Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:30][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:20]=1[NH:19][CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)O)ccc1NC(CC(C)C)c1cc(-c2ccccc2)oc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.1 g), methyl 4-amino-3-methylbenzoate (1.0 g), sodium carbonate (0.6 g) and sodium iodide (2.4 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.5 g, 31%) as an amorphous compound.
Reaction SMILES: [H][H].[C:3]([C:7]([C:10]([C:13]([C:16]([C:19]([F:22])([F:21])[F:20])([F:18])[F:17])(Cl)Cl)(Cl)Cl)([F:9])[F:8])([F:6])([F:5])[F:4]>[Pd]>[C:19]([C:16]([CH2:13][CH2:10][C:7]([C:3]([F:4])([F:5])[F:6])([F:8])[F:9])([F:18])[F:17])([F:22])([F:21])[F:20]
Reactant: [H][H]
Reactant: FC(F)(F)C(F)(F)C(Cl)(Cl)C(Cl)(Cl)C(F)(F)C(F)(F)F
Agent: [Pd]
Product: FC(F)(F)C(F)(F)CCC(F)(F)C(F)(F)F
Temperature: -78 °C
Yield: 80 %

Procedure:
The reactor in this Example consisted of a 1.25 inch diameter pyrex tube heated by means of electrical heating tape and an internal thermocouple to measure the temperature inside the tube. The reactor was packed with a mixture of 50 cm3 of 0.5% Pd/Al2O3 (1/8 inch pellets) and 100 cm3 of glass helices for a total bed volume of 150 cm3. The Pd/A12O3 pellets are available from Aldrich Chemical or Engelhard Industries. Effluent from the reactor was condensed into cold traps maintained at -30° C. and -78° C. Hydrogen was passed into the tube at 155 mL/min, while CF3CF2CC12CC12CF2CF3 was metered into the top of the vertically mounted reactor at a rate of about 10 g/h. The temperature inside the reactor during the reduction was 202°-206° C. After a total reaction time of 3.75 h (38.1 g total CF3CF2CC12CC12CF2CF3 added), 20.15 g of product was collected in the cold traps, which was 99% pure according to GC analysis. The product was identified as CF3CF2CH2CH2CF2CF3 (boiling point 66° C., 80% yield) based on nuclear magnetic resonance and mass spectroscopy analysis.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:21]I>CN(C)C=O.O>[CH3:21][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
17.5 g of cis-4,5-diphenyl-imidazolidine-2-thione are dissolved in 200 ml of dimethylformamide and first a solution of 3.2 g of sodium hydroxide in 20 ml of water and then 11.6 g of methyl iodide are added. The mixture is stirred for 6.5 hours at room temperature and evaporated to dryness, the residue is stirred with 350 ml of water and, after leaving to stand for some time, the mixture is filtered with suction, the solid material from the mixture is dissolved, whilst still moist, in 350 ml of ethanol and 50 ml of 2 N sodium hydroxide solution and 170 ml of water are added. The crystalline precipitate is filtered off with suction, filtered through silica gel using chloroform as the eluant and recrystallised from isopropanol/petroleum ether. cis-2-Methylthio-4,5-diphenyl-imidazoline with a melting point of 132°-134° is obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])=[CH:15][CH3:16])[C:8]=1[NH2:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:17])=[CH:15][CH3:16])[C:8]=1[NH:9][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: CC=C(C)c1cccc(C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC=C(C)c1cccc(C)c1NC(=O)CCl
Reaction time: 8 h
Yield: 102.2 %

Procedure:
0.007 mole of chloroacetyl chloride was added dropwise to a mixture of 0.007 moles of 2-methyl-6-(1-methylprop-1-enyl)-aniline and 0.008 moles (1.15 ml) of triethylamine in methylene chloride at about but below 20° C. The mixture was then refluxed and then allowed to stand overnight at room temperature. The mixture was then again refluxed and allowed to stand for two days (over the weekend) at room temperature. Thin layer chromatographic (plate) analysis showed the presence of a small amount of starting material. An additional 0.55 ml of triethylamine and 0.3 ml of chloroacetyl chloride was added and the mixture again refluxed and allowed to stand overnight at room temperature. The mixture was then washed with aqueous sodium bicarbonate, dried and evaporated affording 1.7 g of the title compound as a slightly crystallized oil (m.p. 71°-74° C.).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])(=[O:3])[CH3:2].S(Cl)(Cl)=O.O[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([O:16][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:15])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: OCc1cccnc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)OCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.00 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 0.5 ml (0.006 mol) of thionyl chloride in 20 ml of methylene chloride are stirred at room temperature for 5 minutes and, then a solution of 2.2 ml (0 023 mol) of 3-hydroxymethylpyridine in 20 ml of methylene chloride is added thereto at 0°. After stirring at room temperature for 1 hour, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with ethyl acetate gives 3-pyridylmethyl 2-(4-acetamidobutyryl)-5chlorohydrocinnamate as a beige oil.
