Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:22]([O:26][C:27](Cl)=[O:28])[CH:23]([CH3:25])[CH3:24]>>[CH3:9][C:6]1[C:7]([O:8][C:27]([O:26][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:28])=[C:2]([CH3:1])[N:3]=[C:4]([NH:10][CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][CH2:14][CH3:15])[N:5]=1
Reactant: CCCC(CNc1nc(C)c(O)c(C)n1)c1ccccc1
Reactant: CC(C)COC(=O)Cl
Product: CCCC(CNc1nc(C)c(OC(=O)OCC(C)C)c(C)n1)c1ccccc1

Procedure:
In a manner similar to that of the method of Example 2, the title compound was prepared from 0.5 g (1.8 mmol) of 4,6-dimethyl-5-hydroxy-2-phenylpentylaminopyrimidine and isobutylchoroformate (0.23 ml, 1.8 mmol) to afford 0.45 g of product. Mass spectrum m/e=385. NMR (CDCl3) delta: 7.27-7.16 (m, 5H): 5.00 (bs, 1H); 4.06 (d, 5 Hz, 2H); 3.00-3.60 (m, 2H); 2.61 (t, 4 Hz, 2H); 2.23 (s, 6H): 1.65-1.36 (m, 6H): 0.99 (d, 4 Hz, 6H). IR (CHCl3) 1760, 1580 cm-1. Anal. Calc'd for C22H31O3N3 : C, 68.54: H, 8.10: N, 10.90. Found: C, 68.14; H, 7.85; N, 10.69.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]Cl)[N:6]=1.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CN
Product: CNCc1csc(C)n1
Yield: 99 %

Procedure:
2-Methyl-4-(chloromethyl)thiazole (2.94 g, CAS#39238-07-8) was dissolved in 40% methylamine (39 mL, 25 equivalents) at 25° C. for 1 h. The mixture was evaporated and purified using 10% methanol/dichloromethane with 0.5% NH4OH to give 2.83 g (99%) of the amine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8]O)[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:20])=O>O>[Cl:20][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH2:10][CH3:11]
Reactant: CCOC(CC)CCCCO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(CC)CCCCCl
Temperature: 25 °C

Procedure:
5-Ethoxyheptanol (238 g, 1.49 moles) is diluted in pyridine (128 g, 1.62 moles). The solution is stirred at room temperature and thionyl chloride (388 g, 3.22 moles) is added dropwise over 2 hours, after which time the reaction is heated in a 70° C. water bath for 2 additional hours. Water (700 ml) is added to the reaction and the organic layer separated. The aqueous layer is extracted with hexane (3×400 ml) and the extracts combined with the organic phase. The organic phase is then washed with a 10% sodium hydroxide solution (1000 ml). The solvent volume is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The remaining solvent is removed leaving 1-chloro-5-ethoxyheptane as a clear light yellow oil. The crude product is fractionally distilled under reduced pressure leaving 1-chloro-5-ethoxyheptane as a clear, colorless oil (162 g, 1.13 moles), BP 96° C./9.5 cm Hg.
Reaction SMILES: F[C:2](F)(F)[CH:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#[N:6].[CH:31](O)(C)[CH3:32]>>[CH:2]1([C@H:3]([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4][C:5]#[N:6])[CH2:32][CH2:31]1
Reactant: CC(C)O
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C(F)(F)F)c3)ncnc21
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC#N)C4CC4)c3)ncnc21
Reaction time: 0.18 h
Yield: 94 %

