Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](=O)(ON1C(=O)CCC1=O)[O:23]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:18][C:22](=[O:23])[O:20][C:19]=2[CH:21]=1)[C:10]([OH:12])=[O:11])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2oc(=O)oc2c1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Boc-L-DOPA (22.3 g, 75 mmol) and disuccinimidyl carbonate (DSC, 80% pure, 24 g, 75 mmol) were suspended in anhydrous dichloromethane (500 mL) and triethylamine (21 mL, 150 mmol) was added dropwise at 0° C. The resulting reaction mixture was stirred at 0° C. for 30 min. The suspension became a clear solution. HPLC indicated a completed reaction. The reaction mixture was washed with 10% citric acid (200 mL) and water (200 mL×5) to remove triethylamine and N-hydroxysuccinamide. The organic layer was collected, dried over MgSO4, and concentrated to provide the title compound (16) (22 g, 91% yield). 1H NMR (400 MHz, CDCl3): δ 1.43 (s, 9H), 3.11 (dd, 1H, J=14, 6.8 Hz), 3.27 (dd, 1H, J=14, 6.8 Hz), 4.59 (dd, 1H, J=14, 6.8 Hz), 5.03 (d, 1H, NH, J=8.0 Hz), 7.05 (dd, 1H, J=8, 2 Hz), 7.11 (d, 1H, J=2 Hz), 7.18 (d, 1H, J=8 Hz). MS (ESI) m/z 321.9 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:16](=[O:18])[CH3:17])[CH:3]1O)=[N:10][O:11][N:12]=3.O1CCCC1.[H-].[Na+]>O>[CH3:1][C:2]1([CH3:20])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[C:4]([NH:15][C:16](=[O:18])[CH3:17])=[CH:3]1)=[N:10][O:11][N:12]=3
Reactant: CC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NC1=CC(C)(C)Oc2cc3nonc3cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a mixture of 80 mg (0.289 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-acetylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 5 ml of dried tetrahydrofuran were added 25 mg of sodium hydride (oil, content of more than 55%) with stirring for 1 hour at the room temperature. After the mixture was carefully added with water and extracted thrice with ethyl acetate. The combined ethyl acetate layer was washed successively with 0.5N hydrochloric acid, water and saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to a preparative thin layer column chromatography using a developing solvent of ethyl acetate-methanol (10:1 (v/v)) to obtain 24 mg (yield: 32%) of the intended compound. The obtained compound was recrystallized from ethanol to obtain the pure intended compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=1.O.[CH3:25][N:26](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:25]#[N:26])[N:12]([S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:11]=1)=[O:23]
Reactant: O=Cc1cc(-c2ccccc2Br)n(S(=O)(=O)c2cccnc2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccccc1-c1cc(C=O)cn1S(=O)(=O)c1cccnc1
Yield: 63 %

Procedure:
A suspension of 5-(2-bromophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (102 mg), zinc cyanide (61.0 mg) and tetrakis(triphenylphosphine)palladium (60.0 mg) in N,N-dimethylformamide (2 mL) was heated (100 W, 4 min 30 sec) using a microwave focused chemical synthesis reactor manufactured by CEM, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 97.4 mg, 63%).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[B-](F)(F)(F)F.CN(C(O[N:27]1[C:32](=[O:33])[CH2:31][CH2:30][C:28]1=[O:29])=[N+](C)C)C>CC#N>[C:28]1(=[O:29])[N:27]([O:12][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])[C:32](=[O:33])[CH2:31][CH2:30]1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: C#CCCCCCCCCC(=O)O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: C#CCCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 10-undecynoic acid (0.40 g, 2.2 mmol) in CH3CN (10 mL) was added O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.99 g, 3.29 mmol). After stirring for 2 min at RT, the reaction was quenched with 1% AcOH and diluted with CHCl3 (150 mL). The organic solution was then extracted with 1% AcOH (10 mL), rinsed with H2O (2×40 mL), then dried over Na2SO4. The solution was then decanted and concentrated. A quantitative yield was assumed and the material was taken on directly to the next step. TLC (10% MeOH/CHCl3) Rf=0.90, UV active.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18](O)[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>ClC1C=CC=CC=1.ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([Cl:28])[C:13]=3[C:12]3[CH:22]=[C:23]([Br:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: N#Cc1ncc2c(c1Cl)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (2.0 g, 4.66 mmol) and phosphorus pentachloride (2.9 g, 14.0 mmol) in chlorobenzene (6 mL) was heated at 105° C. for 1 hour. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo to afford a residue. The resultant residue was dissolved in dichloromethane (300 mL) and the solution was treated with ice/water (300 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (300 mL). The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with methanol and dried to afford the title compound as a tan solid (1.1 g, 53%). 1H NMR (300 MHz, DMSO-d6): 9.70 (s, 1H), 9.06 (d, J=2.2 Hz, 1H), 8.98 (d, J=2.2 Hz, 1H), 8.27-8.22 (m, 2H), 7.77-7.76 (m, 1H), 7.67-7.60 (m, 2H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:22])([F:21])[C:17]([CH3:20])([OH:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)=O>CN(C)C(=O)C>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:19][C:17]([CH3:20])([CH3:18])[C:16]([F:22])([F:21])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CC(C)(O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O=CO
