Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[N-:8]=[N+:9]=[N-:10].[Na+].[Cl-].[Na+]>O>[N:8]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCOCCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCCOCCO
Temperature: 80 °C
Yield: 68.9 %

Procedure:
A solution of 10.0 grams of 2-(2-chloroethoxy)ethanol in 50 mL of deionized water was treated with 10.4 grams (2 eq) of sodium azide, and the reaction mixture was heated at 80° C. for 48 hours. The solution was cooled to room temperature, saturated with sodium chloride and extracted with 3×50 mL of ether. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated to give 7.25 grams (69%) of the desired product as a clear, colorless oil. 1H NMR (400 MHz, CDCl3): δ=2.05 (t, J=6.4 Hz, 1H, OH), 3.42 (t, J=5 Hz, 2H), 3.63 (dd, J=4.4, 5.6 Hz), 3.71 (dd, J=4.4, 4.8 Hz, 2H), 3.77 (dt, J=4.4, 6 Hz, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=2)/[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][N:55]=1>C(Cl)Cl>[Br:60][C:57]1[CH:58]=[CH:59][C:54]([NH:53][C:36](=[O:38])/[C:35](/[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:51])([F:50])[F:52])[CH:40]=2)=[CH:34]/[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[N:55][CH:56]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2ccc(Br)cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
A solution of triphenylphosphine (525 mg, 2 mmol) in methylene chloride (12 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (356 mg, 2 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclohexyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (prepared in Example 12, 376 mg, 1 mmol). The reaction mixture was stirred at 25° C. for 15 min and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-amino-5-bromopyridine (519 mg, 3 mmol), and the resulting suspension was stirred for 3 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded the (E)-N-(5-bromo-pyridin-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide (44 mg, 8.3%) as an amorphous solid: EI-HRMS m/e calcd for C22H22BrF3N2O3S (M+) 530.0487, found 530.0484.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:36][Mg]Br.S([O-])(O)(=O)=O.[K+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([OH:22])[CH3:36])[CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2cccc(C=O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2cccc(C(C)O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2.6 ml) of 6-chloro-4-(3-formylphenyl)-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (130 mg) in THF was added a solution (3 mol/l, 0.10 ml) of methyl magnesium bromide in THF at room temperature with stirring, and the mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 5% aqueous potassium hydrogensulfate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=1/2-ethyl acetate) to give the title compound (69 mg) as colorless crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH2:7]([C:9]1[CH:10]=[C:11]([S:16]C#N)[CH:12]=[CH:13][C:14]=1[OH:15])[CH3:8]>O1CCCC1>[CH2:7]([C:9]1[CH:10]=[C:11]([SH:16])[CH:12]=[CH:13][C:14]=1[OH:15])[CH3:8]
Reactant: CCc1cc(SC#N)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(S)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 150 ml three-necked flask, to a stirred mixture of lithium aluminum tetrahydride (LiAlH4, 1.0 g, 26.2 mmol) and tetrahydrofuran (40 ml) was added dropwise a solution of 3-ethyl-4-hydroxy-phenyl thiocyanic acid (1.3 g, 7.25 mmol) in 20 ml tetrahydrofuran at 0° C. After 30 min of stirring at 0° C., the mixture was allowed to warm up to room temperature and then stirred for another 1 hour at room temperature. The reaction was quenched by adding ethanol (10 ml). The value of pH of the mixture was adjusted to pH 3-4 by adding 6 N hydrochloric acid in an ice water bath, and then the aqueous phase was extracted with ethyl acetate (3×60 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtrated, and evaporated in vacuo to yield the crude product of 3-ethyl-4-hydroxy-mercaptobenzene (yellow liquid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:25][C:26]1([CH2:36][CH:37]=O)[CH2:35][CH2:34][C:29]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:28][CH2:27]1.[OH-].[Na+]>O1CCCC1.O.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:37][CH2:36][C:26]2([OH:25])[CH2:35][CH2:34][C:29]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:28][CH2:27]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=CCC1(O)CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NCCC1(O)CCC2(CC1)OCCO2)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1-(4-Bromo-phenyl)-ethylamine (2.68 g), sodium triacetoxyborohydride (2.84 g), and acetic acid (0.77 mL) are added in the given order to a solution of (8-hydroxy-1,4-dioxa-spiro[4.5]dec-8-yl)-acetaldehyde (7.86 g) in tetrahydrofuran (150 mL) at room temperature. The resulting mixture is stirred at room temperature overnight. Water (100 mL) and 1 M aqueous NaOH solution (100 mL) are then added and the mixture is stirred for another 20 min. The mixture is extracted with ethyl acetate, and the combined extracts are washed with water and brine. After drying (MgSO4), the solvent is evaporated to give the crude title compound that is used without further purification. Yield: 2.91 g (crude); LC (method 3): tR=2.00 min; Mass spectrum (ESI+): m/z=384/386 (Br) [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([CH:22]2[CH2:24][CH2:23]2)[C:20]2[C:25]([C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl.CO>[NH2:14][C@H:15]([C:17]1[N:21]([CH:22]2[CH2:23][CH2:24]2)[C:20]2[C:25]([C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])=[C:26]([F:29])[CH:27]=[CH:28][C:19]=2[N:18]=1)[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@H](N)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
TFA (1 mL) was added to a stirring solution of {(S)-1-[1-cyclopropyl-6-fluoro-7-(morpholine-4-carbonyl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (380 mg, 0.88 mmol) in DCM (3 mL). After stirring at RT for 2 h, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (214 mg, 73%). LCMS (Method B): RT 1.62 and 1.70 min [M+H]+ 333.12
Reaction SMILES: [C:1]([CH2:5][CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:8][C:9]([O:11]C)=O)([O:3][CH3:4])=[O:2].CO.C(C(C(OC)=O)(C(OC)=O)CCC)(OC)=O>CC1C=CC(C)=CC=1>[C:1]([C@H:5]1[C@H:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:8][C:9]1=[O:11])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCC(CC(=O)OC)C(=O)OC
Agent: CCCC(C(=O)OC)(C(=O)OC)C(=O)OC
Solvent: CO
Solvent: Cc1ccc(C)cc1
Product: COC(=O)[C@@H]1C(=O)CC[C@H]1C(=O)OC