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13](O)(=[O:15])[CH3:14]>C(OC(=O)C)(=O)C>[C:13]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: c1ccc2ncccc2c1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC=Cc2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
23.43 g of sodium borohydride are introduced, in portions, into a solution of 20 g of quinoline in 200 ml of acetic acid and 77.5 ml of acetic anhydride, cooled to 0° C. The mixture is then heated for 2 hours at 60° C. and is stirred overnight at ambient temperature. The mixture is concentrated, diluted with water, adjusted to pH=10 with sodium hydroxide solution and extracted with ether. The combined ethereal phases are washed with 1N hydrochloric acid and then at neutral pH and after conventional treatment the expected product is isolated.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH2:30])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:26][CH2:25][C@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:16]([NH:30][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CC[C@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@H](N(C)C)C1
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of acryloyl chloride (0.042 mL, 0.52 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of (S)—N1-[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]-4-[3-(dimethylamino)pyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 61, 250 mg, 0.52 mmol) and DIPEA (0.099 mL, 0.57 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (194 mg, 70%) as a yellow solid; 1H NMR: 1.69-1.83 (1H, m), 2.05-2.16 (1H, m), 2.19 (6H, s), 2.65-2.78 (1H, m), 3.18-3.29 (3H, m), 3.35-3.46 (1H, m), 3.77 (3H, s), 5.67 (1H, dd), 6.16 (1H, dd), 6.48 (1H, dd), 6.54 (1H, s), 7.12 (1H, t), 7.37 (1H, t), 7.43 (1H, s), 8.3-8.46 (2H, m), 8.55 (1H, s), 8.83 (1H, d), 8.94 (1H, s), 9.37 (1H, s); m/z: ES+ MH+ 533.5.
Reaction SMILES: [NH2-:1].[Li+].N.[Li].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16](OC)=[O:17])=[C:10]2[O:20][CH:21]([CH3:23])[CH3:22]>O1CCCC1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]([NH2:1])=[O:17])=[C:10]2[O:20][CH:21]([CH3:23])[CH3:22]
Reactant: [NH2-]
Reactant: COC(=O)c1[nH]c2ccc(OC)cc2c1OC(C)C
Agent: N
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(N)=O)c(OC(C)C)c2c1
Reaction time: 1 h
Yield: 76 %

Procedure:
Lithium amide in liquid ammonia is prepared as described by Unangst PC and Carethers ME, J. Heterocyclic Chem. 1984;21:709, from lithium metal ribbon (0.059 g, 8.5 mmol). A solution of methyl 5-methoxy-3-(1-methylethoxy)-1H-indole-2-carboxylate (0.15 g, 0.57 mmol; Unangst PC, et al., J, Heterocyclic Chem. 1987;24:811) in 4.0 mL of tetrahydrofuran is added dropwise. The mixture is stirred for 1 hour and the excess ammonia is allowed to evaporate. The residue is diluted with ethyl acetate, and the organic layer is washed with 1.0N HCl brine, saturated sodium bicarbonate solution, and brine again. The solution is dried (anhydrous magnesium sulfate) and evaporated. Recrystallization of the residue from ethyl acetatehexane gives 0.11 g (76%) of product; mp 138.5°-140° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[C:13]1[CH:22]=[CH:21][C:20]2[N+:19]3[CH:23]=[C:24]4[CH:33]=[CH:32][C:31]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[N:25]4[C:18]=3[CH:17]=[CH:16][C:15]=2[CH:14]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>CN1CCCC1=O>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[N:34]1([C:13]2[CH:22]=[CH:21][C:20]3[N+:19]4[CH:23]=[C:24]5[CH:33]=[CH:32][C:31]6[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=6[N:25]5[C:18]=4[CH:17]=[CH:16][C:15]=3[CH:14]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNC1
Reactant: Fc1ccc2c(ccc3n4c(ccc5ccccc54)c[n+]23)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)ccc1c[n+]3c4ccc(N5CCCC5)cc4ccc3n12

Procedure:
A mixture of 202 g. of 3-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium p-toluenesulfonate, 600 ml. of N-methyl-2-pyrrolidinone and 111 ml. of pyrrolidine is heated at reflux (158 C. ) for 45 minutes, then cooled to 0°-5° C. The resulting precipitate of 3-(1-pyrrolidinyl)-imidazo[1,2-a:3,4-a']diquinolin-15-ium p-toluenesulfonate is collected by filtration, washed with ethyl acetate, then with water, and dried; m.p. 228°-237° C.
