Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH:2]([S:4]([NH:7][CH2:8][CH2:9][NH3+:10])(=[O:6])=[O:5])=[CH2:3].C(N(CC)CC)C>CO>[S:4]1(=[O:6])(=[O:5])[CH2:2][CH2:3][NH:10][CH2:9][CH2:8][NH:7]1
Reactant: C=CS(=O)(=O)NCC[NH3+]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=S1(=O)CCNCCN1
Reaction time: 28 h

Procedure:
A solution of 2-[(vinylsulfonyl)amino]ethanaminium chloride (1.17 g, 6.24 mmol) in methanol (50 ml) at room temperature, was treated with triethylamine (0.87 mL, 6.24 mmol) and then stirred for 28 hr. Silica gel (10 g) was added to the solution. The solvent was evaporated in vacuo and the remaining silica gel was applied to a column of silica gel and chromatographed eluting with 4% ammonium hydroxide in acetonitrile to afford the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](C2C=CC(Cl)=CC=2)=[C:4]([Cl:15])[CH:3]=1.CC[O:18][CH2:19][CH3:20].[I:21][C:22]1[CH:30]=[C:29]([I:31])[CH:28]=[C:24]([C:25]([OH:27])=O)[C:23]=1[OH:32].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[I:21][C:22]1[CH:30]=[C:29]([I:31])[CH:28]=[C:24]([C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:18][C:19]3[CH:20]=[CH:5][C:4]([Cl:15])=[CH:3][CH:2]=3)=[C:4]([Cl:15])[CH:3]=2)=[O:27])[C:23]=1[OH:32]
Reactant: O=C(O)c1cc(I)cc(I)c1O
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Reactant: CCOCC
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(Oc2ccc(Cl)cc2)c(Cl)c1)c1cc(I)cc(I)c1O
Temperature: 25 °C

Procedure:
A mixture of 31.0 g. of 4-amino-2,4'-dichlorobiphenyl ether, 47.4 g. of 3,5-diiodo salicylic acid, and 4.3 ml. of phosphorus trichloride in 235 ml. of chlorobenzene is refluxed for 3 hours. The hot solution is decanted from some insoluble residue and the crude product settles out of solution upon cooling to room temperature. Upon recrystallization from benzene, 27.8 g. of 3,5-diiodo-3'-chloro-4'-(p-chlorophenoxy)-salicylanilide, m.p. 168°-170°C. is obtained.
Reaction SMILES: [F:1][C:2]([F:15])([CH:12]([F:14])[F:13])[CH2:3]C1C=CC=CC=1C=O.[F:16][C:17]1[CH:18]=[C:19]2[C:26](=[CH:27][CH:28]=1)[C:22]([CH2:23][CH2:24][NH2:25])=[CH:21][NH:20]2.[CH:29]([OH:32])([CH3:31])[CH3:30]>>[F:16][C:17]1[CH:18]=[C:19]2[C:26]([C:22]([CH2:23][CH2:24][NH:25][CH2:27][C:28]3[CH:17]=[CH:18][CH:31]=[C:29]([O:32][CH2:3][C:2]([F:1])([F:15])[CH:12]([F:14])[F:13])[CH:30]=3)=[CH:21][NH:20]2)=[CH:27][CH:28]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: CC(C)O
Reactant: O=Cc1ccccc1CC(F)(F)C(F)F
Product: Fc1ccc2c(CCNCc3cccc(OCC(F)(F)C(F)F)c3)c[nH]c2c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Combine isopropanol (500 g), 2,2,3,3-tetrafluoropropylbenzaldehyde (116.8 g), and 6-fluorotryptamine (1.15 equiv.). Heat to reflux over about 1.5 hour. After 30 minutes at the reflux, distill and over 30 minutes collect about 380 g of distillate. Cool the reaction mixture to 50° C. and add NaBH4 (19.71 g) in one portion. After 1 hour at 50° C., slowly add water over 15 minutes and allow the resulting solution to cool to room temperature overnight. Distill the isopropanol under reduced pressure to give a residue and extract with dichloromethane, combine organic layers, and treat with 1N aqueous HCl (650 mL) to give a solid. Stir the heavy suspension for 2 hours at 20–25° C. Collect the solid by filtration, wash with dichloromethane and dry at 50° C. under vacuum overnight to afford title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14](O)=O)[CH2:9][C:10](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23]>C(O)CO.O>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:10]1[CH2:9][N:8]([CH2:13][C:14]1[NH:24][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Solvent: OCCO
Solvent: O
Product: c1ccc(CN(Cc2nc3ccccc3[nH]2)Cc2nc3ccccc3[nH]2)cc1
Temperature: 190 °C
Reaction time: 4 h