Procedure:
The method of cyclizing 1,2,4-tricarbomethoxy butane, in solution in dry p-xylene containing a trace of methanol, with excess of a suspension in dry p-xylene of a dispersion of an alkali metal hydride in mineral oil, the tricarbomethoxybutane being added portionwise to the alkali metal hydride suspension with mixing at a reaction temperature of about 20° to about 40° C. for a time sufficient to form trans-2,3-dicarbomethoxycyclopentanone.
Reaction SMILES: C1COCC1.[C:6]1([Li])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][C:18]=2[O:24][CH3:25].C(O)C>CCCCCC.C1(C)C=CC=CC=1>[C:6]1([C:15]2[C:14]([CH3:13])=[CH:23][C:22]3[C:17](=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]c1ccccc1
Reactant: COc1cccc2cc(C)cnc12
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1cccc2cc(C)c(-c3ccccc3)nc12
Temperature: 0 °C
Yield: 35 %

Procedure:
84 ml of anhydrous THF and 42 ml of a 2M solution of phenyllithium in hexane are placed in a 1 l triple-necked flask cooled to 0° C. with an ice bath. The reaction medium is heated to 65° C. and a solution of 12 g (69 mmol) of 3-methyl-8-methoxyquinoline in 50 ml of toluene is added dropwise. The mixture is brought to reflux for 6 h and cooled to ambient temperature, and 50 ml of ethanol are added dropwise. The mixture is concentrated under vacuum and the residue is purified by silica gel chromatography (eluent: heptane/ethyl acetate 9/1) to provide 5.9 g of 2-phenyl-3-methyl-8-methoxyquinoline. (Yield: 35%)
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([OH:14])=O)[CH2:4]1.[C:15]1([S:21]([NH2:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[N+:9]([O-:11])([O:8][C@H:7]1[CH2:6][C@H:5]([C:12](=[O:14])[NH:24][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH2:4][C@@H:3]1[O:2][CH3:1])=[O:10]
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Reactant: NS(=O)(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](C(=O)NS(=O)(=O)c2ccccc2)C[C@@H]1O[N+](=O)[O-]
Reaction time: 12 h

