Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:32])[O:26][CH2:27][C:28]([F:31])([F:30])[F:29]>>[F:29][C:28]([F:31])([F:30])[CH2:27][O:26][C:25](=[O:32])[NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1
Reactant: O=C(Cl)OCC(F)(F)F
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(CNC(=O)OCC(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 42 and 2,2,2-trifluoroethyl carbonochloridate were treated using a method similar to that described in Example 128 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.36-8.27 (m, 2H), 8.07 (d, J=7.5, 1H), 8.03-7.96 (m, 1H), 7.95-7.87 (m, 1H), 7.45-7.36 (m, 4H), 4.67 (q, J=9.1, 2H), 4.56 (d, J=5.9, 2H), 3.68 (s, 2H); MS (ESI−) M/Z 467 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][C@@H:7]([C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].ClS([N:24]=[C:25]=[O:26])(=O)=O.O>ClCCl>[NH2:24][C:25]([N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:19])[C@@H:7]([C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[O:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)[C@@H](C)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CN(C(N)=O)[C@H](C(=O)OC(C)(C)C)[C@@H](C)CC
Temperature: 0 °C
Reaction time: 16 h
Yield: 103.3 %

Procedure:
A solution containing the product from Example 36A (5.7 g, 20.9 mmol) in dichloromethane (60 mL) at 0° C. was treated with chlorosulfonyl isocyanate (2.7 mL, 31.0 mmol) and the mixture was stirred at 0° C. for 16 hours. Water (60 mL) was added to the cold reaction and the mixture was warmed to 25° C. and stirred for 4 hours. The reaction was partitioned between dichloromethane and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (6.83 g), which was used without further purification.
Reaction SMILES: S(O[CH2:6][CH2:7][NH:8][C:9](=[O:29])[CH:10]([OH:28])[CH:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH:11]([CH:10]1[O:28][CH2:6][CH2:7][NH:8][C:9]1=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: CS(=O)(=O)OCCNC(=O)C(O)C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCOC1C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 50 °C
Yield: 38.7 %

Procedure:
To a solution of 4.24 g of N-(2-mesyloxyethyl)-3-phenyl-2-hydroxy-3-(2-nitro-phenoxy)-propionamide in 150 ml of DMF there was added 1.38 g of potassium carbonate. The stirred mixture was heated at 50° C. for 5 hours, then poured into water and extracted with ethyl acetate. The dehydrated organic extracts were evaporated to dryness and the residue was chromatographed on silica gel, to obtain 1.27 g of 2-[α-(2-nitro-phenoxy)-benzyl]-morpholin-3-one. Yield 38.6%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1cccc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.273 mmol) and 3-fluorobenzylamine (370 mg, 2.95 mmol) in N,N-dimethylformamide (7 mL) was treated with potassium carbonate (1.00 g, 7.24 mmol) and heated at 80° C. for 1 hour. The mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([N:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24].CCOC(C)=O>CN(C=O)C>[O:24]=[C:23]([N:25]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:22][NH:14][C:9]1[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CBr)N1CCCCc2ccccc21
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1ccccc1Nc1ccccc1)N1CCCCc2ccccc21
Yield: 99.2 %

Procedure:
To a stirring solution of N-phenyl-o-phenylene diamine (10 g, 54.3 mM) in 100 ml of DMF at RT was added K2CO3 (8.25 g, 60 mM) followed by 1-(bromoacetyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (14.56 g 54.3 mM). The resulting mixture was stirred at RT until TLC (Hex:AcOEt 3:1) showed completion of reaction. The mixture was filtered to remove the K2CO3 and then diluted with 800 mL of EtOAc and 200 mL of Et2O. This solution was washed successively with H2O (2×400 mL), brine (1×400 mL), 1 N HCl (2×400 mL), and H2O (1×400 mL), and the organics dried (MgSO4) and concentrated to give a greenish-black oil. The resultant oil was purified by silica gel flash column chromatography using hexane/EtOAc4/1 and the combined filtrates evaporated in vacuo to give 20 g of product. 1H NMR (300 MHz, CDCl3) 1.25–1.40 (m, 1H), 1.66–2.00 (m, 3H), 2.55.2.75 (m, 2H), 2.88 (t, J=13 Hz, 1H), 3.54(d, J=17 Hz, 1H), 4.10 (d, J=17 Hz, 1H), 4.57 (m, 1H), 6.80–7.80 (m, 12H), 7.47 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[NH:10][C:11](=O)[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]=2[C:7]([CH3:18])=[N:6]1)([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:11]1[CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:8]2[C:7]([CH3:18])=[N:6][N:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:9]=2[N:10]=1
Reactant: Cc1nn(C(C)(C)C)c2[nH]c(=O)cc(C(=O)O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(C(C)(C)C)c2nc(Cl)cc(C(=O)O)c12
Reaction time: 0.25 h

