Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=O)(C)(C)C.Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2>>[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:15]2[C:16]3[CH:17]=[CH:18][N:19]=[CH:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH2:9]1
Reactant: Brc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Product: c1cc(N[C@H]2CCNC2)c2ccncc2c1

Procedure:
Reaction of (S)-tert-butyl3-aminopyrrolidine-1-carboxylate and 5-bromoisoquinoline using the method of Example 16 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C@H:12]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[NH2:13])=[CH:3]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OC(C)C)(C)C>C(O)(C)C>[C:19]1([C:17]2[N:18]=[C:14]([C@H:12]3[CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[NH:2][C:3]=4[C:35]4([CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)[NH:13]3)[NH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N[C@@H](c1nc(-c3ccccc3)c[nH]1)Cc1c2[nH]c2ccccc12
Yield: 79.8 %

Procedure:
To a solution of (1R)-2-(1H-indol-3-yl)-1-(4-phenyl-1H-imidazol-2-yl)-1-ethanamine hydrochloride (14 g, 35 mmol) in isopropanol (210 ml) was added 1-tert-butoxycarbonyl-4-piperidone (35 g, 170 mmol) and the mixture refluxed for about two hours. The solvent was evaporated under reduced pressure. Water (150 ml) was added to the residue followed by 10% NaHCO3 solution until neutral pH and extracted by ethyl acetate (4×50 ml). The combined organic extracts were washed with water (2×50 ml) and dried over MgSO4. The solvent was removed under reduced pressure to afford an oil which solidified on addition of diisopropyl ether (150 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried to afford 13.5 g of the desired product. Melting point: 118-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:13][CH:14]=O.C(OCC)(=O)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[CH:14][N:11]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(F)cc1
Reactant: O=CCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1ccc(Nc2nccs2)cc1
Temperature: 80 °C

Procedure:
1-(4-fluorophenyl)thiourea (2.00 g, 11.7 mmol) and 2-chloroacetaldehyde(3.72 mL, 58.6 mmol) in anhydrous ethanol (5 mL) were added to a microwave vial. The reaction mixture was heated to 80° C. in a microwave reactor for 20 min. On cooling, ethyl acetate (2 mL) was added to the crude product reaction mixture and pure product crystallized out. This filtered off, washed with hexane and air-dried to afford the title compound as a crystalline brown solid, 1.568 g. MS (M+H)+ 195.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[O:28][C@H:27]([CH2:29][O:30]C(=O)C3C=CC(Cl)=CC=3)[C@@H:16]([O:17]C(=O)C3C=CC(Cl)=CC=3)[CH2:15]2)=[C:7]([NH:40][Si](C)(C)C)[N:6]=1>CO>[Cl:4][C:5]1[N:6]=[C:7]([NH2:40])[C:8]2[N:9]=[CH:10][N:11]([C:12]=2[N:13]=1)[C@@H:14]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:16]([OH:17])[CH2:15]1
Reactant: C[Si](C)(C)Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a mixture of 25% sodium methoxide in MeOH (0.11 Kg, 0.5 mol, 0.1 eq.) and MeOH (14.8 Kg, 5 P) at about at 25° C. was added 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofurano syl]-purine (IVa) and non-silylated derivative 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2′-deoxy-β-D-ribofuranosyl]-purine (IVb) (3.70 Kg, combined HPLC purity of >96.3%) and the mixture was agitated at about 25° C. for 2 hours. The solids were filtered, washed with MeOH (1.11 Kg, 0.4 P) and then dried in vacua at 60° C. for 4 hours to give 1.43 Kg of a crude cladribine with 97.8% HPLC purity in ca. 87% yield.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[C:2]([F:1])=[CH:3][C:4]([F:13])=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: O=C1COc2cc(F)cc(F)c2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2cc(F)cc(F)c2N1CCCCl
Yield: 50 %

