Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[S:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12]>CC(C)=O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11](=[O:12])[CH2:10][N:4]2[C:5](=[O:7])[CH2:6][S:2][C:3]2=[O:8])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CSC(=O)N1
Agent: [K]
Solvent: CC(C)=O
Product: O=C(CN1C(=O)CSC1=O)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A little at a time, 1.3 g (8.4 mmol) of 1,3-thiazolidine-2,4-dione potassium salt were added to a solution of 2.0 g (8.2 mmol) of 2-bromo-1-(4-nitrophenyl)ethanone in 80 ml of acetone, and the mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water/dichloromethane. After phase separation, the organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield: 2.3 g (98% of theory)
Reaction SMILES: [N:1]1(N)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:13]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>CCO>[CH:8]1[C:9]2[C:17]3[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=3[N:1]3[C:10]=2[C:5]([CH2:4][CH2:3][CH2:2]3)=[CH:6][CH:7]=1
Reactant: O=C1CCCNCC1
Reactant: NN1CCCc2ccccc21
Agent: Cl
Solvent: CCO
Product: c1cc2c3c(c1)c1c(n3CCC2)CCNCC1
Temperature: 20 °C
Yield: 25.2 %

Procedure:
To a solution of 3,4-dihydro-1(2H)-quinolinamine (1.0 g, 14 mmol) and hexahydro-4H-azepin-4-one hydrochloride (1.0 g, 14 mmol) in EtOH (13 mL) was added concentrated HCl (1.2 mL). The reaction was stirred at reflux for 14 h, then cooled to 20° C. A brown precipitate was filtered from the reaction mixture, affording the title compound (800 mg, 45%) as a brown solid. 1H NMR (CD3OD, 300 MHz) δ2.14-2.23 (m, 2H), 2.91 (t, 2H, J=6.0 Hz), 3.16-3.21 (m, 2H), 3.27-3.33 (m, 2H), 3.39-3.50 (m, 4H), 4.04 (t, 2H, J=5.7 Hz), 6.70 (d, 1H, J=6.9 Hz), 6.87-6.93 (m, 1H), 7.22 (d, 1H, J=8.0 Hz) ppm. MS (ESI): 227.2 (base, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][C:6]1=[O:17])=[O:4].[C:18]1([CH2:24]CO)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:1]([O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][C:6]1=[O:17])=[O:4])[CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCCCC1CC(C(=O)OC)C(=O)O1
Reactant: OCCc1ccccc1
Solvent: CO
Product: CCCCCCCC1CC(C(=O)OCCc2ccccc2)C(=O)O1
Temperature: 25 °C

Procedure:
A mixture of 24.2 g 5-heptyl-2-oxo-tetrahydro-furan-3-carboxylic acid methyl ester, 24.4 g phenylethyl alcohol and 1.4 g tetraisopropyl-ortho-titanate was heated under nitrogen atmosphere to 130° C. for 5 minutes while methanol was distilled off. Then the reaction mixture was cooled to room temperature, poured into water and extracted with hexane. The organic layer was dried and evaporated to dryness. The residue was chromatographed to yield 23.9 g of a slightly yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][N:30]([CH3:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:14][CH:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:16]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1
Reactant: CN(C)c1nc2ccccc2[nH]1
Product: CN(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine from Example 126 (75 mg) was reacted with N,N-dimethyl-1H-benzo[d]imidazol-2-amine via General Procedure D to produce 6.8 mg of 167 following reverse phase HPLC purification. MS (Q1) 530.2 (M)+
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:29]=O)[C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:14]=2[CH:28]=1>C(O)C.O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:29]=[N:2][OH:3])[C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C=NO)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.4 h