Procedure:
1-(1,1-Dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5.07 g, 20.34 mmol) and phosphorus oxychloride (28.4 ml, 305 mmol) were heated at 100° C. for 16 hours. The contents were concentrated in vacuo. The residue was added to ice water followed by 1N NaOH until basic (pH>10). After stirring for 15 minutes, the mixture was adjusted to pH 3-4 by addition of 1N HCl. The contents were extracted with EtOAc, then washed with water, brine and concentrated in vacuo. The crude product was purified by reverse phase HPLC (40-70% ACN/H2O, 0.1% TFA). The product was collected as a solid, 0.50 g (9%). LCMS E-S (M+H)=268.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 (s, 9H), 2.56 (s, 3H), 7.48 (s, 1H), 14.17 (br. s., 1H).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:12](=O)[CH2:13][CH3:14])=[CH:9][CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:6]=2)[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:6]=2)[C:11]([CH2:12][CH2:13][CH3:14])=[C:3]1[CH2:1][CH3:2]
Reactant: Clc1ccccc1CBr
Reactant: CCC(=O)c1c(CC)[nH]c2cc(C(=O)OC)ccc12
Product: CCCc1c(CC)n(Cc2ccccc2Cl)c2cc(C(=O)OC)ccc12

Procedure:
Methyl 1-(2-chlorobenzyl)-2-ethyl-3-propylindole-6-carboxylate (278 mg) was prepared from methyl 2-ethyl-3-propionylindole-6-carboxylate (215 mg and 2-chlorobenzyl bromide (0.24 ml) in a similar manner to that of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[NH:7][CH:8](OC)[CH:9]([F:12])[C:10]=2[CH:11]=1.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([F:12])[CH:8]=[N:7][C:6]=2[Cl:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC1NC(=O)c2ncc(Cl)cc2C1F
Solvent: CC#N
Product: Fc1cnc(Cl)c2ncc(Cl)cc12
Temperature: 75 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
A vial was charged with 3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one (7.5 g, 32.5 mmol), acetonitrile (130 mL) and phosphorus oxychloride (9.09 mL, 98 mmol), and the mixture was stirred at 75° C. for 15 hours. The mixture was concentrated, and the crude material was purified by silica gel chromatography, eluting with 0-50% ethyl acetate in heptanes, to provide the title compound (5.57 g, 25.7 mmol, 79% yield) as a white solid. LC/MS (ESI+) m/z=217 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[CH:27]=[CH:26][C:25](=[O:31])[NH:24][C:23]=2[N:22]=1)[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:32])[N:7]([CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][C:25](=[O:31])[NH:24][C:23]=2[N:22]=1)[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[C:15]([F:17])([F:16])[F:18])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2ccc(=O)[nH]c2n1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(n1)NC(=O)CC2)C1CCN(C(=O)C(F)(F)F)CC1
Temperature: 47.5 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of 0.30 g of tert-butyl((7-oxo-7,8-dihydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate in 40 mL of methanol, 0.10 g of 10% palladium-carbon was added, and the mixture was stirred at 45 to 50° C. for 9 hours 30 minutes under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, the insoluble substance was filtered off, and the filtration residue was washed with methanol. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:3 to obtain 0.18 g of tert-butyl((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)methyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate as a colorless foam.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[N:7]=1)(=[O:5])[CH3:4].[BrH:17].C(O)(=O)C>C(O)(=O)C.CO>[BrH:1].[C:14]([NH:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[O:5])[CH2:4][Br:17])[N:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCc1cccc(C(C)=O)n1
Reactant: BrBr
Agent: Br
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)NCc1cccc(C(=O)CBr)n1