Procedure:
5,7-Difluoro-4H-benzo[1,4]oxazin-3-one (0.24 g, 1.3 mmol), Cs2CO3 (1.08 g, 3.3 mmol), and 1-chloro-3-iodopropane (0.296 g, 1.45 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound (0.17 g, 49%). Rf=0.66 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 6.67-6.58 (m, 2H), 4.55 (s, 2H), 4.16-4.10 (m, 2H), 3.59-3.52 (m, 2H), 2.21-2.10 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](=[O:18])([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+].[C:27](#N)[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:27][CH2:28][O:18][CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: O=C([O-])[O-]
Reactant: CC#N
Agent: [K+]
Agent: [Na+]
Product: COCCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.29 g, 1.45 mmol), acetonitrile (15 mL), potassium carbonate (0.4 g, 2.9 mmol) and 2-bromoethylmethyleter (0.145 mL, 1.55 mmol) was stirred at ambient temperature for 4 h. and then at 80° C. for 1 h. Aqueous sodium carbonate (10%, 5 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 10:1) gave the title compound (0.157 g). [α]D=−18.9° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 130-131° C.; MS m/z (relative intensity, 70 eV) 257 (M+, 2), 212 (bp), 182 (52), 127 (12), 213 (12), 58 (8).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=O>C(O)C>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[S:15][C:26]4[CH2:27][CH2:28][CH2:29][CH:24]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:18][CH:19]=5)[C:25]=4[N:16]=3)=[CH:11][CH:12]=2)=[CH:5][N:6]=1
Reactant: Cc1ncc(-c2ccc(NC(N)=S)cc2)o1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: Cc1ncc(-c2ccc(Nc3nc4c(s3)CCCC4c3ccccc3)cc2)o1
Yield: 43.8 %

Procedure:
A solution of [4-(2-methyl-oxazol-5-yl)-phenyl]-thiourea (100 mg, 0.43 mmol) and 2-bromo-6-phenyl-cyclohexanone (114 mg, 0.45 mmol) in ethanol (5 mL) was heated to reflux over night. The solvent was removed under reduced pressure and the residue purified on silica gel using methylene chloride and methylene chloride/methanol (19:1 v/v) as eluent to yield the title compound (73 mg, 44%) as a yellow gum. MS ISP (m/e): 388.2 (100%) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.18 (s, 1H), 7.49 (m, 4H), 7.11-7.29 (m, 6H), 4.04 (m, 1H), 2.70 (m, 2H), 2.43 (s, 3H), 2.14 (m, 1H), 1.70-1.93 (m, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][N:5]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4]1
Reactant: BrCCCc1ccccc1
Reactant: CC1(O)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(CCCc2ccccc2)C1
Reaction time: 12 h
Yield: 70.4 %

Procedure:
According to Example 15, 3-methylpyrrolidin-3-ol hydrochloride was synthesized. To a 100 mL reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (1 g, 7.2 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol) and acetonitrile (15 mL). To the resulting mixture was slowly added a solution of 3-bromopropylbenzene (1.29 g, 6.48 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. To the residue was added a mixed solution of dichloromethane and water for extraction. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce a crude product. The crude product was purified by column chromatography (silica gel column, eluted with petroleum ether: ethyl acetate=10:1 (volumetric ratio)) to produce 3-methyl-1-(3-phenylpropyl)pyrrolidin-3-ol (1 g) in a yield of 70.4%.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[Br:20]Br>C(Cl)Cl>[Br:20][CH:2]([CH2:3][CH3:4])[C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CCCC(=O)c1ccc(NC(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(Br)C(=O)c1ccc(NC(C)=O)cc1
Reaction time: 0.17 h