Procedure:
A slurry of 1.5 Kg of 20-micron Chiralcel® OD chiral stationary phase (CSP) made by Daicel in 3.0 L of isopropanol (IPA) was packed into a PROCHROM Dynamic Axial Compression Column LC110-1 (11 cm ID×25 cm L; Column Void Vol.: approximate 1.5 L) under 150 bar of packing pressure. The packed column was then installed on a Novasep Hipersep HPLC unit. The column and HPLC system were flushed with methanol (17 L) and the mobile phase made by a mixture of isopropanol and hexane (2:8 by volume, 17 L). The feed solution was then prepared by dissolving 4,4,4-trifluoro-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)butanenitrile (33, racemic SEM-protected compound, 3100 g, 7.1 mol) in the mobile phase to a concentration of 120 g/L. The feed solution (120 mL per injection) was then sequentially injected into the preparative HPLC chiral column for separation. The chiral column was eluted with the mobile phase at a flow rate of 570 mL/min at room temperature. The column elution was monitored by UV at wavelength 330 nm. Under these conditions, a baseline separation of the two enantiomers was achieved. The cycle time for each injection was 11 minutes and a total of 210 injections were performed for this separation process. Fractions for Peak 1 (the undesired (S)-enantiomer, (S)-34) and Peak 2 (the desired (R)-enantiomer, (R)-34) were collected separately from each injection, and fractions collected for each peak were continuously concentrated at 40° C. under reduced pressure (40-120 bar). The residue from each evaporator was further dried under high vacuum to constant weight to afford (3R)-3-cyclopropyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((R)-34, 1457 g, 1550 g theoretical, 94%) from Peak 2 as a light yellow oil which solidified upon standing at room temperature in vacuo and (3S)-cyclopropyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile ((S)-34, 1488 g, 1550 g theoretical, 96%) from Peak 1 as an yellow oil which solidified upon standing at room temperature in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13]
Reactant: N#Cc1cccc(OCc2cccc([N+](=O)[O-])c2)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: N#Cc1cccc(OCc2cccc(N)c2)c1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
2.32 g (9.12 mmol) of 3-[3-nitrobenzyloxy]benzonitrile and 4.38 g of zinc were suspended in 50 ml of acetic acid, and the obtained suspension was stirred at 45° C. for 4 hours. The insoluble matter was filtered out, and the filtrate was evaporated. 100 ml of chloroform and 50 ml of 1 N aqueous sodium hydroxide solution were added to the residue. After the separation of the liquids followed by the treatment by an ordinary method, the title compound was obtained.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].OO.[NH2:16][C:17]1[C:21]([C:22]#[N:23])=[CH:20][N:19]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[Cl:35])[N:18]=1.[OH2:36]>ClCCl>[Cl:30][C:29]1[CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=[C:25]([Cl:35])[C:24]=1[N:19]1[CH:20]=[C:21]([C:22]#[N:23])[C:17]([N+:16]([O-:4])=[O:36])=[N:18]1
Reactant: O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1N
Agent: OO
Solvent: ClCCl
Product: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
Trifluoroacetic anhydride (3.5 ml) was added dropwise to a stiffed mixture of 85% w/v hydrogen peroxide solution (0.56 ml) in dichloromethane (15 ml) maintaining at 0-10° C. After warming to 20° C. during 5 minutes, a solution of 3-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyanopyrazole (1.0 g; hereinafter described in Reference Example 33) in dichloromethane (10 ml) was added dropwise over 5 minutes. A temperature rise of 10° C. was observed during the addition, and the mixture heated under reflux for 1.5 hours. After cooling, the solution was poured onto excess water, and the organic solution washed in turn with solutions of sodium bicarbonate and sodium bisulphite. Drying over anhydrous magnesium sulphate, followed by evaporation in vacuo gave a buff solid, which was purified by chromatography on silica (Merck, 40-230 mesh, 0.7 kg cm−2) eluting with dichloromethane. The resultant white solid was recrystallized from a mixture of dichloromethane and hexane to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-cyano-3-nitropyrazole as white crystals (0.7 g), m.p. 163-165° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:10]([NH:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:14]=1)=[O:11].[S:32]1[CH:36]=[C:35]([CH:37]=O)[N:34]=[CH:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>ClCCCl>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][C@H:9]([NH:8][CH2:37][C:35]2[N:34]=[CH:33][S:32][CH:36]=2)[C:10]([NH:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:14]=2)=[O:11])=[CH:30][CH:29]=1
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)Nc1cc(-c2ccncc2)no1
Reactant: O=Cc1cscn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2ccncc2)no1)[C@H](Cc1ccc(Cl)cc1)NCc1cscn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 6.7 %

