Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([F:23])([F:22])[C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])=[CH:13][N:12]=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:30])([CH2:24][N:25]1[CH:29]=[N:28][N:27]=[N:26]1)[C:10]([F:22])([F:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][N:12]=1
Reactant: COC/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of (E)-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(3-methoxyprop-1-en-1-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (48; 80 mg, 0.18 mmol) in EtOH (10 mL) was added 10% Pd/C (8 mg), and the mixture was stirred under hydrogen atmosphere for 1 h. The reaction mixture was filtered through a pad of Celite®, the Celite® cake was washed thoroughly with EtOAc (3×30 mL) and then the filtrate was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 45-50% EtOAc/hexanes) afforded 50 (65 mg, 0.14 mmol, 77%) as a semi-solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[N:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)nc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (66 mg, 78%), MS (ISP) m/z=335.5 [(M+H)+], mp 318° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[Cl:25]Cl.O>CCOCC>[Cl:25][C:5]1[CH:4]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:22]=[CH:21][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Reactant: ClCl
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
Methyl 5-(4-trifluoromethylphenoxy)-2-nitrobenzoate is stirred with a catalytic amount of ferric chloride. The reaction mixture was heated to 70° C. under a continuous stream of chlorine gas. After 2.5 hours, the mixture was taken up in ether, shaken with water and the organic phase was dried over MgSO4. The ether was evaporated to afford methyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate. NMR (CDCl3)δ8.2-7 (m,6) 4.0 (2,3). TLC (40% ether/hexane) Rf ≈.4.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:30][CH:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:19]([C:20]5[CH:29]=[CH:28][N:27]=[CH:26][C:21]=5[C:22]=4[CH2:23][CH2:24][CH:25]=3)[CH:13]2[CH2:12][CH2:11]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCOCC>[CH2:12]1[CH:13]2[CH:14]([CH:15]=[CH:16][C:17]3[C:18]4[N:19]2[C:20]2[CH:29]=[CH:28][N:27]=[CH:26][C:21]=2[C:22]=4[CH2:23][CH2:24][CH:25]=3)[CH2:30][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH2:11]1
Reactant: CCOC(=O)CCCCCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCCCCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1

Procedure:
1.5 grams (0.036 moles) of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine-3-hexanoic acid ethyl ester dissolved in 25 ml of dry ether was added dropwise to a stirred suspension of 380 mg (0.010 moles) of lithium aluminum hydride in 50 ml of ether under a nitrogen atmosphere. The resulting mixture was then heated for 1 hour at reflux, cooled, and decomposed with 1N sodium hydroxide solution. The ether solution was decanted from the inorganic salts, dried over anhydrous potassium carbonate, and evaporated. The solid residue thus obtained was recrystallized from benzene-hexane to give the title compound as colorless plates, m.p. 101°-102.5° C.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN(Cc2ccccc2)C(=O)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CN(Cc2ccccc2)C(=O)O1
Yield: 84.6 %

Procedure:
A 40 ml vial was charged with 5-(azidomethyl)-3-benzyl-1,3-oxazolidin-2-one (100 mg, 0.43 mmol, INTERMEDIATE 14), palladium on carbon (5 mg), and methanol (15 ml). The reduction was effected using a balloon filled with hydrogen at room temperature overnight. The catalyst was removed through filtration on a pad of Celite pre-rinsed with methanol. The Celite pad was further rinsed with methanol (2×5 ml) and the eluent concentrated in vacuo to provide 75 mg (85%) of the title compound. Mass spectrum (ESI) 207.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH3:39][C:40]([C:43]1[CH:50]=[CH:49][C:46]([CH:47]=[O:48])=[CH:45][CH:44]=1)([CH3:42])[CH3:41]>>[CH3:42][C:40]([C:43]1[CH:44]=[CH:45][C:46]([CH:47]([OH:48])[C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])=[CH:49][CH:50]=1)([CH3:39])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)c1ccc(C=O)cc1
Product: CC(C)(C)c1ccc(C(O)c2cn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c(=O)[nH]c2=O)cc1

