluting with 30% DCM in heptane to give the title compound as a pale yellow oil (109.8 g, 86%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C1(O[C:13]2[C:14](=[O:26])[N:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][N:18]=2)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Cl:3][C:13]1[C:14](=[O:26])[N:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:16]=[CH:17][N:18]=1
Reactant: O=c1c(OC2CCCCC2)nccn1-c1ccc(F)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1c(Cl)nccn1-c1ccc(F)cc1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
Phosphorus oxychloride (0.94 mL, 10 mmol) was added to a solution of 3-cyclohexyloxy-1-(4-fluoro-phenyl)-1H-pyrazin-2-one (0.97 g, 3.36 mmol) in DCE (10 mL). The reaction mixture was stirred at 160° C. for 15 minutes under microwave irradiation. The reaction was poured into ice-water, then basified with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 3-chloro-1-(4-fluoro-phenyl)-1H-pyrazin-2-one (0.71 g, 95% yield) that was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1)([O-])=O.[C:13]1(=O)[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12.Cl.[OH-].[NH4+]>C1(C)C=CC=CC=1.O>[C:13]1(=[O:18])[N:10]([CH2:9][CH2:8][C:7]2[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(CCN2C(=O)[C@H]3CC=CC[C@H]3C2=O)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
16.6 g of p-nitrophenethylamine and 15.1 g of cis-1,2,3,6-tetrahydrophthalic anhydride are heated under reflux in 300 ml of toluene, with stirring and a water trap, for 16 hours. This mixture is cooled and take to dryness by warming under reduced pressure. The residue is transferred to a flask containing 500 ml of water, 270 g ferrous sulfate heptahydrate and 1.3 ml concentrated hydrochloric acid. Steam is delivered to the mixture. When the temperature reaches 90° C., 75 ml of concentrated ammonium hydroxide is added in one portion, and at two-minute intervals three 25 ml portions of ammonium hydroxide are added. Continue stirring and heating during the additions. The total reaction time is 8-10 minutes. Immediately pour the mixture onto 1 kg of cracked ice. The solid is collected by filtration and washed with water. Recrystallize from water ethanol to obtain -4-(cis-1,2,3,6-tetrahydrophthalimidoethyl) aniline (1f).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:19]=O>C(O)=O>[CH2:1]([N:6]([CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: C=O
Reactant: CCCCCCCCCCCCNCCC(C)C
Solvent: O=CO
Product: CCCCCCCCCCCCN(C)CCC(C)C

Procedure:
To 30 g of N-isoamyldodecanamine in 100 ml of formic acid was added 30 ml of formalin (40% formaldehyde) and the reaction mixture was refluxed for 8 hrs. Most of the solvent was removed under vacuum and the remaining material was made alkaline with 3 N sodium hydroxide solution and the amine extracted into hexane. The hexane phase was washed with water, and then dried over sodium hydroxide pellets. Removal of the hexane under vacuum gave 28 g of N-isoamyl-N-methyldodecanamine, ND20 1,4507.