Procedure:
Hydroxylamine hydrochloride (1.30 g, 18.7 mmol), sodium acetate (1.50 g, 19.4 mmol), and a mixture of ethanol-water (80:20, 15 mL) were stirred at room temperature for 0.4 hours. The aldehyde (Example 76, Step 3)(3.07 g, 9.0 mmol) was dissolved in a solution of ethanol-water (4:1, 25 mL) and added to this mixture and stirred at 100° C. for 1 hour. The reaction was filtered hot and the filtrate allowed to cool to room temperature. An orange solid crystallized in the filtrate which was collected by vacuum filtration. The solid was dissolved in ethyl acetate and the solution washed with water, brine, dried over MgSO4, concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-hexane yielding the oxime as a tan powder (1.50 g, 47%): mp 186.6–187.6° C. 1H NMR (acetone-d6/300 MHz) 10.87 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H, J=2.6 Hz), 7.60 (d, 1H, J=2.6 Hz), 6.02 (q, 1H, J=7.1 Hz), 4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([O:20]CC3C=CC=CC=3)=[O:19])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[C:12]3[CH:34]=[CH:35][CH:36]=[CH:37][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[C:12]3[CH:34]=[CH:35][CH:36]=[CH:37][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OCC(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A mixture of a solution of (±)-cis-2-(4-methoxyphenyl)-3-(benzyloxycarbonylmethyl)oxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (880 mg) in a mixed solvent of 10% aqueous sodium hydroxide solution (2 ml), water (15 ml) and ethanol (15 ml) is stirred at 50° C. for 30 minutes. After the completion of the reaction, ethanol is distilled off under reduced pressure. The aqueous layer is washed with ethyl acetate and acidified with acetic acid under ice-cooling, and then, saturated with ammonium sulfate. The precipitated crystal is collected by filtration, washed with water and dried to give (±)-cis-2-(4-methoxyphenyl)-3-(carboxymethyl)oxy-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (230 mg), m.p. 184°-188° C. (decomposed).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[C:17]#[N:18].[CH3:20][S:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[C:17]([C:10]1[CH:11]=[C:12]([C:14]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:30][CH:29]=2)=[O:16])[S:13][C:9]=1[S:8][C:7]1[C:6]([Cl:19])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])#[N:18]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1cc(C(=O)O)sc1Sc1c(Cl)cncc1Cl
Product: CS(=O)(=O)c1ccc(NC(=O)c2cc(C#N)c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-cyano-thiophene-2-carboxylic acid (47 mg, 0.14 mmol) from step C of example 203 and 4-methylsulfonylaniline (26.0 mg, 0.15 mmol). The crude material was purified by reverse phase HPLC and the title compound was obtained as a yellow solid (3.5 mg, 5% yield). MS m/z: 484.94, 485.94 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4](O)([C:7]#[N:8])[CH2:3][CH2:2]1.CC(C)(O)C#[N:13]>>[NH2:13][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1
Reactant: N#CC1(O)CCCCC1
Reactant: CC(C)(O)C#N
Product: N#CC1(N)CCCCC1

Procedure:
In a similar manner, 1-aminoisobutyronitrile was prepared by substituting for cyclohexanone cyanohydrin an equivalent amount of acetone cyanohydrin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:33]1N=C(C2CC2)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:33][CH2:31]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br
Product: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.94–1.02, 1.14–1.19, 1.26–1.30, 1.68–1.86, 2.06, 2.28–2.49, 3.08–3.32, 4.06–4.18, 4.83–4.87, 5.49, 5.62–5.66, 7.27–7.50; MS (ESI+) for C24H23Cl2N3O m/z 440 (MH)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20](Cl)=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>ClCCl>[CH:5]1[C:17]2[CH:16]([CH2:18][O:19][C:20]([NH:1][CH2:2][CH2:3][OH:4])=[O:21])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(NCCO)OCC1c2ccccc2-c2ccccc21
Reaction time: 1.25 h