Procedure:
A mixture of 4.00 g (17.9 mmol) N-benzyliminodiacetic acid and 3.86 g (35.8 mmol) o-phenylene diamine in 30 ml ethylene glycol was stirred at 190° C. for 4 hours. The water produced during was distilled off continuously. At the end of the reaction, the reaction mixture was allowed to cool down to room temperature and then poured in 150 ml water. The obtained slurry was triturated for 30 min, filtered, washed with water (3×30 ml) and dried at 60° C. under reduced pressure for 48 hours. Yield 4.94 g (75.0%). 1H NMR (250 MHz, DMSO-d6), δ 3.72 (s, 2H), 3.92 (s, 4H), 7.13–7.57 (m, 13H), 12.37 (Br. s, 2H). +CI MS (m/z): [368]. (+CI-MS is Positive Chemical Ionisation Mass Spectroscopy).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]=1[C:24]([F:27])([F:26])[F:25])=O)(=O)OC.O.[NH2:33][NH2:34]>>[C:28]([N:22]1[C:23]([C:24]([F:27])([F:26])[F:25])=[C:19]([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:34][N:33]=2)[CH:20]=[N:21]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F)OC
Solvent: O
Product: CC(C)(C)n1ncc(-c2cc3c(nn2)C2CCC3C2)c1C(F)(F)F

Procedure:
light yellow crystalline solid. MS (ESI): 336.9 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(1-tert-Butyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH2:20]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23].BrC1C=CC(F)=C(C2N=C(NC3C=CN=CC=3)C3C(=NC=CN=3)N=2)C=1>>[CH2:20]([N:24]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[C:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:19])[N:17]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: CCCCNc1ccncc1
Agent: Fc1ccc(Br)cc1-c1nc(Nc2ccncc2)c2nccnc2n1
Product: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-butylaminopyridine 113 following the procedure described for 4-(4-pyridylamino)-2-(5-bromo-2-fluorophenyl)pteridine 1 (LCMS analysis).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH:27]1([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:34]([C:33]3[CH:35]=[CH:36][C:30]([CH:27]4[CH2:29][CH2:28]4)=[CH:31][CH:32]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
Light brown solid. MS (ESI): 445.11 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 4-cyclopropyl-aniline.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.CS(O[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[N:28]([C:31]2[S:32][C:33]([C:37](=[O:46])[NH:38][CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[C:34]([CH3:36])[N:35]=2)[CH:27]=[N:26]1)(=O)=O>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[N:28]([C:31]3[S:32][C:33]([C:37]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:46])=[C:34]([CH3:36])[N:35]=3)[CH:27]=[N:26]2)=[CH:13][CH:12]=1
Reactant: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Reactant: Nc1ccc(F)cc1
Agent: NCc1ccc(F)cc1
Product: Cc1nc(-n2cnn(CCNc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 66 %

