Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH3:23])=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:24][O-:25].[Na+].O>CN(C=O)C>[CH3:23][C:3]1[C:2]([O:25][CH3:24])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1
Reactant: Cc1c(N2CCC(N3CCCCC3)CC2)ccc([N+](=O)[O-])c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])ccc(N2CCC(N3CCCCC3)CC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.7 %

Procedure:
To 1′-(3-chloro-2-methyl-4-nitrophenyl)-1,4′-bipiperidine (0.50 g, 1.5 mmol) in DMF (15 mL) was added sodium methoxide (0.97 g, 1.8 mmol) at 0° C., and the mixture was stirred at rt overnight. The mixture was poured into H2O, extracted with EtOAc, washed with H2O, dried and concentrated to provide the title compound of step B (0.53 g, 1.6 mmol, 100% crude). 1H NMR (400 MHz, CDCl3) δ ppm 1.41-1.50 (m, 2H), 1.61-1.71 (m, 4H), 1.70-1.81 (m, 2H), 1.91-2.01 (m, 2H), 2.25 (s, 3H), 2.35-2.45 (m, 1H), 2.51-2.60 (m, 4H), 2.65-2.75 (m, 2H), 3.21-3.30 (m, 2H), 3.9 (s, 3H), 6.75 (d, J=9.2 Hz, 1H), 7.75 (d, J=9.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1nc(-c2ccc(Cl)cc2)co1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g), benzyl bromide (0.25 ml), potassium carbonate (0.33 g) and dimethylformamide (DMF)(10 ml) was stirred for 3 hours at room temperature. The reaction mixture was poured into water to obtain crystals of benzyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.664 g, 98%). Recrystallization from ether-hexane gave colorless prism crystals of mp 66°-67° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30](=[O:31])[NH:14][CH:7]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[CH:22][CH:23]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CNC(=O)CCc1ccc(Cl)cc1
Agent: Cl
Product: O=C(CCc1ccc(Cl)cc1)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and [3-(4-chloro-phenyl)-propionylamino]-acetic acid (Example 2.1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[N:9][NH2:10])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:20](O)=O.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(OCC)(OCC)OCC>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[CH:20]=[N:10][N:9]=[C:8]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: NN=C(Nc1cccc(F)c1F)c1nccnc1N
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(OCC)OCC
Product: Nc1nccnc1-c1nncn1-c1cccc(F)c1F
Reaction time: 0.5 h
Yield: 92 %

Procedure:
3-Amino-N-(2,3-difluorophenyl)-N′-aminopyrazine-2-carboxamidine (500 mg, 1.89 mmol) was dissolved in CH(OEt)3 (20 mL) and HCOOH (5 mL) was added slowly at RT. The solution was kept at RT for 30 min and carefully neutralized with saturated NaHCO3 and 6N NaOH until a pH of 10 was achieved. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated to produce 3-(4-(2,3-Difluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine as yellow solid (480 mg, 92%). A small amount of the crude product was purified by HPLC for characterization and the remainder used directly in the next reaction without further purification. LC-MS m/e=274.8 (M+H). Using the same procedure, 3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, 3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, and 3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine can be produced from 3-amino-N-(2,3-dichlorophenyl)-N′-aminopyrazine-2-carboxamidine, 3-amino-N-(3-chloro-2-fluorophenyl)-N′-aminopyrazine-2-carboxamidine, 2-amino-N-(2,3-difluorophenyl)-N′-aminopyridine-3-carboxamidine, 2-amino-N-(2,3-dichlorophenyl)-N′-aminopyridine-3-carboxamidine, and 2-amino-N-(3-chloro-2-fluorophenyl)-N′-aminopyridine-3-carboxamidine, respectively.
Reaction SMILES: [Cl-].[Li+].O1CCCC1.O.[OH:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:11]([N:13]([CH3:18])[C:14](=[O:17])[CH2:15][NH2:16])[CH3:12].I[CH2:26][CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1>O>[NH2:16][CH:15]([CH2:26][CH2:27][CH2:28][CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[C:14]([N:13]([CH:11]([CH3:12])[CH:10]([OH:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])=[O:17]
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)CN
Reactant: ICCCC1OCCO1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(O)c1ccccc1)N(C)C(=O)C(N)CCCC1OCCO1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A 0.5 liter, 4-necked, round-bottom flask, equipped with an overhead stirrer, thermocouple, addition funnel and a nitrogen inlet/outlet was charged with 11.4 g of lithium chloride (dried in vacuo at 130° C. for 6 hours and then at 100° C. for 18 hours prior to use), 9.1 g of diisoproylamine and 80 ml of tetrahydrofuran. After cooling to −78° C., a 2.5 M solution of n-butyllithium in hexanes (35 ml) was added over about 20 minutes while maintaining the temperature at less than or equal to −60° C. This mixture was allowed to stir at −78° C. for 45 minutes. A tetrahydrofuran solution of [R-(R*,R*)]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-α-aminoacetamide monohydrate [10 g., 0.04 mol, prepared as described by Myers et al., Tetrahedron Letters, Vol. 36, p. 4555-4558 (1995)] was added over 50 minutes while maintaining the temperature at less than or equal to−68° C. After the addition was complete, the mixture was stirred for an additional 45 minutes. The solution was allowed to warm to about 0° C. and held at that temperature for 45 minutes. The 2-(3-iodopropyl)-1,3-dioxolane (12g) from part (a) was added as a tetrahydrofuran (10 ml) solution in one portion. After 3 hours reaction time at 0° C., TLC analysis indicated no observable starting material present and water (100 ml) was added as a quench. The tetrahydrofuran/hexane phase was separated from the lower aqueous phase. The aqueous phase was extracted with methylene chloride (4×100 ml). The methylene chloride phases were combined with the tetrahydrofuran/hexane phase and washed with 100 ml of brine. After drying over sodium sulfate and filtration, concentration in vacuo (bath temperature less than or equal to 40° C.) afforded an oil (9.57g). The oil was chromatographed over silica gel 60 (column size: 3.5 cm×21 cm) eluting with 5% triethylamine in methylene chloride, collecting 100 ml fractions. Fractions number 6 through 12 were combined and concentrated in vacuo (bath temperature less than or equal to 45° C.) to afford an oil. This oil was dissolved in toluene (100 ml) and concentrated to remove residual triethylamine and give 4.54 g of the desired product as an oil.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C(=O)(O[CH2:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)OCC>>[C:17]1([CH:16]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH2:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)OCC=Cc1ccccc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: C=CC(Oc1ccccc1)c1ccccc1
Reaction time: 32 h
Yield: 81.3 %