Procedure:
Step-2: A solution of N-(4-butyryl-phenyl)acetamide (3.47 g, 16.9 mmol) in 100 mL of anhydrous DCM was cooled to 0° C. under N, and treated with AlCl3 (180 mg, 1.35 mmol). Approximately 10 mL of Br2 was added and the mixture was stirred for 10 min. The reactor was removed from the cooling bath and the remaining Br2 was added dropwise via syringe over 0.5 min. After 3 hr, the dark orange color of Br2 had faded and by 3¼ hr a precipitate had formed. The reaction was quenched with saturated NaHCO3. The phases were separated and the aqueous phase extracted three times with DCM. The combined extracts were dried over Na2SO4, filtered through a Celite® pad and concentrated in vacuo to give N-(4-(2-bromobutanoyl)phenyl)acetamide which was used without purification. MS ESI: m/z 284.10 [M+].
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]2[O:14][CH:13]([CH2:15][OH:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:18][C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[O:20].[H-].[Na+].O>CS(C)=O>[CH2:22]([N:21]([CH2:25][CH2:26][CH3:27])[C:19](=[O:20])[CH2:18][O:16][CH2:15][CH:13]1[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:14]1)[CH2:23][CH3:24]
Reactant: OCC1CCC(COCc2ccccc2)O1
Reactant: CCCN(CCC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCC)C(=O)COCC1CCC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A mixture of 4.44 g of tetrahydro-5-[(phenylmethoxy)methyl]-2-furanmethanol (0.02 mole) and 3.55 g of 2-chloro-N,N-dipropylacetamide (0.02 mole) is dissolved in 125 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly, 0.50 g of sodium hydride (0.02 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4×300 ml portions of water. The CHCl 3 is then removed in vacuo yielding a pale yellow oil which is vacuum distilled and the fraction distilling at 210°-225° @0.5 mm is collected yielding 5.2 g (72%) of the above compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1>CN(C=O)C>[CH2:22]([N:1]([CH2:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1)[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-aminobenzonitrile (1.0 g, 8.47 mmol, 1 eq), K2CO3 (5.85 g, 42.4 mmol, 5.0 eq) and KI (422 mg, 2.54 mmol, 0.3 eq) in dry DMF (10 mL) was added dropwise BnBr (4.0 mL, 33.9 mmol, 4.0 eq) under Ar(g). The reaction mixture was stirred at rt overnight, and was then partitioned with H2O (30 mL), and subsequently extracted with EtOAc (5×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (9:1-4:1) to furnish the product, 2, as a pale yellow solid (970 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([CH2:10]Br)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:12]([NH2:14])=O.[NH3:15]>>[CH3:1][C:2]1([C:8]2[N:15]=[CH:12][NH:14][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N
Reactant: NC=O
Reactant: CC1(C(=O)CBr)CCCCC1
Product: CC1(c2c[nH]cn2)CCCCC1

Procedure:
A mixture of 387 g. bromomethyl 1-methylcyclohexyl ketone and 1000 ml. formamide was heated with stirring. A stream of ammonia was passed through the reaction mixture over a period of one hour, the mixture being maintained at a temperature of 140°-160° C. After the passage of ammonia had been completed the reaction mixture was heated to 180°-190° C. The reaction mixture was maintained at this temperature for a period of two hours. Excess of formamide was evaporated under reduced pressure and the residue diluted with a little warm water and made alkaline with potassium carbonate. The resulting mixture was extracted with ether. After separation the ethereal extract was washed with water, dried over sodium sulphate, evaporated and distilled to give the novel intermediate 4-(1-methylcyclohexyl)imidazole, b.p. 146°-148° C./0.2 mm. Hg. The distillate crystallized from petroleum ether (b.p. 60°-80° C.) to give the product, m.p. 73°-75° C.
Reaction SMILES: COC(=O)[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[CH3:32][Li].CC[O:36][CH2:37][CH3:38]>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:15]2[CH2:14][C:13](=[C:4]([C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=3)[C:37]([CH3:38])([OH:36])[CH3:32])[CH2:16]2)=[CH:29][CH:28]=1
Reactant: CCOCC
Reactant: [Li]C
Reactant: COC(=O)C(=C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Product: CC(C)(O)C(=C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.044 g (0.1 mmol) of methyl{1-[(4-chlorophenyl)(phenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 5 mL dry ether was cooled to −78° C. under nitrogen. To this was added 0.45 mL of a 1M solution of methyllithium and the resulting solution was stirred at −78° C. for 30 minutes. A second aliquot of 0.45 mL of a 1M solution of methyllithium was added and the solution was allowed to warm to −60° C. After 1 h, the reaction was quenched by addition of 5 mL water and the layers were separated. The aqueous layer was washed with three 10 mL portions of ethyl acetate and the organic extracts were combined, dried over Na2SO4 and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound; 1NMR(CDCl3) δ 1.37 (s, 6H), 3.52 (m, 2H), 4.12 (m, 2H), 4.50 (s, 1H), 6.68-6.76 (m, 3H), 7.22-7.42 (m, 9H); Mass Spectrum: m/e=440 (M+1 35Cl and 442 (M+1 37Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:4]([F:29])[CH:3]=1.ClC1C=CC(C(C2C=CC(Cl)=CC=2)C2C3C(=C(CS(C)=[O:49])C=CC=3)NC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:29])[C:5]([CH:9]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:49])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[C:6]([F:8])[CH:7]=1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3c(F)cc(Cl)cc3F)c[nH]c12
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3c(F)cc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 40 mg (0.09 mmol) of the compound from Example 285 in analogy to the synthesis of the compound from Example 296. 38 mg (92% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[OH:45][C:46]([CH3:50])([CH3:49])[CH2:47][NH2:48].[Cl-].[Na+]>CN(C=O)C>[OH:45][C:46]([CH3:50])([CH3:49])[CH2:47][NH:48][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Reactant: CC(C)(O)CN
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NCC(C)(C)O)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
To a solution of 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (0.212 mmol) in DMF (5 mL) was added 1-hydroxybenzotriazole hydrate (0.318 mmol), N-ethyldiisopropylamine (0.848 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (0.318 mmol) and 2-hydroxy-2-methylpropylamine (0.318 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by preparative HPLC afforded the title compound (13 mg, 14%) as an off white solid. MS: m/e=402.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[N:7][CH:8]=1.[F:15]F>C(#N)C>[F:15][N+:7]1[CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)c1ccc(C(F)(F)F)cn1
Reactant: FF
Solvent: CC#N
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)c[n+]1F