Procedure:
5-((4-(1,1-Dimethylethyl)phenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 4-(1,1-dimethylethyl)benzaldehyde instead of benzophenone) as a colourless foam.
Reaction SMILES: [ClH:1].[CH2:2]([CH:9]([CH2:20][N:21](C)C)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.NO.C(C([CH2:45][N:46](C)[CH3:47])C(C1C=CC=C(OC)C=1)=O)C1C=CC=CC=1>O.C(O)C>[ClH:1].[CH2:2]([CH:9]([CH2:20][NH2:21])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[N:46]([CH3:47])[CH3:45])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)C(Cc2ccccc2)CN(C)C)c1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: COc1cccc(C(C(CN)Cc2ccccc2)N(C)C)c1
Reaction time: 0.08 h

Procedure:
The synthesis was carried out up to the third stage according to Example 1. 2-benzyl-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one hydrochloride was then converted with hydroxylamine hydrochloride to the corresponding oxime. For this purpose 5 g (0.015 mole) of 2-benzyl-3-dimethylamino-1-(3-methoxyphenyl)-propan-1-one with 2.1 g (0.03 mole) of hydroxylamine hydrochloride were dissolved in 15 ml of water and 20 ml of ethanol. The reaction time was 5 minutes and the yield of oxime was 1.7 g (33%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=O)[CH:8]=2)[NH:3]1.[CH3:14][N:15](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.CN>C1COCC1.CN(C=O)C>[CH3:14][NH:15][C:11]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2)=[O:13]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1ccc2c(c1)CC(=O)N2
Reaction time: 0.08 h
Yield: 11.6 %

Procedure:
An oven-dried round-bottom flask was charged with 2-oxoindoline-5-carboxylic acid (89 mg, 0.500 mmol), TBTU (193 mg, 0.600 mmol), HOBt hydrate (81 mg, 0.600 mmol), DIPEA (0.13 mL, 0.750 mmol) and DMF (3.0 mL) and stirred for 5 minutes. Methyl amine (0.75 mL of a 2.0 M solution in THF) was then added and reaction was stirred for 4 hours at which time NaHCO3(sat) (2 mL) was added. Solvents were removed in vacuo and the residue was purified by column chromatography (silica gel, 92:8 CH2Cl2/MeOH) to give the title compound (11 mg, 12%). 1H NMR (400 MHz, CD3OD) δ ppm 7.69-7.75 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 3.58 (s, 2H), 2.97 (s, 3H); MS ESI 191.0 [M+H]+, calcd for [C10H10N2O2+H]+ 191.08.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20]C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28].O1CCOCC1>C(O)(=O)C>[ClH:28].[CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH2:20])[CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1