Procedure:
2-Aminoethanol (1.2 g, 19.7 mmol) in dry dichloromethane (5 ml) was added dropwise to a solution of 9-fluorenylmethylchloroformate (5.0 g, 19.3 mmol) together with pyridine (1.5 g, 19.4 mmol). The mixture was stirred for a total of 1.25 hours then diluted with dichloromethane (50 ml), washed with water (25 ml), a saturated solution of ammonium chloride (25 ml), the organic phase was separated dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo to give a white solid. This material was crystallised from dichloromethane to give 2-(9-fluorenylmethoxycarbonyl)aminoethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1)=[O:29].[NH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[O:35])[CH2:31][CH2:32]1)=[O:29]
Reactant: Nc1cccnc1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5cccnc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 30 h
Yield: 31.8 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added 3-aminopyridine (15.5 mg), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 30 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (14.7 mg, 32%).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:22](Br)([CH3:24])[CH3:23]>>[C:1]([O:9][CH:10]1[CH2:11][C:12]([CH3:20])([CH3:19])[N:13]([O:18][C:22]([O:18][N:13]2[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][C:12]2([CH3:20])[CH3:19])([CH3:24])[CH3:23])[C:14]([CH3:16])([CH3:17])[CH2:15]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(Br)Br
Product: CC(C)(ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C

Procedure:
The title compound is prepared from 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 2,2-dibromopropane according to the procedure of Example 16.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])[CH3:2].[N:12]#[C:13]Br>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:13]#[N:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])[CH3:2]
Reactant: CCNc1c(C)cccc1C
Reactant: N#CBr
Solvent: Cc1ccccc1
Product: CCN(C#N)c1c(C)cccc1C

Procedure:
N-ethyl-2,6-dimethylaniline (5.9 g, 39.6 mmol) was added to a stirred solution of cyanogen bromide (2.1 g, 19.8 mmol) in toluene (50 mL). The reaction mixture was allowed to react overnight at room temperature during which a solid formed. A small temperature rise to 30° C. was observed. The suspension was filtered and the residue was washed with toluene (3×25 mL). The combined filtrates were evaporated to dryness by rotatory evaporation and the resulting residue was purified by Kugelrohr distillation (0.2 mbar, 110-125° C.) yielding a brown oil. Yield: 3.09 g (90%). The residue (N-ethyl-2,6-dimethylaniline hydrobromide) of the filtration step was used in the following synthetic step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH:24]=[O:25])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:27]1[O:28][CH:24]([CH2:23][S:22][C:11]2[S:12][C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)[O:25][CH2:26]1
Reactant: COc1ccc(-c2nc(SCC=O)sc2-c2ccc(OC)cc2)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc(SCC3OCCO3)sc2-c2ccc(OC)cc2)cc1