Reaction SMILES: [N:1]([P:6]([Cl:8])Cl)([CH2:4][CH3:5])[CH2:2][CH3:3].[CH:9]1([Mg]Cl)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH2:4]([N:1]([P:6]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[Cl:8])[CH2:2][CH3:3])[CH3:5]
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCN(CC)P(Cl)Cl
Product: CCN(CC)P(Cl)C1CCCCC1
Yield: 57.5 %

Procedure:
U.S. Pat. No. 2,934,564 relates to compounds of the general formula R2PX wherein R represents an alkyl or aryl group and X represents chlorine, bromine or iodine. For example, the reaction of Me2NPCl2 (0.42 mole) with p-tolylmagnesium bromide (0.84 mole) produces dimethylamino-di-p-tolylphosphine. The isolated dimethylamino-di-p-tolylphosphine (31.88 mmoles) was treated with 1428 cc (63.75 mmoles) of anhydrous HCl yielding di-p-tolylchlorophosphine, which was purified by distillation. Similarly, Burg, et al. (J.A.C.S. 80, 1107-09, 1958) disclose the preparation of chlorodimethylphosphine from Me2NPCl2 and suggest the viability of a Grignard route to R2PR'-type phosphines. K. Issleib, et al. (Chem. Berichte 29, 2682-3008, 1959) have shown that Et2NPCl2 (Et=ethyl) and cyclohexylmagnesium chloride react in a 1:1.25 molar ratio to form diethylaminocyclohexylchlorophosphine in 57.5% yield. The authors suggest this reaction can be exploited to prepare unsymmetrical chlorophosphines of the type RR'PCl, but no mention is made of the possibility of further reaction to unsymmetrical tertiary phosphines of the type RR'R"P.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:28][C:26]1[CH:27]=[C:22]([S:21][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=2)[CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])[CH:23]=[C:24]([CH3:30])[C:25]=1[C:38]1[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(SC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 358 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 582.3 [M−H]−.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C(O)(=O)C(O)=O.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>C(O)C.O>[Br:19][C:20]1[CH:21]=[C:22]([C:23]2[NH:10][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=3[N:9]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: O
Product: Brc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Method 1—Step a O-phenylenediamine (81.8 g, 756.6 mmol) and oxalic acid (3.40 g, 37.8 mmol) were completely dissolved in EtOH—H2O/1:1 (2 L) previously warmed at 80° C. 3-Bromobenzaldehyde (44.10 mL, 378.30 mmol) was then added dropwise to the solution. The reaction mixture was stirred overnight at 70° C. to the open air. The day after solid was filtered off and triturated with MeOH (150 mL) to give the product as a pale yellow solid (27.50 g). 3.8 g were recovered from the mother liquors. Total yield 31.30 g (30%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8](O)=[O:9].S(Cl)([Cl:25])=O>>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:8]([Cl:25])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Product: O=C(Cl)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1

Procedure:
(3-Trifluoromethylphenoxy) (4-chlorophenyl)acetic acid (6.6 g., 0.02 mole) is placed in a 25 ml. 3-necked flask fitted with a condenser, stirrer and an addition of thionyl chloride (2.2 ml, 0.03 mole) over a 2-minute period at room temperature. The reaction mixture is refluxed for 5 hours and the solvent removed under vacuum to afford (3-trifluoromethylphenoxy) (4-chlorophenyl)acetyl chloride which is employed without purification.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][N:12]=[N:11]2)[CH:5]=1.N(C1C=C(C=CC=1)C(OC)=O)=[N+]=[N-].O=S(Cl)Cl.CNC.[C:40]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])(=[O:42])[CH3:41].[Li]>C1COCC1>[C:44]([O:43][C:40](=[O:42])[CH2:41][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([CH2:15][N:16]([CH3:17])[CH3:18])=[CH:13][N:12]=[N:11]2)[CH:5]=1)=[O:19])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-n2nncc2CN(C)C)c1