Procedure:
By the procedure for entry 9 of Table 1, the reaction of sodium phenoxide (232 mg, 2.00 mmol) and ethyl cinnamyl carbonate (192 mg, 0.930 mmol) with [(COD)IrCl]2 (6.7 mg, 0.010 mmol) and L1 (Sa,Sc,Sc) (10.8 mg, 0.0200 mmol) as catalyst was conducted at room temperature for 32 h. 1H NMR analysis of the crude reaction showed the ratios of branched to linear products to be 99/1. After purification, 159 mg of the title compound (75%) was isolated. HPLC analysis as described above indicated that the enantiomeric excess of the major product was 94%.
Reaction SMILES: [CH3:1][C:2]1([C:10]([OH:12])=[O:11])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:9])[F:8].[C:13](OC)(=O)C(C)=C.FC(F)=C(F)Cl>C1(C=CC(O)=CC=1)O>[CH3:1][C:2]1([C:10]([O:12][CH3:13])=[O:11])[CH2:5][C:4]([F:7])([F:6])[C:3]1([Cl:9])[F:8]
Reactant: C=C(C)C(=O)OC
Reactant: CC1(C(=O)O)CC(F)(F)C1(F)Cl
Agent: FC(F)=C(F)Cl
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1(C)CC(F)(F)C1(F)Cl
Temperature: 140 °C
Yield: 54 %