Procedure:
Following the procedure as described in Example 47, making variations as required to replace (4-fluorophenyl)methanamine with 4-fluoroaniline to react with 2-(4-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)thiazol-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl methanesulfonate, the title compound was obtained as a colorless solid in 66% yield: mp 163-164° C. (ethyl acetate/hexane); 1H MNR (300 MHz, CDCl3) δ 8.56 (br s, 1H), 8.51-8.41 (m, 1H), 8.22 (s, 1H), 7.71-7.62 (m, 1H), 7.23-7.19 (m, 1H), 6.91-6.75 (m, 3H), 6.54-6.47 (m, 2H), 4.57 (d, J=5.8 Hz, 2H), 4.09-3.92 (m, 3H), 3.53-3.39 (m, 2H), 2.61 (s, 3H); MS (ES+) m/z 454.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][C:24]([CH3:27])=[N:25][CH:26]=[C:21]2[C:20]([C:28](=[NH:31])[NH:29][NH2:30])=[N:19]1>C(O)C>[F:14][C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:22]2=[N:23][C:24]([CH3:27])=[N:25][CH:26]=[C:21]2[C:20]([C:28]2[N:29]=[N:30][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:31]=2)=[N:19]1
Reactant: Cc1ncc2c(C(=N)NN)nn(Cc3ccccc3F)c2n1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3nc(C)ncc23)nc1O
Yield: 19.1 %

Procedure:
615 mg (3.27 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 13 ml of ethanol and heated to reflux. Subsequently, 652 mg (2.18 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 13 ml of ethanol were added and the mixture was boiled under reflux overnight. After cooling, the mixture was filtered, the filtercake was washed with a little ethanol and the filtrate was concentrated. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 30:70→100:0). 182 mg of the target compound were obtained (19% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13](=[O:33])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:16]2)[CH2:12][CH2:11][CH2:10]1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([CH:13]([OH:33])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)[CH2:16]2)[CH2:10][CH2:11][CH2:12]1
Reactant: COc1ccccc1C1(C(=O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccccc1C1(C(O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Yield: 59.7 %

Procedure:
1-[1-(2-Methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanone (15 mg) was dissolved in 2 mL of dry methanol and solid sodium borohydride (10 equiv.) was added in portions. Water (5 mL) was added and the mixture was extracted with ether and the ether extracts were concentrated in vacuo and purified on silica gel to give the desired 1-[1-(2-methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanol (9 mg, 60%). Data for this mixture of diastereomeric amino alcohols: MS 464 (M+1); 1H NMR (300 MHz, CDCl3) partial: δ 6.8-7.6 (m, 8H), 3.85-3.95 (m, 2H, methylene adjacent to aryl ether), the 53.09 singlet for the starting material was absent.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:14][CH2:15][C:16](O)=[O:17]>O>[CH3:6][N:7]([C:16](=[O:17])[CH2:15][Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCl
Reactant: CNc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C(=O)CCl)c1ccccc1
Reaction time: 1.25 h
Yield: 85.5 %

Procedure:
76.75g (0.50 moles) of phosphoryl chloride and 107g (1.00 moles) of N-methyl aniline were added to 99.2g (1.05 moles) of monochloracetic acid. Alternate additions of 10% of the total amount of each of the N-methyl aniline and of the phosphoryl chloride were made with stirring at a temperature of 60° to 70°C over a period of 75 minutes. The reaction mixture was then stirred at 100° to 110°C for 4 hours, after which the reaction mixture was cooled to 70° to 80°C and then poured into warm water. The aqueous suspension was stirred vigorously whilst cooling until the product crystallised and then cooled further until the temperature reached 30° to 35°C. The precipitated crystalline product was separated from the aqueous phase by filtration and then washed with water. The washed product was dried in an oven at a temperature of 50° to 60°C. 157g of dry off-white crystals of N-methyl chloro acetanilide having a melting point of 69°C were obtained. The yield was 85.5% based on the theoretical yield from the N-methyl aniline in the starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](O)(=O)[CH3:10].[OH-].[NH4+]>O>[CH3:9][C:10]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: CC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cnccc2[nH]1
Temperature: 125 °C