Procedure:
To a 20 ml vial were added (S)-2-amino-3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)propanamide 3.1.C (50 mg, 0.15 mmole), thiazole-4-carbaldehyde (20 mg, 0.18 mmole), sodium triacetoxyborohydride (62 mg, 0.29 mmole), 5 ml of DCE, and DIEA (97 μl, 0.15 mmole). The reaction was stirred at 70° C. for 12 hours. The reaction was then partitioned between 10 ml of water and 20 ml of DCM and the solvent was removed by rotary evaporation. The crude was purified using reverse phase preparative HPLC to give 5.55 mg of (S)-3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)-2-(thiazol-4-ylmethylamino)propanamide TFA salt 3.1 as a clear film (5.6 mg, 9% yield). LCMS ESI (pos.) m/e: 440.1 (M+1): 1H NMR (500 MHz, MeOH) δ ppm 9.01 (d, J=1.71 Hz, 1H), 8.76-8.78 (m, 2H), 8.19 (d, J=6.60 Hz, 2H), 7.69 (dd, J=13.82, 8.68 Hz, 1H), 7.24 (d, J=1.96 Hz, 1H), 7.13 (d, J=8.31 Hz, 2H), 6.99 (d, J=8.31 Hz, 2H), 4.35-4.45 (s, 1H), 4.26 (m, 2H), 3.34 (dd, J=8.56, 5.87 Hz, 1H), 3.17 (dd, J=13.69, 5.87 Hz, 1H).
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7][CH2:6]1.Cl[C:16]1[N:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[N:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=3)[CH2:13][C@@H:8]2[CH2:7][CH2:6]1
Reactant: Fc1cnc(Cl)nc1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Temperature: 25 °C
Yield: 114.7 %

Procedure:
A solution of 4.41 g (18.2 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine dihyrochloride (Preparation 1), 3.78 g (28.5 mmol) of 2-chloro-5-fluoropyrimidine (B. Baasner, E. Klauke J. Fluroine Chem., 1989, 45, 417-430), and 9.07 g (85.6 mmol) of sodium carbonate in 180 mL of water were heated at 95° C. for 16 h. The mixture was cooled to room temperature, extracted with chloroform (2×), dried (magnesium sulfate), filtered and evaporated. Purification by flash chromatography on silica gel using 95:5 chloroform:methanol gave 5.56 g (81%) of title compound. mp 148-149.5° C. 13C NMR (CDCl3): δ26.8, 29.0, 39.1, 44.2, 49.7, 54.8, 58.7, 60.8, 66.2, 145.0, 145.3, 149.9, 153.2, 158.7. Anal calcd for C13H19FN4O: C, 58.63; H, 7.19; N, 21.04; found: C, 58.36; H, 7.18; N, 20.87.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](C)([C:21]([O-])=O)[C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:21])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 200 °C

Procedure:
Ethyl 2-(2', 4'-difluoro-4-biphenylyl)-2-methylmalonate (5.42 g.) was refluxed for 2 hours with a mixture of 2.5N aqueous sodium hydroxide (27 ml.) and ethanol (13.5 ml.). The solution was then evaporated to a small bulk; the solid sodium salt was dissolved in water and the solution acidified with dilute hydrochloric acid. The resulting precipitate of crude 2-(2',4'-difluoro-4-biphenylyl)-2-methylmalonic acid was decarboxylated by heating for 20 minutes at 200°C. The product was purified by preparative layer chromatography using 5% acetic acid/petroleum ether b.p. 60°-80°C. and eluting with ethyl acetate; recrystallisation from petroleum ether b.p. 80°-100°C. gave 2-(2',4'-difluoro-4-biphenylyl)propionic acid, m.p. 125°-127°C.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>C(O)C>[CH3:17][N:13]1[C:14]2=[CH:15][N:22]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: CCOC(=O)CCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (1.38 g, 4.09 mmol), ethyl 5-aminovalerate hydrochloride (1.109 g, 6.14 mmol) and triethylamine (1.711 mL, 12.28 mmol) were combined in ethanol (20 mL) and the mixture heated at reflux for 40 mins. The reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was partitioned between water and DCM and the phases separated. The organic phase was passed through a hydrophobic frit and evaporated onto silica. The silica was deposited onto a 25 g silica cartridge and the system eluted with 20% EtOAc/hexane, 40% EtOAc/hexane, 60% EtOAc/hexane and 80% EtOAc/hexane. The product fractions were combined and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(=O)N([Br:19])C(=O)C1>C1COCC1.OS(O)(=O)=O>[Br:19][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(N)cc1OC
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1cc(N)c(Br)cc1OC
Temperature: 25 °C