Procedure:
One drop of dimethylformamide is added to a mixture 91.2 g (0.45 mol) of 1-methyl-2,3,3-trifluoro-2-chloro-cyclobutane-1-carboxylic acid and 450 ml of chloroform. After this, 80.3 g (0.675 mol) of thionyl chloride are added dropwise at 25°-30° C. with stirring, and the stirred mixture is heated to the boil. After 6 hours the mixture is cooled, the solvent is stripped off, and the residue is subjected to fractional distillation under reduced pressure. 75 g (75% of theory) of 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carbonyl chloride are obtained in form of a liquid of boiling point 65 - 70° C. at 20 mbar. ##STR61## 108.3 g (0.5 mol) of methyl 1-methyl-2-th(oro-2,3,3-trifluoro-cyclobutane-1-carboxylate are added dropwise at 20°-25° C. in the course of 15 minutes to a stirred solution of 127.3 g of potassium hydroxide in 540 ml of methanol. Stirring is continued for 12 hours at 20°-25° C., and part of the methanol is then stripped off under reduced pressure. The residue is diluted with water, and the mixture is extracted using methylene chloride. The aqueous phase is acidified using dilute hydrochloric acid and extracted using methylene chloride. The combined organic phases are dried and concentrated under reduced pressure. 93.3 g of an oil are obtained which consists of 99% 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carboxylic acid. The yield is thus calculated at 90% of theory. 174 g (1.74 mol) of methyl methacrylate and 1.5 g o& hydroquinone are initially introduced into an autoclave, and 200 g (1.74 mol) of trifluorochloroethylene are added at -70° C. 7 bar of nitrogen are injected, and the mixture is then heated to 140° C. The pressure which is established at this temperature is increased to 28 bar by injecting more nitrogen. The mixture is maintained at 140° C. for 17 hours and then allowed to cool, the pressure is released, and the mixture is distilled. In this process, 203 g (54% of theory) of methyl 1-methyl-2-chloro-2,3,3 -trifluoro-cyclobutane-1-carboxylate are obtained in form of a liquid of boiling point 57° C. at 17 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:20][C@H:10]2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:5][CH:4]=1.ClC1C=CC=CC=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35]>CO>[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: Nc1ccccc1S
Reactant: COc1ccc([C@@H]2O[C@H]2C(=O)Nc2ccccc2)cc1
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxy-N-phenylpropionamide (539 mg) and chlorobenzene (5 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (275 mg) and ferric chloride hexahydrate (0.054 mg) in methanol (0.1 ml) is added immediately to the reaction mixture. The mixture is stirred at the same temperature for 5 minutes, and cooled to room temperature. The precipitated crystals are collected by filtration, washed with chlorobenzene, and dried at 50° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-phenylpropionamide (582 mg).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]=[O:27])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:29][Mg+].[Br-]>C1COCC1>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]([OH:27])[CH3:29])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C[Mg+]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C=O)cccn34)c(C)nc12
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)O)cccn34)c(C)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A solution of 3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-imidazo[1,2-a]pyridine-8-carboxaldehyde (1.07 g, 2.84 mmol) in THF (30 mL) is cooled at 0° C., treated with 3.0 M CH3MgBr (1.1 mL, 3.41 mmol). The reaction is stirred at 0° C. for 30 min. It is then quenched with sat. NH4Cl (15 mL), diluted with H2O (15 mL), extracted with EtOAc (2×30 mL). The combined organic layers is dried with Na2SO4, filtered and concentrated. Purification of the crude material by silica gel chromatography gives the title compound (0.93 g, 2.38 mmol, 83). 1H NMR (CDCl3): δ 0.91 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.1 Hz, 3H), 1.75 (d, J=6.6 Hz, 3H), 1.79-1.94 (m, 4H), 2.41 (s, 6H), 2.45 (s, 3H), 3.32-3.42 (m, 1H), 5.17 (m, 1H), 5.39 (m, 1H), 6.72 (t, J=7.0 Hz, 1H), 6.73 (s, 1H), 7.13 (d, J=7.1 Hz, 1H), 7.43 (d, J=7.1 Hz, 1H) ppm. ES-MS (m/z): calcd for C23H29N5O (M+H)+: 392.5. found: 392.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCC=Cc1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCc1ccccn1
Yield: 91.4 %

Procedure:
7-(2-Pyridyl)-6-heptenoic acid (0.97 g, 4.7 mmol) was dissolved in ethanol (15 ml), and 10% palladium-carbon (0.16 g) and a solution of ammonium formate (1.7 g, 27.0 mmol) in water (2 ml) were added thereto. The reaction mixture was refluxed for 2 hrs. Palladium-carbon was filtered off. The reaction mixture was combined with water, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give the titled compound (0.89 g, 91%).
Reaction SMILES: Br[C:2](=[N:12][OH:13])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[CH3:5][C:4]([CH3:7])([CH3:6])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:2](=[N:12][OH:13])[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CNC(=O)C(C(Br)=NO)C(C)(C)C
Reactant: C1CCNC1
Solvent: CCOCC
Product: CNC(=O)C(C(=NO)N1CCCC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 12.6 g of 1-bromo-3,3-dimethyl-2-methylcarbamyloximinobutane in 100 ml of anhydrous ether is added, dropwise, 7.8 (0.11 m) of pyrrolidine. The mixture is stirred at room temperature for 1 hour and at reflux for 0.5 hour, then cooled and washed with water. The ether solution is separated, dried, and stripped of solvent to give 11.8 g of amber oil which solidifies on standing to an amber solid, m. 43°-46° C. Properties of this and analogous compounds prepared by substantially the same procedure are shown in Tables 5 and 6.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH:36]=O)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.4 %