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Temperature: 170 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of 2.75 mmol 2-fluoro-5-methanesulfonyl-benzoic acid in 10 ml N,N-dimethylacetamide were added 14.7 mmol 1,1,1-trifluoro-2-methyl-propan-2-ol and 8.29 mmol cesium carbonate and the mixture was stirred at 170° C. for 72 hours. The reaction mixture was then cooled to room temperature, acidified by addition of formic acid, and then concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound as a light brown solid (yield 99%). MS (m/e): 325.3. ([M−H]−, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[C:21]([O:26][CH3:27])(=[O:25])[C:22]([CH3:24])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:21]([O:26][CH3:27])=[O:25])[CH3:24])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: COC(=O)C(C)=O
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Product: COC(=O)C(C)=NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
In the manner given in Example 1, 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-bromo-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(2-pyridyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25]O)[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][N:50]5[C:46](=[O:56])[C:47]6[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=6)[C:49]5=[O:51])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reaction time: 16 h

Procedure:
To a solution of the (4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methanol (20 mg, 0.057 mmol, 1.0 eq) in 2 mL of THF was added triphenyl phosphine (22 mg, 0.085 mmol, 1.5 eq), phthalimide (12.5 mg, 0.085 mmol, 1.5 eq) and diisopropyl azodicarboxylate (17 mg, 0.085 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at that temperature for 16 hours. Then the solvent was removed. The crude product was purified by preparative TLC sheet to give 2-((4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methyl)isoindoline-1,3-dione.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=3[CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:34][C:32]1[CH:33]=[C:28]([N:23]2[CH2:24][CH2:25][CH2:26][CH:22]2[C:10]2[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]3=[O:17])[CH:29]=[C:30]([F:35])[CH:31]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COC(=O)c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 80 °C
Reaction time: 23 h
Yield: 58.4 %

Procedure:
Palladium complex (33 mg, 0.04 mmol, see below) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (270 mg, 0.75 mmol), 1-bromo-3,5-difluorobenzene (0.095 ml, 0.83 mmol) and cesium carbonate (368 mg, 1.13 mmol) dissolved in 1,4-dioxane (5 mL). The resulting suspension was degassed with argon and then stirred at 80° C. for 23 h. The reaction mixture was allowed to cool to room temperature, filtered and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 6% MeOH in EtAc. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (206 mg, 58%) as a clear yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.N([O-])=O.[Na+].[BrH:19]>O1CCOCC1.O.[Cu]Br>[Br:19][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: Nc1ccc(F)c(-c2cccnc2)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(Br)cc1-c1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A warm solution of 4-fluoro-3-(pyridin-3-yl)phenylamine (3.64 g, 19.3 mmol) in 1,4-dioxane (10 ml) was treated with a solution of 48% aqueous hydrobromic acid (100 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 20 min with a solution of sodium nitrite (1.53 g, 22.2 mmol) in water (4 ml). After stirring at 0° C. for 2 h, a cooled (0° C.) solution of copper(I) bromide (8.31 g, 57.9 mmol) in 48% aqueous hydrobromic acid (30 ml) was added to the reaction which was stirred at 0° C. for 10 min then heated at 50° C. for 20 min. The reaction was cooled to ambient temperature, poured onto ice-cold concentrated ammonia (500 ml) and the product was extracted into ethyl acetate (500 ml). The organics were washed with water (300 ml) and brine (300 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a dark oil. Purification by dry flash column chromatography (silica gel, 10-30% EtOAc/isohexane) gave 3-(5-bromo-2-fluorophenyl)pyridine (3.1 g, 64%) as a white solid: 1H NMR (360 MHz, CDCl3) δ7.09 (1H, dd, J 9, 1 Hz), 7.37-7.40 (1H, m), 7.46-7.51 (1H, m), 7.56-7.59 (1H, m), 7.83-7.86 (1H, m), 8.63-8.65 (1H, m), 8.77-8.79 (1H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.Cl>C(Cl)Cl>[C:15]1([CH2:14][CH2:13][NH:21][C:10](=[O:12])[CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[I:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CCc1ccccc1I
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(CCc1ccccc1I)NCCc1ccccc1
Reaction time: 72 h
Yield: 120.9 %

Procedure:
To a solution of 2-iodobenzenepropionic acid (8 g, 0.029 mol) and phenethylamine (10.9 g, 0.090 mol) in methylene chloride (200 mL) was added N-ethyl-N-[3-(dimethylamino)propyl]carbodiimide hydrochloride (6.13 g, 0.032 mol) at room temperature. After 3 days, water (100 mL) and 2.5N HCl (50 mL) were added. The organic phase was separated, dried and concentrated to give an oil (13.3 g). The oil was chromatographed on silica gel and eluted with hexane: ethyl acetate (2:1) then hexane: ethyl acetate (1:1) to give a fraction containing a yellow solid 7.6 g (69%). Recrystallization from toluene (15 mL) and petroleum ether (150 mL) afforded 7.1 g of product, mp. 94.5°-95.5° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[N:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([C:24]([S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])([CH3:26])[CH3:25])[N:21]=[C:20]([C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:35][CH:34]=2)[N:19]=1