Procedure:
To a solution of 3,4-dimethoxybenzenamine (20.0 g, 0.130 mol) in dry THF (200 mL) was added concentrated H2SO4 (20 drops) under N2 at −78° C. After 10 mains, NBS (23.2 g, 0.130 mol) was added in potions at −78° C. Then the reaction mixture was allowed to gradually warm up to room temperature over 1 hour. THF was removed under reduced pressure. The residue was diluted with EtOAc (200 mL), and washed with water (80 mL×3). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (15:1 hexanes/ethyl acetate) to afford 2-bromo-4,5-dimethoxyaniline as a yellow solid. MS (M+H)=232 and 234.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:11]=[C:10]([CH3:12])[NH:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(O[C:22]([CH3:25])([CH3:24])[CH3:23])(=O)C>C(O)(=O)C>[CH3:6][C:7]1[C:11]([C:22]([CH3:25])([CH3:24])[CH3:23])=[C:10]([CH3:12])[NH:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(C)c(C(C)(C)C)c1C

Procedure:
A solution of acetic acid (5.0 ml), sulfuric acid (1.2 ml), ethyl 3,5-dimethylpyrrole-2-carboxylate 5a (5.0 g, 0.03 mol) and tert-butyl acetate (3.5 g, 0.03 mol) was heated at 75° C. for 2 h and combinedwith sodium carbonate (8 g) in ice water (100 ml) to bring about the precipitation of ethyl 3,5-dimethyl-4-tert-butylpyrrole-2-carboxylate 4g as a colorless solid, mp 108°-110° C. (lit. 107°-109° C.), 3.1 g (47%); 1H NMR (CDCl3): δ 9.80 (s, 1H), 4.28 (q, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 1.35 (s, 9H), 1.33 (t, 3H).
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.CC(OC)(C)C>[F:17][C:16]([F:18])([F:19])[CH2:15][O:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:13])([F:11])[F:12])[C:4]#[N:5]
Reactant: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: N#Cc1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Yield: 79.1 %

Procedure:
To a solution of 2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile from step 4 (14.47 g, 50.9 mmol) in dry THF (153 mL) was added isoamyl nitrite (15.0 mL, 112.0 mmol), and the mixture was refluxed for 20 h. The solvent was removed in vacuum to give an orange oil, which was dissolved in TBME, washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown solid (15.05 g), which was purified by Kugelrohr distillation (up to 155° C. bath temperature at 1.2 mbar) to give the title compound as a light yellow solid (10.83 g, 79%). MS (EI) 269 [M].
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH:7]=[CH2:8])[CH3:5])[CH:2]=[CH2:3].[Cl:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]>CC(C)=O>[Cl-:9].[C:11]([CH2:10][N+:4]([CH3:5])([CH2:6][CH:7]=[CH2:8])[CH2:1][CH:2]=[CH2:3])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCl
Reactant: C=CCN(C)CC=C
Solvent: CC(C)=O
Product: C=CC[N+](C)(CC=C)CC(=O)OC
Product: [Cl-]
Reaction time: 48 h
Yield: 82.6 %