Procedure:
Using N-benzyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (820 mg, 2.2 mmol), 4N hydrochloric acid-dioxane (10 ml) and acetic acid (30 ml), a similar procedure to Production Example 213 was carried out to obtain N-benzyl-2-amino-5-indan carboxamide hydrochloride (660 mg, 2.2 mmol) having the following physical properties:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Br>CN(C)C=O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][N:10]1[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:12]=2[N:8]([C@H:5]2[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]2)[C:9]1=[O:21]
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(CBr)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C(F)(F)F)cc32)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-one (200 mg) in anhydrous N,N-dimethylformamide (2 mL) was added portionwise sodium hydride (29.3 mg, 60% dispersion in mineral oil) at 5° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. After adding 3,4-dimethoxybenzylbromide (154 mg), the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed successively with 1 N-hydrochloric acid, water, an aqueous saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a preparative silica gel column chromatography eluting with 5% methanol in chloroform. The obtained amorphous was recrystallized from diethyl ether to give 3-(3,4-dimethoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-one (217.9 mg) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:20]=[C:19]([F:21])[C:18]([Br:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(OCC)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:22][C:18]1[C:19]([F:21])=[CH:20][C:12]([O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1ccc(O)c(F)c1
Reactant: O=C(O)c1cc(Br)c(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2cc(F)c(Br)cc2C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A 2 L RB flask was charged with 2-fluoro-4-methoxyphenol (49.6 g, 349 mmol), 2,5-dibromo-4-fluorobenzoic acid (80 g, 269 mmol), ethyl acetate (1.316 mL, 13.43 mmol), cesium carbonate (192 g, 591 mmol) and toluene (1200 mL). To the mixture at was added copper(I) triflate toluene complex (2:1) (1.713 g, 8.06 mmol) and it was stirred at room temperature for 20 minutes. The solution was then heated to 75° C. for 16 hours at which point the toluene was removed under reduced pressure. The solution was dissolved in 1.5 liters of water and washed with 250 ml of EtOAc. The aqeuous layer was acidified to pH 1 with concentrated HCl and the resulting precipitant was collected by filtration and washed with water. The derived solid was washed with a 1:1 solution of ethyl acetate and hexane, then dried under vacuum to afford 5-bromo-4-fluoro-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a light brown solid. MS m/z=358.8 [M+H].
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>[N+](C)([O-])=O.O>[N+:18]([C:4]1[CH:3]=[CH:2][C:1]([C@@H:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:11]3)=[CH:6][CH:5]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)N1C[C@@H]2C[C@@H](c3ccccc3)[C@@H]2C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc([N+](=O)[O-])cc3)[C@@H]2C1
Temperature: -8 °C
Yield: 106.2 %

Procedure:
1.0 g of 1-((1R,5S,6R)-6-Phenyl-3-aza-bicyclo[3.2.0]hept-3-yl)-propan-1-one (4.36 mmol) were dissolved in 12 ml of nitromethane. At −8° C., a mixture of 0.3 ml of nitric acid (65%, 4.36 mmol) and 4.6 ml of sulphuric acid (95%) in 0.76 ml of water were added dropwise within 45 minutes. Stirring at −8° C. was continued for 30 minutes, before 20 ml of ice water were added and the aqueous phase was extracted twice with diethyl ether, the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 1.27 g of the product as a mixture of 2:1 para versus ortho substituted product which was used without further separation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15]C)=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9]C)=[O:8].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(OC)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)c(C(=O)O)c1
Yield: 101.3 %

Procedure:
A solution of dimethyl 4-methoxyphthalate (36.75 g, 0.16 mol) in methanol (100 ml) was treated with a solution of potassium hydroxide (28.0 g, 0.5 mol) in water (50 ml) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid. The solid material was filtered off, washed with water and sucked dry under reduced pressure overnight to afford 4-methoxyphthalic acid (31.8 g, 99%) as an off white solid. 1H NMR (DMSO-d6) 12.90 (2H, br s), 7.74 (1H, d), 7.12-7.05 (2H, m), 3.84 (3H, s). MS: [M+H]+ 197.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1>>[O:12]=[C:4]1[C:3](=[CH:2][NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([NH2:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc(NS(N)(=O)=O)cc1
Product: NS(=O)(=O)Nc1ccc(NC=C2C(=O)Nc3ccccc32)cc1
Yield: 52 %

Procedure:
The title compound was prepared from 3-hydroxymethylene-1,3-dihydro-indol-2-one and 4-aminophenylsulfamide according to Procedure J in 52% yield: 1H NMR (DMSO-d6): δ6.85 (d, J=7.5 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 7.01 (t, J=7.5 Hz, 1H), 7.08 (s, 2H), 7.21 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8 Hz, 2H), 7.57 (d, J=7.5 Hz, 1H), 8.53 (d, J=12.7 Hz, 1H), 9.38 (s, 1H), 10.48 (s, 1H), 10.70 (d, J=12.7 Hz, 1H): APCI−MS m/z 329 (M−H)−. Anal. Calcd for C15H14N4O3S: C, 54.54, H, 4.27; N, 16.96; S, 9.71. Found C, 54.48, H, 4.30; N, 16.90; S, 9.63.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[C:24](C(F)(F)F)[C:22]=5[N:23]=4)[C:15]([NH2:18])=[N:16][CH:17]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Cl[C:33]1SC2C=C(C#N)C=CC=2[N:37]=1>>[NH2:18][C:15]1[C:14]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([C:33]#[N:37])[CH:25]=[CH:24][C:22]=3[N:23]=2)=[CH:13][C:12]([C:10]2[CH:9]=[N:8][N:7]([CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[CH:11]=2)=[CH:17][N:16]=1
Reactant: N#Cc1ccc2nc(Cl)sc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)cccc2s1
Product: N#Cc1ccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc2c1