Procedure:
A solution, cooled to 0° C., of 90.9 g of tetrabromomethane in 100 ml of methylene chloride was treated under argon gasification within 20 minutes with a solution of 143.9 g of triphenylphosphine in 200 ml of methylene chloride. The clear orange solution was stirred at 0° C. for a further 5 minutes and then treated dropwise within 10 minutes at 0° C. with a solution of 25 g of trans-4-pentylcyclohexanecarboxaldehyde (purity about 82%) in 80 ml of methylene chloride. After stirring at 0° C. for 30 minutes, the mixture was poured into 2.5 l of hexane and the precipitate which separated was filtered off. The filtrate was concentrated, digested with 1 l of hexane, filtered and again concentrated. Low-pressure chromatography (0.5 bar) of the residue (52.7 g) on silica gel with hexane gave 35.9 g (77.4%) of trans-1-(2,2-dibromovinyl)-4-pentylcyclohexane as a colourless oil; Rf-value (hexane) 0.58.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[N:6][CH:7]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:22]([C:19]2[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[CH:17][CH:18]=2)=[O:24])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: NN1CCOCC1
Reactant: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)O)nn1
Product: Cn1nnc(-c2ccc(F)cn2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 56 %

Procedure:
As described for example 51c, 6-[5-(5-fluoro-pyridin-2-yl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (50 mg, 0.15 mmol) was converted, using N-aminomorpholine instead of 2-amino-2-methyl-1-propanol, to the title compound (35 mg, 56%) which was obtained as a light yellow solid. MS: m/e=415.3 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[K].[NH2:14][C@H:15]([C:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17]>[Cl-].C[N+](C)(C)C.S1(CCCC1)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[NH:14][CH:15]([CH:16]([CH3:18])[CH3:17])[C:19]([OH:21])=[O:20]
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 125 °C

Procedure:
A mixture of 3.04 parts of 3-chloro-4-fluorobenzotrifluoride, 4.5 parts of anhydrous potassium salt of valine, 0.98 parts of tetramethyl-ammonium chloride and 24.0 parts of sulfolane solvent was charged to a reaction vessel, the mixture was heated to 125° C. and maintained thereat for about 16 hours then cooled, diluted with water and acidified to a pH of 1. The aqueous layer was extracted several times with diethyl ether. The ether layer was then washed with copious amounts of water, then dried and concentrated to yield 3.4 parts of 2-(2-chloro-4-trifluoromethylphenyl-amino)-3methylbutanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]3)=[N:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:14].[C:33](O)(=O)C.C=O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][N:29]([CH3:33])[CH2:28]3)=[N:24][CH:23]=2)=[CH:20][CH:21]=1)=[O:14]
Reactant: O=C(Nc1ccc(-c2cnc(C3(O)CCNC3)s2)cc1)Nc1cc(C(F)(F)F)ccc1F
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: CN1CCC(O)(c2ncc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)s2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To an ambient solution of Example 14 (0.050 g, 0.107 mmol) in methanol containing 1% v/v acetic acid 1 mL) was added formaldehyde (0.012 mL, 0.161 mmol, 37 wt % in H2O) and MP-CNBH3 (0.054 g, 0.161 mmol, 3.0 mmol/g). The reaction was heated to 50° C. and shaken for 16 h. The reaction was then filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min). The fractions containing the desired product were diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.01-2.13 (m, 1H), 2.25-2.33 (m, 3H), 2.35-2.46 (m, 1H), 2.51-2.58 (m, 1H), 2.73-2.94 (m, 3H), 6.22-6.31 (m, 1H), 7.37-7.44 (m, 1H), 7.47-7.56 (m, 3H), 7.56-7.62 (m, 2H), 7.98 (s, 1H), 8.62 (m, 1H), 8.92 (m, 1H), 9.32 (s, 1H); MS (ESI) m/z 481 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][CH:28]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[I:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:32][CH:31]=1
Reactant: Ic1ccc(CCCCCCCCCCCCCCCCCCOCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Reaction time: 2 h

Procedure:
Finally, to a solution of 1-benzyloxy-18-(p-iodophenyl)octadecane (Compound V) (185 mg; 0.33 mmol) and anisole (0.15 ml; 1.32 mmol) in dichloromethane (3 ml) was added anhydrous aluminum chloride (135 mg; 1 mmol) at the room temperature. Stirring was continued for 2 h. The reaction was quenched by diluted hydrochloric acid and extracted by chloroform. Extract was dried (Na2SO4) and evaporated. The residue was chromatographed in hexane-ethyl acetate (gradient from 95:5 to 85:15) to give 18-(p-iodophenyl) octadecanol, Compound VI (123 mg; 77%).