Reactant: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Phenyl chloroformate (0.42 mL, 3.34 mmol) was added dropwise to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-propan-2-ylsulfonylpropan-2-yl)pyrimidin-2-yl]aniline (1.4 g, 3.34 mmol) and sodium carbonate (0.421 g, 5.02 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to give crude product which was triturated with diethyl ether to give the desired product (1.57 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH3:14])([CH3:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][N:9]1[C:8]([CH3:14])([CH3:13])[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[S:10]1(=[O:12])=[O:11])[CH3:16]
Reactant: CC1(C)NS(=O)(=O)c2cccc(Cl)c21
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(CN1C(C)(C)c2c(Cl)cccc2S1(=O)=O)OCC
Temperature: 120 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
7.7 g (33 mmol) of 4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide, 8.25 ml (55 mmol) of bromoacetaldehyde diethyl acetal and 7.0 g of potassium carbonate were taken up in 100 ml of dry DMF and stirred at 120° C. for 5 h. The reaction mixture was poured into ice-water and then extracted with ethyl acetate, and the organic phase was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure, the crude product was purified by column chromatography. 7.5 g (65%) of the product were obtained as an oil in this way.
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[NH2:21][C:22]1[C:23]([CH3:29])=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:23]([CH3:29])=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13]
Reactant: Cc1c(N)cccc1O
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(N)cccc1Oc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
3.6 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 9.2 mmol, 1 eq.), 1.1 g 3-amino-2-methyl phenol (9.2 mmol, 1 eq.) and 4.5 g caesium carbonate (13.8 mmol, 1.5 eq.) were suspended in 35 mL DMF and stirred at rt for 16 h. LCMS analysis showed complete turnover. The reaction mixture was diluted with ethyl acetate, quenched with saturated sodium chloride solution, the layers were separated and the aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (n-hexane/ethyl acetate gradient) providing 1.18 of the desired product (26% yield).
Reaction SMILES: [O-][CH2:2]C.[Na+].[F:5][C:6]([F:23])([F:22])[C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[C:10]([CH2:12][C:13]#[N:14])=[O:11].CI>CCO>[F:5][C:6]([F:22])([F:23])[C:7]1[CH:8]=[C:9]([C:10](=[O:11])[CH:12]([CH3:2])[C:13]#[N:14])[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=1
Reactant: N#CCC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CC(C#N)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of sodium ethoxide (0.127 g, 1.87 mmol) in EtOH (5 mL) was treated with 3,5-bis(trifluoromethyl)benzoyl acetonitrile (0.500 g, 1.78 mmol) portionwise over 5 min. The reaction was heated at reflux for 30 min before the addition of methyl iodide (0.41 mL, 6.6 mmol). Heating at reflux was continued for a further 2 h before the reaction mixture was allowed to cool and concentrated in vacuo. The residue was partitioned between H2O (10 mL) and EtOAC (20 mL) and the aqueous phase was separated and re-extracted with EtOAC (2×20 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography on silica gel (0-20% EtOAc in hexanes gradient) to afford 3-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-3-oxopropanenitrile. 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 2H), 8.10 (s, 1H), 4.42 (q, J=7.1 Hz, 1H), 1.71 (d, J=7.1 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[Cl:14])[N:4]([CH3:15])[N:3]=1.[I:16]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:6]([I:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[Cl:14])[N:4]([CH3:15])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1nc(Br)cc1-c1ccc(F)cc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nc(Br)c(I)c1-c1ccc(F)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-bromo-5-(2-chloro-4-fluorophenyl)-1-methyl-1H-pyrazole (i.e. the product of Step C) (620 mg, 2.14 mmol) in N,N-dimethylformamide (8 mL) at 60° C. was added N-iodosuccinimide (963 mg, 4.28 mmol). The reaction mixture was stirred at 60° C. for 3 h, and then diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The material was purified by silica gel chromatography (5 to 30% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a pale yellow solid (515 mg) melting at 139-141° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 430 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].C[N+]1C=CN([C:26]([N:28]2[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])C=1>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]3)=[O:27])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CC1CCN(C(=O)n2cc[n+](C)c2)CC1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 1-methyl-3-(4-methyl-piperidine-1-carbonyl)-3H-imidazol-1-ium iodide. The crude product was purified by flash chromatography using a Quad flash 25 (ethyl acetate/heptane (1:6), (73%, white crystals). HPLC-MS m/z=381.1 (M+1), Rt: 5.4 min.