Procedure:
A mixture of (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylic acid (example 1, 105 mg, 0.510 mmol) and benzenesulfonamide (173 mg, 1.10 mmol) was dissolved in dichloromethane (4 mL). Triethylamine (240 pl, 1.72 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (291 mg, 0.765 mmol). The reaction mixture was stirred for 12 hours. Purification of the crude product by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 1.93-2.02 (m, 1H), 2.15-2.26 (m, 2 H), 2.34 (dt, J=6.8, 15.7 Hz, 1H), 2.93-3.01 (m, 1H), 3.50 (s, 3H), 3.90-3.94 (m, 1H), 5.33-5.37 (m, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.65 (t,J=7.5 Hz, 1H), 8.03-8.07 (m, 2H), 9.42 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: S=C=Nc1c(Cl)cccc1Cl
Yield: 39.7 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2,6-dichloro aniline (2.0 g, 12.34 mmol), thiophosgene (1.41 g, 12.34 mmol) and N-ethyl di-isopropyl amine (7.42 g, 57.51 mmol) in DCM (20 mL) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 7.62 (d, J=7.8 Hz, 2H), 7.39 (t, J=7.8 Hz, 1H).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[C:4]([SH:7])([CH3:6])[CH3:5].[CH2:11](O)[CH3:12]>>[ClH:1].[CH2:11]([O:9][C:8](=[O:10])[C@H:3]([C:4]([SH:7])([CH3:6])[CH3:5])[NH2:2])[CH3:12]
Reactant: CCO
Reactant: CC(C)(S)[C@H](N)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)C(C)(C)S
Temperature: -30 °C
Yield: 39 %

Procedure:
Dry hydrogen chloride is bubbled through a suspension of penicillamine (25 g, 0.167 mole) in 300 ml of dry ethanol until all is in solution. The warm solution is then cooled in an ice bath to 0°-5° C. and saturated with dry HCl. The ice bath is removed and the reaction mixture is heated to reflux for 2 hours, then is concentrated in vacuo to a viscous golden oil which is cooled (-30° C.) overnight. After warming to room temperature, the material, now a mixture of white crystalline solid and oil, is triturated with 500 ml Et2O for 30 minutes, then is filtered. An insoluble oil passes through the filter funnel with the Et2O and the residue is washed (3 times, 150 ml portions) further with Et2O. After drying on the funnel under a stream of dry N2, 14.14 g (mp 125°-145° C., 39% yield) of the desired product is obtained as white powder. NMR (CDCl3 ) δ8.85 (bs, 3, --NH3Cl), 4.34 (q, 2, J=7 Hz, OCH2 --C), 4.6-4.15 (m, 1, NCHCO2); 3.83 (s, 1, --SH), 1.70 (s, 3, C--CH3), 1.59 (s, 3, C--CH3), 1.35 (t, 3, J=7 Hz, OCH2CH3); IR (KBr): 1725 cm-1 (s) (C=O).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.[C:15]([CH:17]1[CH2:19][CH2:18]1)#[CH:16].C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CC#N.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH:17]1([C:15]#[C:16][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[NH2:12])[CH2:19][CH2:18]1
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: C#CC1CC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(C#CC2CC2)c(N)c1
Yield: 95.1 %

Procedure:
bromo-4-methylsulfonyl-2-nitrobenzene (1.5 g, 5.36 mmol), ethynylcyclopropane (0.7 g, 10.72 mmol), K2CO3 (1.5 g, 10.72 mmol) in CH3CN (30 ml), Pd(ACN)2Cl2 (55.5 mg, 0.21 mmol) and X-phos (128 mg, 0.27 mmol) under N2 were heated at 45° C. for 3 h. EA extractive work up and preparative TLC (PE:EtOAc=5:1) gave the title compound (1.2 g).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].FC(F)(F)C(O)=O.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][S:24][C:25]1[N:30]=[C:29]([NH:31][S:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:28]=[C:27]([O:41][CH3:42])[N:26]=1>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([N:38]1[CH2:39][CH2:40][N:35]([S:32]([NH:31][C:29]2[CH:28]=[C:27]([O:41][CH3:42])[N:26]=[C:25]([S:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=3[F:15])[N:30]=2)(=[O:33])=[O:34])[CH2:36][CH2:37]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCN(S(=O)(=O)N(C)C)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared by adding dimethyl sulfamoyl chloride to a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, trifluoroacetate salt (the product from example 36) (0.25 g) in DCM (5 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with Toluene, DCM followed by Et2O to give the title compound as a white solid. Yield: 0.11 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([N+:18]([O-])=O)[CH:3]=1>C(OCC)(=O)C.[Pt]>[NH2:18][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)ccc1Nc1ccccc1C(=O)O
Reaction time: 5 h