Procedure:
A mixture of 5 g of 3,4-diaminopyridine, 3.9 ml of acetic acid and 50 ml of polyphosphoric acid was heated to 125° C. for 2 hours. The reaction mixture was poured into water and the pH adjusted to 8 with ammonium hydroxide. The product was extracted with methanol-chloroform (1:1) and the extracts dried over sodium sulfate and concentrated to dryness. Extraction of the residue with 50 ml of hot ethanol gave 3.98 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17]=[CH2:18]>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:7]=1)[CH2:9][C:10](=[O:11])[CH2:18][CH2:17]2
Reactant: C=C
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2cc(Cl)cc(Cl)c2C1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
149.4 g of 2,4-dichlorophenylacetyl chloride dissolved in 200 ml of methylene chloride were added dropwise within 60 minutes to 115 g of aluminum chloride in 700 ml of methylene chloride while stirring at 0° to 5°. Thereafter, ethylene was introduced at between 0° and 5° during 30 minutes, whereupon the mixture was stirred further at room temperature for 1 hour and thereafter treated at between 0° and 5° with 300 ml of ice-water. The methylene chloride phase was washed, respectively, with 2N hydrochloric acid, with water, with saturated sodium bicarbonate solution and again with water. The aqueous phases were extracted with methylene chloride. The methylene chloride phases were combined, dried and evaporated. The residue was triturated with 100 ml of low-boiling petroleum ether, a further 250 ml of low-boiling petroleum ether were later added thereto and the mixture was left to stand in a refrigerator for 72 hours. The solid was filtered off and filtered over 600 g of silica gel (particle size 0.2-0.5 mm) while eluting with chloroform. There was obtained 6.8-dichloro-3,4-dihydro-2(1H)-naphthalenone which exhibits a melting point of 90°-92° after recrystallization from low-boiling petroleum ether at 0° to 5°.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>>[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: Cc1noc(N)c1Br
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(C(C)C)cc2)c1Br
Yield: 77 %

Procedure:
4-iso-Propyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 45 from 5-amino-4-bromo-3-methylisoxazole and 4-iso-propylbenzenesulfonyl chloride in 77% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 130°-133° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-bromophenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-methylpyridin-4-yl)propan-1-one (example 282, step 1) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=443.0 ([M+H]+).
Reaction SMILES: [F:1][CH:2](O)C.[H-].[Na+].Cl[C:8]1[N:13]=[C:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])[C:9]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40].Cl.CN(C)[CH:44]=[O:45]>>[F:1][CH2:2][CH2:44][O:45][C:8]1[N:13]=[C:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:11]=[C:10]([NH:20][S:21]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])[C:9]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40]
Reactant: CC(O)F
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(-c2ncccn2)nc1OCCF
Reaction time: 0.5 h