Agent: CNC
Agent: COC(=O)c1cccc(N=[N+]=[N-])c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from 3-(5-dimethylaminomethyl -[1,2,3]triazol-1-yl)-benzoic acid methyl ester [prepared from methyl 3-azidobenzoate following the synthetic steps i.) to iii.) as described in the preparation of Example K5 and reacting the obtained product with SOCl2 in THF at 0 to 23° C. for 1 h, followed by addition of dimethylamine (7.9 M in H2O ) and stirring at 23 to 70° C. for 1 h.] (2.14 g, 8.22 mmol) by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (2.90 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=O>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: O=Cc1cccc(B(O)O)c1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-formylphenylboronic acid in step 1.F.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1)C1C=CC=CC=1>>[CH2:20]([O:19][C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@@H:28]1[C:29](=[O:30])[NH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:16][CH:15]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
This compound was prepared from 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol) and (+)-N-carbobenzyloxy-d-proline (4.44 g, 17.8 mmol), using the same method to prepare pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide, to give the product as a colorless solid, which was used without further purification in the subsequent step. 1H NMR (DMSO-d6) δ 1.80-1.95 (m, 3H), 2.10-2.27 (m, 1H), 3.35-3.55 (m, 2H), 4.33 (m, 1H), 5.0 (m, 4H), 6.95 (d, 2H), 7.12-7.53 (m, 12H) and 9.95 (d, 1H).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)[N+:14]([O-])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:1][S:2]([O:5][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[OH:10])=[CH:19][CH:18]=[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:16]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: [O-][n+]1ccc(O)c2ccc(-c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Oc1cnc2cc(-c3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonic anhydride (3.05 g) in dichloromethane (10 ml) was added to a mixture of 4-hydroxy-7-phenylquinoline-1-oxide (3.28 g), potassium carbonate (2.13 g) and dichloromethane (160 ml) at 0°, the mixture was stirred at 0° for 2 hours, then allowed to warm to room temperature. Water (250 ml) was added, the layers were separated and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined dichloromethane layer and extracts were dried over magnesium sulphate and the solvent was removed by distillation. The residue was subjected to flash chromatography on two successive silica gel columns eluted with dichloromethane: industrial methylated spirit (19:1) to give crude 4-hydroxy-7-phenylquinol-3-yl methanesulphonate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[C:4]([F:21])[C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a cooled (ice bath) solution of (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.095 g, 0.307 mmol) and 5-cyano-2-pyridinecarboxylic acid (0.055 g, 0.369 mmol) in THF (2.5 mL) and MeOH (1.5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.118 g, 0.399 mmol). After stirring for 30 min, the ice bath was removed. The reaction was stirred at ambient temperature for 15 h. The reaction was quenched with saturated sodium bicarbonate solution. MeOH was removed by rotary evaporation. The aqueous residue was extracted with EtOAc (2×). The organic extracts were combined, concentrated and purified by Shimadzu HPLC to afford N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-cyanopicolinamide (0.053 g, 0.121 mmol, 39.3% yield) as white solid. MS m/z=440.1 [M+H]+. Calculated for C19H14F5N5O2: 439.3