Procedure:
A solution of bromine (1.56 g) in acetic acid (5 ml) was added dropwise to a solution of 2-acetyl-6-(acetylaminomethyl)pyridine (1.87 g) and 30 weight % hydrogen bromide-acetic acid solution (4.2 ml) in a mixture of acetic acid (40 ml) and methanol (10 ml) at ambient temperature with stirring. The mixture was warmed to 60° to 70° C. and stirred for two hours. The solvent was evaporated in vacuo and the residue was triturated with diisopropyl ether to give 2-(acetylaminomethyl)-6-bromoacetylpyridine hydrobromide (3.78 g). IR (Nujol) : 1720, 1620 cm-1 NMR (CD3OD, δ): 2.10 (3H, s), 3.90 (2H, s), 4.83 (2H, s), 7.77 (1H, br s), 8.13 (2H, t, J=8 Hz) and 8.70 (1H, t, J=8 Hz)
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:21][C@H:20]3[C@H:16]([N:17]=[C:18]([N:22]4[CH2:25][CH2:24][CH2:23]4)[S:19]3)[C@@H:15]([OH:26])[C@@H:14]2[OH:27])(=O)=O)=CC=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:22]1([C:18]2[S:19][C@H:20]3[O:21][C@H:13]([CH2:12][NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[C@@H:14]([OH:27])[C@H:15]([OH:26])[C@H:16]3[N:17]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: NC1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H]3SC(N4CCC4)=N[C@@H]3[C@@H](O)[C@@H]2O)cc1
Product: O[C@H]1[C@H](O)[C@@H](CNC2CCCC2)O[C@@H]2SC(N3CCC3)=N[C@H]12
Reaction time: 0.08 h
Yield: 11 %

Procedure:
A solution of ((3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl 4-methylbenzenesulfonate (350 mg, 0.85 mmol) in cyclopentanamine (3 mL) was heated to 50° C. for overnight. The reaction mixture was condensed under vacuum to give a residue, which was purified by Prep-HPLC with the following conditions [(Agilent 1200 prep HPLC): Column, x-Bridge 19*50 mm; mobile phase, Water with 0.05% NH4OH and CH3CN (15% CH3CN up to 28.6% in 5 min Flow rate 20 mL/min; Detector, UV 220 nm)] to give compound 5 as a light yellow solid (30 mg, 11%). (ES, m/z) [M+H]+ 328.0; 1H NMR (300 MHz, DMSO+D2O) 6.25-6.27 (d, J=6.3 Hz, 1H), 3.97 (m, 1H), 3.86 (m, 4H), 3.71 (m, 1H), 3.45 (m, 1H), 3.25 (m, 1H), 2.95 (m, 1H), 2.75 (m, 1H), 2.55 (m, 1H), 2.23 (m, 2H), 1.56-1.72 (m, 6H), 1.25 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[NH:8][C:9]=1[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(=O)[nH]c1C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(=O)[nH]c1C=CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture containing 15.1 g of 5-acetyl-6-methyl-2(1H)-pyridinone, 200 ml of dimethylformamide and 15 ml of dimethylformamide dimethyl acetal was stirred at room temperature for 30 minutes, heated gently with stirring on a steam bath for 2 hours, then allowed to cool and stirred at room temperature overnight. The golden yellow needles that separated were collected, washed with methanol and dried in a vacuum oven at 80° C. to yield 10.7 g of 5-acetyl-6-(2-dimethylaminoethenyl)-2(1H)-pyridinone, m.p. 238°-240° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH2:20]Cl)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].Cl>C(N(CC)CC)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH2:20][N:5]2[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: OCC1CCCNC1
Reactant: COc1ccc(CCCl)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CCN2CCCC(CO)C2)cc1OC
Yield: 38.1 %

Procedure:
A mixture of 5.75 g of 3-(hydroxymethyl)piperidine, 13.8 ml of triethylamine and 10 g of 2-(3,4-dimethoxyphenyl)-ethyl chloride was heated under reflux for 4 hours. After the reaction mixture had cooled, it was acidified with about 30 ml of aqueous 2N hydrochloric acid solution, and unreacted 2-(3,4-dimethoxyphenyl)-ethyl chloride was separated by extraction with tert-butyl methyl ether. The aqueous phase was then rendered alkaline by addition of sodium hydroxide solution and was extracted with dichloromethane. The organic phase was separated, dried and concentrated. 5.3 g of N-[2-(3,4-dimethoxyphenyl)-ethyl]-3-(hydroxymethyl)-piperidine were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#N)=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH:3]=1.C(O)=[O:28]>>[NH2:1][C:2]1[C:7]([CH:8]=[O:28])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[O:14])[CH:3]=1
Reactant: O=CO
Reactant: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C#N
Product: CCOc1nc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cc(N)c1C=O
Temperature: 25 °C
Yield: 36 %