Procedure:
0.2 g of 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]acetaldehyde are dissolved in 50 ml of toluene. While stirring vigorously, 1 ml of ethylene glycol and then 0.2 g of p-toluenesulphonic acid are added. The mixture is heated for 40 hours in a water separator, cooled to 20°, filtered with suction, crystallised from hexane/benzene and dried under reduced pressure to constant weight. 2-[4,5-bis-(p-methoxyphenyl)-thiazol-2-ylthio]acetaldehyde-ethyleneacetal is obtained in the form of a viscous oil.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30](O)[CH2:31][CH3:32])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:38].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[CH:30]([Br:38])[CH2:31][CH3:32])[C@H:14]2[CH3:34])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCC(O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Br)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-hydroxypropyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (212.4 mg, 0.402 mmol) in CH2Cl2 (5 mL) was added CBr4 (333 mg, 1.00 mmol) and a solution of PPh3 (250 mg, 0.956 mmol) in CH2Cl2 (5 mL). The reaction was allowed to warm to room temperature. After 72 hours, the reaction was concentrated and purified by flash chromatography (10 to 50% EtOAc/hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-bromopropyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=594.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89-7.46 (m, 6H), 5.81-5.69 (m, 1H), 5.25-4.97 (m, 2H), 4.36-3.83 (m, 2H), 2.46-2.34 (m, 1H), 2.25-2.14 (m, 1H), 1.29-1.01 (m, 3H), 0.83-0.78 (m, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:13])[CH:10]=2)[CH2:5]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[NH2:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH2:5][CH:4]([NH:3][S:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH2:12]2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2c(c1)CC(N)C2
Agent: Cl
Product: Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
2,5-Diaminoindan dihydrochloride and 4-chlorophenylsulfonyl chloride are treated similarly as in Reference example 1 - (4) to give 5-amino-2-(4-chlorophenyl)sulfonylaminoindan.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].[OH-].[Na+]>CN(C=O)C.O>[F:16][CH:12]([F:17])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OC(F)F)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
4-Nitrophenol (0.10 g, 0.72 mmol, Aldrich), sodium chlorodifluoroacetate (0.11 g, 0.72 mmol, Alfa Products) and sodium hydroxide (0.03 g, 0.72 mmol) were combined in dry DMF (1 mL) under an atmosphere of argon. After stirring at 125° C. for 1 h, the mixture was cooled to RT, was diluted with water and was extracted twice with ether. The combined organic extracts were washed twice with brine, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 25% ethyl acetate/hexanes ) to provide the title compound as a white solid (0.10 g, 73%). mp 33°-35° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:30][CH2:29][C:28]([F:32])([F:31])[F:27])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,2,2-trifluoroethylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2,2,2-trifluoroethyl)terephthalamide. MS (Q1) 469 (M)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[N:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:27]3[CH2:28][CH2:29][CH:24]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH2:25][CH2:26]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(Cl)nn2)cc1
Reactant: C1CCN(C2CCNCC2)CC1
Product: CS(=O)(=O)c1ccc(-c2ccc(N3CCC(N4CCCCC4)CC3)nn2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-methanesulfonylphenyl)pyridazine and 4-(piperid-1-yl)piperidine.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=3[O-:17])[CH2:7][CH2:6]2)[O:4]CC1.C(O)(=O)C.Cl.[OH-].[Na+]>O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])[CH2:7][CH2:6]1
Reactant: [O-][n+]1ccccc1C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(c2cccc[n+]2[O-])CC1
Temperature: 45 °C
Yield: 73.8 %

Procedure:
2-(1,4-Dioxaspiro[4.5]dec-8-yl)pyridine N-oxide (3 g, 12.75 mmol) was combined with glacial acetic acid (20 mL), concentrated hydrochloric acid (10 mL), and water (10 mL). The resulting mixture was heated to 45° C. for 24 hours. The reaction was cooled to 0° C. and the pH was adjusted to 6 with 20% sodium hydroxide solution. The phases were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with water and brine, then dried (sodium sulfate), and concentrated under reduced pressure to yield 1.8 g of the product as an oil.
Reaction SMILES: [C:1]([N:4]([C:17]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=1)[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[N:13][OH:14])=[CH:8][C:7]=1[CH3:15])(=[O:3])[CH3:2].ClN1C(=O)CCC1=O.[Cl:32][C:33]1[CH:34]=[C:35]([C:41]([C:43]([F:46])([F:45])[F:44])=[CH2:42])[CH:36]=[C:37]([Cl:40])[C:38]=1[Cl:39].C(=O)([O-])O.[K+]>COCCOC.O>[C:1]([N:4]([C:17]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=1)[C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:42][C:41]([C:35]3[CH:36]=[C:37]([Cl:40])[C:38]([Cl:39])=[C:33]([Cl:32])[CH:34]=3)([C:43]([F:46])([F:45])[F:44])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(=O)c1ccc(C=NO)cc1C)c1ncc(Cl)cn1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncc(Cl)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
In a solution of 30 mg of N-acetyl-N-(5-chloro-2-pyrimidinyl)-4-hydroxyiminomethyl-2-methyl benzoic acid amide in 5 mL of 1,2-dimethoxyethane, 16 mg of N-chlorosuccinic acid imide was added and stirred at 40° C. for 30 minutes. Then the reaction mixture was left and cooled to room temperature, and 24 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 10 mg of potassium hydrogen carbonate and 1 drop of water were added, and continued to stir at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (10 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:3 to 1:1) to obtain 11 mg of the aimed product as colorless resinous substance.