Procedure:
To a solution of diallyl methylamine (17.90 g) in acetone (35 ml) was added methyl chloracetate (17.47 g). The mixture was allowed to stand at ambient temperature for 48 hours. The solvent was then removed by evaporation under reduced pressure. The residue, a thick oil, was made more mobile by the addition of isopropanol (5.0 ml) and the product re-precipitated by the addition of ether (700 ml). The product separated as a heavy oil. The ether layer was decanted and the product again mobilised by the addition of isopropanol (5.0 ml). Any residual ether and the isopropanol were removed by evaporation under a vacuum of 1 mmHg and gentle heating. The product N-carbomethoxy methyl-N-methyl-N,N-diallyl ammonium chloride (29.20 g) was isolated as a pale yellow oil (free from starting materials by glc).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.C=C[C@@H:16](C)[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2(C)[C:24](=CC(=O)C[CH2:28]2)CC3)[CH2:19][CH2:18]1.[CH3:38][C:39]([CH3:41])=[O:40]>>[CH3:16][C@H:17]1[CH2:18][CH2:19][C@H:20]2[C@H:21]3[C@H:31]([CH2:32][CH2:33][C@:34]12[CH3:35])[C@:29]1([CH3:28])[C:41](=[CH:1][C:2](=[O:3])[CH2:4][CH2:24]1)[C:39](=[O:40])[CH2:38]3
Reactant: CC(C)=O
Reactant: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
Refer to FIG. 189. Jones reagent (2.67 M, 0.88 ml, 2.3 mmol) was added to a solution of 17β-methylandrost-5-en-3β-ol (5, 135.5 mg, 0.4697 mmol) (J. B. Jones and K. D. Gordon, Can. J. Chem. 1972, 50, 2712-2718) in acetone (15 ml) and the mixture was 10 stirred 45 min. The reaction was quenched with the addition of 2-propanol (0.44 ml). After stirring a further 10 min. the reaction mixture was poured into 30 ml of water and extracted with three 15 ml portions of ethyl acetate. The combined organic extracts were washed with 15 ml of saturated sodium bicarbonate+15 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (silica gel GF, 1000μ, 25% ethyl acetate/hexanes as eluent), and recrystallization from aqueous ethanol gave lustrous off-white crystals (37.5 mg, 0.125 mmol, 27%), m.p. 94-95° C., homogeneous to TLC (25% ethyl acetate/hexanes on silica gel, Rf 0.39).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.N([O-])=O.[Na+].[Br-:15]>Br>[Br:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCC2
Reactant: [Br-]
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1ccc2c(c1)CCC2
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
5-Aminoindane was treated with concentrated hydrobromic acid. The suspension was cooled to −5° C., and 5 M sodium nitrite solution was added at a temperature between 0° C. to 5° C. in period of 30 minutes through an addition funnel. Stirring was continued for 20 minutes at 0° C. to 5° C. The reaction mixture was now very dark fluid slurry. In a second reaction vessel, a solution of cupper (I) bromide in concentrated hydrobromic acid had been prepared and preheated to 40° C. When the diazonium salt slurry was added in portions, a very slow gas evolution was observed which became vehement when heating to 60° C. After stirring at 60° C. for 40 min, the gas evolution ceased. The mixture was poured onto water. The product was extracted twice with ethyl acetate. Some of the precipitated copper bromide was removed by filtration to facilitate phase separation. The organic extracts were washed twice with water and one time with brine. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. After flash chromatography, the title compound was obtained as pale yellow oil.
Reaction SMILES: C1([O:7][C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]([C:22](=[O:31])[C:23]4[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=4[F:30])=[C:19]([NH2:21])[N:20]=3)=[CH:11][C:10]=2[OH:32])C=CC=CC=1.[C:34]1([NH:40][CH2:41][CH2:42][NH2:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[NH2:21][C:19]1[N:20]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:43][CH2:42][CH2:41][NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:7])=[C:10]([OH:32])[CH:11]=2)[S:17][C:18]=1[C:22](=[O:31])[C:23]1[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Nc1nc(Nc2ccc(C(=O)Oc3ccccc3)c(O)c2)sc1C(=O)c1c(F)cccc1F
Reactant: NCCNc1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccc(C(=O)NCCNc3ccccc3)c(O)c2)sc1C(=O)c1c(F)cccc1F

Procedure:
A solution of 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-2-hydroxy-benzoic acid phenyl ester (16) and N-phenyl-ethylene-diamine (5 eq) in DMF was heated at 70° C. for 1 hour. DMF was removed under reduced pressure and the solution of resultant residue in ethyl acetate was washed with saturated aqueous NaHCO3 solution, brine, dried with MgSO4, filtered and concentrated. The product was purified by HPLC.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]1([CH3:34])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:34])[CH2:29][CH2:30]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3C)CC2)c(OC)nc1C
Yield: 89 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-tolyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.