Procedure:
Following the procedure for 5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3-(4-trifluoromethylbenzothiazol-2-yl)-pyridin-2-ylamine, but using 2-chloro-1,3-benzothiazole-6-carbonitrile, the title compound was obtained as yellow solid. MS (ES+): m/z=402.13 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][C@H:36]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:37][OH:38].OS([O-])(=O)=O.[Na+]>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][C@@H:36]([CH2:37][OH:38])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.064 mmol) and (2R)-2-amino-4-methyl-1-pentanol (75 μL, 0.64 mmol) was heated in EtOH (3 mL) at 175° C. for 45 min. in a microwave. The reaction mixture was cooled to rt and let stand overnight. Added 1N NaHSO4 (2 mL) filtered the resulting suspension, washed with EtOH:water 1:1, and Et2O then concentrated the filtrate in vacuo. Dissolved the residue in CH2Cl2, washed with 0.5N NaHSO4, water, and brine then dried the organics over Na2SO4, filtered and concentrated in vacuo. Triturated the residue with Et2O, filtered and dried in vacuo to provide the product as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.53 Hz, 6 H), 1.40-1.50 (m, 2 H), 1.53-1.67 (m, 6 H), 1.99-2.11 (m, 2 H), 3.18-3.29 (m, 2 H), 3.35-3.50 (m, 4 H), 3.53-3.59 (m, 1 H), 4.09 (dd, J=4.32, 3.26 Hz, 1 H), 4.17 (s, 2 H), 4.93 (t, J=5.16 Hz, 1 H), 7.10-7.18 (m, 2 H), 7.37-7.44 (m, 2 H), 8.21 (d, J=1.47 Hz, 1 H), 8.56 (d, J=1.69 Hz, 1 H), 10.31 (d, J=9.06 Hz, 1 H), 17.27 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
The 2.2 mL of benzo[d][1,3,2]dioxaborole (1.22 g, 10.2 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate (2.6 g, 5.66 mmol) and 1.7 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (471 mg, 1.7 mmol) in toluene (50 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3 (15 mL), diluted with EtOAc, and stirred for 20 min. The organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (5-45% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-hydroxyacetate 2.0 g (71%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.34-7.29 (m, 4H), 7.22-7.19 (m, 1H), 5.95 (s, 1H), 4.99-4.94 (m, 1H), 3.78-3.75 (m, 1H), 3.51-3.47 (m, 1H), 3.04-3.02 (m, 1H), 2.90-2.87 (m, 1H), 2.66-2.61 (m, 1H), 2.54 (s, 3H), 2.41 (s, 3H), 1.87-1.72 (m, 4H), 1.14 (d, J=6.2 Hz, 3H), 1.07 (d, J=5.9 Hz, 3H). UPLC (M+H)=463.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Br:12])[CH:3]=1.[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[C:4]([Br:12])[CH:3]=1
Reactant: Nc1cc(Br)c(C(=O)O)cc1F
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1cc(Br)c(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 1 h
Yield: 57.8 %

Procedure:
4-Amino-2-bromo-5-fluorobenzoic acid (2.045 mmol, 0.479 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.7 g) and triethylamine (6.14 mmol, 0.853 mL, 0.621 g) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (660 mg). MS (ESI) m/z 558.5 [M+H]+