Procedure:
To a solution of 2-[(4-chloro-2-nitrophenyl)amino]benzoic acid (12.8 g, 43.7 mmol) in ethyl acetate (300 mL) was added platinum on sulfide coal 5%. The reaction mixture was hydrogenated at 2 bar for 5 h. After filtration through dicalite, washing with ethyl acetate and removal of the solvent under reduced pressure the title compound (11.8 g, 100%) was obtained.
Reaction SMILES: CS(N(C1C=CC(Cl)=CC=1)[C@@H](C(O)=O)C)(=O)=O.[C:18]([N:25]1[CH2:27][CH:26]1[C:28]([O:30]C)=[O:29])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:18]([N:25]1[CH2:27][CH:26]1[C:28]([OH:30])=[O:29])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: COC(=O)C1CN1C(=O)OC(C)(C)C
Agent: C[C@H](C(=O)O)N(c1ccc(Cl)cc1)S(C)(=O)=O
Product: CC(C)(C)OC(=O)N1CC1C(=O)O

Procedure:
The title compound was prepared following the procedure described in Step B of Intermediate 135 using methyl 1-BOC-2-aziridinecarboxylate prepared in Step B.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([O-:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>CN(C=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
To a solution of 24.2 g of sodium p-nitrophenoxide in 60 ml of DMF was added 23.5 g of 4-methoxybenzyl chloride. The precipitate was collected after 24 hours, washed with water, and recrystallized from chloroformcyclohexane, providing 1-methoxy-4-[(4-nitrophenoxy)methyl]benzene, mp 122°-124° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[C:29]1([CH2:28][S:25]([NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:2]3[O:3][C:4]([C:7]4[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=4)=[CH:5][N:6]=3)[CH:19]=2)(=[O:26])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Reactant: Nc1cccc(NS(=O)(=O)Cc2ccccc2)c1
Solvent: CC(C)O
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.651 g, 2.63 mmol) and N-(3-aminophenyl)-1-phenylmethanesulfonamide 26 (0.69 g, 2.63 mmol) in 2-propanol (50 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 1-phenyl-N-(3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino) phenyl) methane sulfonamide. 34 (0.407 g, 33% yield) as a solid. MS (ES) m/z 474 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21](OC)=[O:22])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[OH:29][CH2:28][CH2:30][NH:31][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:10]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CCc2ncccc2OCc2ccccc2)cc1
Reactant: NCCO
Solvent: O
Product: O=C(NCCO)c1ccc(CCc2ncccc2OCc2ccccc2)cc1
Temperature: 160 °C
Yield: 29 %

Procedure:
Methyl 4-[2-(3-benzyloxy-2-pyridyl)ethyl]benzoate (0.20 g, 0.576 mmol) was dissolved in ethanolamine (3 ml) and heated to 160° C. under argon for 2 hours. Water was added (3 ml) and the aqueous layers were extracted with ethyl acetate and the organic phase was dried (MgSO4) and evaporated. The residue was recrystallised from EtOAc/hexane and washed with ether to give the title product (0.064 g, 29%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([CH:12]=1)[NH2:11])(=[O:5])=[O:4])[CH3:2].[C:15](Cl)(Cl)=[S:16].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N:11]=[C:15]=[S:16])[CH:12]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(OC)c(N)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(OC)c(N=C=S)c1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of 5-(ethylsulfonyl)-2-methoxyaniline (15.6 g, 72.5 mmol) in dichloromethane (100 mL) was added dropwise over 1 h to a stirred solution of thiophosgene (9 g, 78.0 mmol) in dichloromethane (300 mL) at RT. After the addition was complete, the reaction was stirred for 2 h. Subsequently, saturated aqueous sodium bicarbonate (200 mL) was added, and the reaction was stirred for an additional 1 h. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (18.6 g, 72.4 mmol) as a tan solid. 1H NMR (400 MHz, d6-DMSO): δ 7.78 (dd, J1=2.2, J2=8.8, 1H), 7.71 (d, J=2.2, 1H), 7.35 (d, J=8.8, 1H), 3.95 (s, 3H), 3.22 (q, J=7.4, 2H), 1.02 (t, J=7.3, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7][OH:8].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:13]1([C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:7][OH:8])[CH:9]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1CO
Temperature: 110 °C
Reaction time: 18 h
Yield: 0.2 %

Procedure:
A mixture of 5-chloro-2-nitrobenzyl alcohol (1.9 g, 10.0 mmol), morpholine (0.9 mL, 10 mmol), and K2CO3 (1.4 g, 10 mmol) in DMF (20 mL) was stirred at 110° C. for 18 h. The reaction mixture was concentrated in vacuo, poured into aqueous sodium bicarbonate (NaHCO3) (5% w/v, 25 mL), and extracted with dichloromethane (25 mL). The organic extract was washed with brine (25 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 90/10 EtOAc/MeOH) to yield a solid impure product. The residue was repurified in the same manner and the resulting solid was triturated with hexanes (10 mL) to afford the product as a yellow solid (5 mg, 2%).