Procedure:
To a solution of 258 mg of fluoroethanol in 20 ml of dimethylformamide was added 194 mg of sodium hydride (60%) with ice cooling followed by stirring for 30 minutes. To this reaction solution was added 400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide with stirring under ice cooling followed by stirring for 30 minutes. The reaction mixture was stirred at room temperature for two hours and poured into a mixture of 1N hydrochloric acid and ice. This solution was extracted with chloroform and the chloroform layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by a silica gel column chromatography (chloroform-methanol=40:1). The resulting amorphous substance was crystallized in ether and collected by filtration to give 240 mg of N-[6-(2-fluoroethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[NH:11]([CH2:18][CH2:19][OH:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([OH:8])[CH2:7][N:11]([CH2:18][CH2:19][OH:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OCCNc1ccccc1
Reactant: Clc1ccc([C@@H]2CO2)cc1
Product: OCCN(C[C@H](O)c1ccc(Cl)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
To (R)-4-chloro-styrene oxide (1.55 g, 10.0 mmol), 2-anilinoethanol (1.44 g, 1.05 equivalents) was added; and the mixture was stirred at 60° C. for 15 hours. The mixture was cooled to room temperature to obtain 3.38 of the reaction mixture of the title compound (chemical purity: 52.1 area %, 2-anilinoethanol: 1.5 area %, 28.4 area % of regioisomer was contaminated). The reaction mixture was purified by column chromatography (gel: silica gel, solvent: ethyl acetate/hexane=1/1), and the obtained fractions were concentrated and dried under vacuum, to obtain 1.68 g of the title compound as pale yellow oil (yield: 49%, chemical purity: 91.7 area %; 2-anilinoethanol was not detected; 4.7 area % of regioisomer was contaminated). The retention time in the chemical purity analysis method was 5.6 min.
Reaction SMILES: C(O)(=[S:3])C.C(=O)([O-])[O-].[Na+].[Na+].Br[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14].[CH:20]([O:23]C(C)C)(C)[CH3:21].C1(NC2CCCCC2)CCCCC1>CN(C=O)C.CCOC(C)=O>[C:20]([C@@:12]([SH:3])([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])(=[O:23])[CH3:21]
Reactant: CC(C)OC(C)C
Reactant: CC(C)C[C@@H](Br)C(=O)O
Reactant: CC(O)=S
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)[C@@](S)(CC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
Thioacetic acid (4.2 g, 54.4 mmol) and DMF (100 mL, 1.0 mol) were combined, and the mixture cooled in an ice bath. Sodium carbonate (5.8 g, 54.4 mmol) was added. After 30 minutes, (R)-2-bromo-4-methylpentanoic acid (10.1 g, 51.8 mmol) in DMF (20 mL) was added dropwise and the mixture was stirred at 0° C. to room temperature over 6 hours. The mixture was diluted with 100 mL EtOAc and extracted with 100 mL of a 1:1 1N HCl: saturated aqueous NaCl solution. The layers were separated and the aqueous phase was extracted with additional EtOAc (100 mL). The organics were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The recovered oil was dissolved into diisopropyl ether (45 mL, 320 mmol) and chilled at 0° C. Dicyclohexylamine (10.1 mL, 50.7 mmol) was added dropwise and the solid was allowed to crash out of solution. After stirring for an additional 30 minutes the material was filtered and washed with 75 mL cold diisopropyl ether. The recovered solid (14 g) was suspended in 100 mL EtOAc. 150 mL of 5% KHSO4 was added and the layers were separated. The organic was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The recovered oil was then azeotroped (3×25 mL toluene) to yield the title compound (6.1 g) as a dicyclohexylamine salt.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2cccc3ccccc23)ccn1
Yield: 94.8 %

Procedure:
Using the method of Example 3, Step A, naphthalen-1-ol (909 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) afforded 2-chloro-4-(naphthalen-1-yloxy)pyridine (1.53 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 7.93 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.48-7.56 (m, 3H), 7.21 (d, 1H), 6.79-6.83 (m, 2H).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1.[CH:22](O)([CH3:24])[CH3:23]>ClCCl.C(=O)(O)[O-].[Na+].O>[CH:22]([O:20][C:19](=[O:21])[C:15]1[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][N:16]=1)([CH3:24])[CH3:23]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CC(C)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(Cl)ccn1
Reaction time: 1 h
Yield: 87 %

Procedure:
N,N-Dimethylformamide (0.3 mL) was added dropwise to a suspension of oxalyl chloride (6.6 mL, 76 mmol) and 4-chloropicolinic acid (10.0 g, 63.5 mmol) in dichloromethane (200 mL). The reaction mixture was stirred for 1 hour and additional oxalyl chloride (4 mL) and N,N-dimethylformamide (0.2 mL) was added. After a further 30 minutes, isopropanol (100 mL) was slowly added, followed by, after a further 15 minutes, solid sodium bicarbonate (12 g). The reaction mixture was diluted with 1:1 saturated sodium bicarbonate solution and water, the aqueous phase extracted with dichloromethane (3×100 mL), and solvent removed from the extract under reduced pressure. The residue was purified by flash chromatography (rf: 0.48 in 2:1 hexanes:ethyl acetate) to give 4-chloropicolinic acid isopropyl ester (11.0 g, 87% yield). 200.1 (M+1).