Procedure:
To a mixture of 5-(trifluoromethyl)pyridine-2-sulfonic acid (227 mg, 1 mmol) and acetonitrile (60 ml) in a flask on a cooling bath kept at -10° C., a mixed gas of 10% fluorine/90% nitrogen was introduced at a flow rate of 15 ml/min. The total amount of the fluorine gas was 3.1 mmol. Thereafter, the nitrogen gas alone was introduced for 30 minutes. After the reaction mixture was concentrated, ethyl acetate was added to the residue. The precipitated crystal was recovered by filtration to obtain N-fluoro-5-(trifluoromethyl)pyridinium-2-sulfonate (212 mg, 0.86 mmol). Yield, 86%. Melting point, 190°-220° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1.O.O.[OH-].[Li+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C2(C)SC(N[C@@H](C)c3ccc(F)cc3)=NC2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)O)cc2)S1)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(2-((S)-1-(4-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzoate (0.64 g, 1.7 mmol) in THF (3 mL), MeOH (1 mL), and H2O (1 mL) was added lithium hydroxide monohydrate (0.10 g, 2.5 mmol), and the mixture was stirred at ambient temp. overnight. The mixture was then heated to reflux for 5 h. The mixture was neutralized with 1N HCl, and then extracted with CH2Cl2 five times. The organic extracts were dried over Na2SO4, concentrated in vacuo, and the product was dried on vacuum. MS: 373 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[OH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1/[CH:16]=[C:1](/[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)\[CH3:2])(=[O:24])[CH3:23]
Reactant: O=Cc1ccccc1O
Reactant: CCc1ccc2ccccc2n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccccc1/C=C(\C)c1ccc2ccccc2n1
Temperature: 150 °C
Yield: 73.2 %

Procedure:
2-Ethylquinoline (1.57 g, 10.0 mmol, 1.0 eq.) and 2-hydroxybenzaldehyde (1.06 mL, 1.22 g, 10.0 mmol, 1.0 eq.) were dissolved in acetic anhydride (1.89 mL, 2.04 g, 20.0 mmol, 2.0 eq.). The resulting mixture was heated at 150° C. for 16 h. The mixture was allowed to cool down to r.t. and was poured onto water (100 mL) and was stirred vigorously. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure which gave the crude product (3.63 g) as a clear orange oil. The crude product was purified by column chromatography (SiO2, 1:5 ethyl acetate-cyclohexane) twice, which yielded the product (2.22 g, 73% yield) as a clear colourless oil.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>>[CH2:27]([P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CCCCCCCCCCCC=C
Product: C=CCCCCCCCCCCCCP(c1ccccc1)c1ccccc1
Yield: 36.8 %

Procedure:
A magnetically stirred solution of an equimolar mixture of 93 grams (0.5 moles) of diphenyl phosphine and 97 g (0.5 moles) of 1,13-tetradecadiene in a closed cylindrical quartz tube was irradiated from about 3 cm distance with two 75 Watt Hanau tube immersion lamps with a wide spectrum of ultraviolet radiation, in a 15° C. water bath for 28 hours. A subsequent nmr analysis indicated a partial disappearance of the double bond due to the diphenyl phosphine addition. The resulting reaction mixture was fractionally distilled to recover the unreacted tetradecadiene and diphenyl phosphine and to obtain 70 g (35%) of 13-tetradecenyl diphenyl phosphine monoadduct as a clear colorless liquid distillate of bp. 185°-190° C. at 0.05 mm. The terminal olefinic unsaturation was clearly indicated by the nmr pattern of the vinylic portions of the distillate product. Anal. Calcd. for C26H37P; C, 82.06; H, 9.80; P, 8.14. Found: C, 82.02, H, 9.60; P, 8.32.