Procedure:
To a suspension of Example 176 (73 mg, 0.2 mmol) in HCOOH (5 ml, 98%) was added AlNi3 (84 mg, 0.6 mmol). The mixture was refluxed for overnight and filtered after cooled down to r.t. The filtrate was concentrated and the remainder was purified on HPLC (10 mM ammonium acetate, 5% acetonitrile in H2O/CH3CN) to yield the titled compound (25 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.20 (t, J=6.44 Hz, 1H) 8.46 (s, 1H), 7.95 (s, 1H), 7.88 (d, J=8.48 Hz, 1H), 7.55 (d, J=8.48 Hz, 2H), 7.08 (s, 1H) 4.57 (d, J=8.48 Hz, 2H), 4.54 (d, J=6.44 Hz, 2H), 3.18 (s, 3H), 1.35 (q, J=6.44 Hz, 3H); MS (APCI) m/z 378 [M+H]+, 376 [M−H]−.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19][CH2:18][C:17]1=[O:31].[H][H]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:32])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19][CH2:18][C:17]1=[O:31]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1CC#CCCCC(=O)OC
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: NCCN
Solvent: CCO
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1C/C=C\CCCC(=O)OC
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
A 50 mL round bottom flask was charged with nickel (II) chloride (273 mg, 2.10 mmol) and sodium borohydride (40 mg, 1.05 mmol), then 95% ethanol (2.0 mL) was added. The mixture immediately turned black. After 15 min at rt, ethylene diamine (0.23 mL, 3.36 mmol) was added. After another 15 min at rt, 7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (152 mg, 0.42 mmol) in 95% ethanol (2.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the resulting residue by flash column chromatography (10→50% EtOAc/CH2Cl2, gradient) afforded 65 mg (43%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])C.C1(C)C=CC=CC=1>CCCCCC>[O:15]=[C:16]1[C:5]2[C:3](=[CH:2][CH:8]=[CH:7][C:6]=2[C:9]([F:12])([F:11])[F:10])[NH:4][CH:23]=[C:17]1[C:18]([OH:20])=[O:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 140 °C
Yield: 133 %

Procedure:
2-Chloro-5-(trifluoromethyl)aniline 2 (200 g, 1.023 mol), diethyl 2-(ethoxymethylene)malonate 3 (276 g, 1.3 mol) and toluene (100 mL) were combined under a nitrogen atmosphere in a three-neck, 1-L round bottom flask equipped with Dean-Stark condenser. The solution was heated with stirring to 140° C. and the temperature was maintained for 4 h. The reaction mixture was cooled to 70° C. and hexane (600 mL) was slowly added. The resulting slurry was stirred and allowed to warm to room temperature. The solid was collected by filtration, washed with 10% ethyl acetate in hexane (2×400 mL) and then dried under vacuum to provide a white solid (350 g, 94% yield) as the desired condensation product diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino) methylene) malonate 4. 1H NMR (400 MHz, DMSO-d6) δ 11.28 (d, J=13.0 Hz, 1H), 8.63 (d, J=13.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.50 (dd, J=1.5, 8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.17 (q, J=7.1 Hz,2H),1.27 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1.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>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.6) (0.46 g, 0.71 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.23 g, 0.78 mmol), tetrakis(triphenylphosphine)palladium (0.049 g, 0.042 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.34 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:17]1[N:22]=[C:21]([C:23]2[CH:35]=[CH:34][C:26]3[N:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[S:29][C:25]=3[CH:24]=2)[CH:20]=[CH:19][N:18]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([C:17]2[N:22]=[C:21]([C:23]3[CH:35]=[CH:34][C:26]4[N:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[S:29][C:25]=4[CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH3:13])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CNS(=O)(=O)c1ccc(OC)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(S(=O)(=O)N(C)c2nccc(-c3ccc4nc(NC(C)=O)sc4c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methoxy-N-methylbenzenesulfonamide (228 mg, 1.13 mmol) was dissolved in DMSO (1.6 mL) and NaH (57.5 mg, 60% in mineral oil, 1.44 mmol) was added and the reaction was stirred under nitrogen at RT. After 1 hour, N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (82.3 mg, 0.270 mmol) was added, and the reaction flask was heated in a preheated oil bath (125° C.) and stirred under nitrogen overnight. The reaction was cooled to RT and filtered through a pad of Celite®(diatomaceous earth). Filtrate was concentrated and the crude material was purified on HPLC (10-95% MeCN/water with 0.1% TFA over 30 minutes) to provide N-(6-(2-(4-methoxy-N-methylphenylsulfonamido)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 470 (MH+). Calculated exact mass for C21H19N5O4S2: 469. 1H NMR (400 MHz, DMSO-d6): 12.52 (s, 1H), 8.64 (d, J=5.0 Hz, 1H), 8.56 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz, 1H), 7.72 (d, J=5.0 Hz, 1H), 7.10 (d, J=9.0 Hz, 2H), 3.82 (s, 3H), 3.69 (s, 3H), 2.23 (s, 3H).