Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[S:34]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35]1>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][N:22]([S:39]([C:36]3[CH:37]=[CH:38][S:34][CH:35]=3)(=[O:41])=[O:40])[CH2:21][CH2:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)c1ccsc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccsc4)CC3)c[nH]c12
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
To a solution of 5-Phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (31 mg/0.067 mmol) in CHCl3 (1.0 ml) was added diisopropyl ethylamine (3 eq). The mixture was cooled to −10° C. and then added to 3-thiophenesulfonyl chloride. The solution was agitated for 1.5 h. Solid phase extraction (SPE) using an aminopropyl cartridge (500 mg) and elution with CHCl3 followed by ethyl acetate provided the title compound (19 mg 61%). LC/MS: m/z 465 Rt 2.29 min.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCc2ccccc2)cc1

Procedure:
A sample of 10.0 g. of 4-(hexadecylamino)hydrocinnamoyl chloride hydrochloride is treated with 9.5 g. of 4-dimethylaminopyridine and 2.5 g. of benzyl alcohol in 80 ml. of methylene chloride and the solution is heated to reflux for 4 hours. The reaction solution is then cooled, washed twice with water and dried over magnesium sulfate. The methylene chloride solution is passed through a pad of alumina. The filtrate is concentrated and the residue recrystallized from chloroform-hexane to yield benzyl 4-(hexadecylamino)hydrocinnamate.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1>C(O)C>[CH:8](=[C:7]1[S:1][C:2](=[S:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=S)SC1=Cc1ccccc1
Yield: 6.4 %

Procedure:
To a solution of 10 g (75.1 mmol) of rhodanine and 7.63 ml (75.1 mmol) of benzaldehyde in 150 ml of ethanol, 0.74 ml (7.5 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 1.07 g of the desired compound (66.6% yield, pale yellow crystals).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([O:12]CC)=O)=[N:2]1.[NH2:19][CH2:20][CH:21]([OH:33])[CH2:22][N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CCO.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([NH:19][CH2:20][CH:21]([OH:33])[CH2:22][N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:12])=[N:2]1
Reactant: CCOC(=O)COc1ccccc1-c1cc[nH]n1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(COc1ccccc1-c1cc[nH]n1)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 51 %

Procedure:
To a solution of ethyl 2-(2-(1H-pyrazol-3-yl)phenoxy)acetate (100 mg, 0.41 mmol) in EtOH (10 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (84 mg, 0.41 mmol). The mixture was stirred at 120° C. under microwave heating for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (10 mL), dried over Na2SO4 and concentrated to give the crude product. The residue was purified by prep-HPLC to afford the desired title compound (85 mg, 44%). 1H NMR (400 MHz, MeOD): δ 7.71-7.69 (m, 2H), 7.34-7.33 (m, 1H), 7.10-7.01 (m, 6H), 6.74 (d, J=2 Hz, 1H), 4.67 (s, 1H), 4.04-4.02 (m, 1H), 3.67 (s, 2H), 3.50-3.49 (m, 1H), 3.37-3.33 (m, 1H), 2.89-2.87 (m, 2H), 2.81-2.78 (m, 2H), 2.58-2.57 (m, 2H) ppm; ESI-MS (m/z): 469.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:23]Cl)[CH:9]=2)=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[N:11]=[C:10]([CH2:23][C:25]#[N:26])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(CCl)cc2-c2ccc(Cl)cc2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
A solution of 4-[5-(4-chlorophenyl)-3-chloromethyl-1H-pyrazol-1-yl]benzenesulfonamide from step 1 (350 mg, 0.9 mmol) and sodium cyanide (200 mg), dissolved in 15 mL of dimethylsulfoxide, was warmed to 100° C. for 4 hours. The solution was cooled to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were combined and washed with water, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 1:1 (v:v) hexane/ethyl acetate. The appropriate fractions were combined and concentrated, and the residue crystallized from ethanol/water to give 4-[5-(4-chlorophenyl)-3-cyanomethyl-1-H-pyrazol-1-yl]benzenesulfonamide as a white solid (251 mg, 75%): mp 212-214° C. Anal. Calc'd. for C17H13ClN4O2S1: C, 54.77; H, 3.51; N, 15.03. Found: C, 54.94; H, 3.61; N, 14.88.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:16][C:11]1[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]2[C:5]([NH:17][C:18]3[CH:19]=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2Nc2cnc(C)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 113.7 %

Procedure:
To a 15 mL round-bottom flask was added 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.050 g, 0.209 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.046 g, 0.230 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (0.169 mL, 0.835 mmol) was then added to the solution in one portion. The now burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and partitioned between water and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (100 mg). MS (ESI pos. ion) m/z: 421.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (s, 6H) 3.06 (s, 3H) 7.84 (br. s., 1H) 7.97 (br. s., 1H) 8.24 (d, J=2.05 Hz, 1H) 8.38 (d, J=2.63 Hz, 1H) 8.64 (d, J=2.19 Hz, 1H) 8.75 (d, J=2.63Hz, 1H) 9.32 (br. s., 1H) 11.98 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:18]=[O:19])=[C:13]3[C:17]=2[S:16][CH:15]=[CH:14]3)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:18]=[O:19])=[C:13]3[C:17]=2[S:16][CH:15]=[CH:14]3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C=O)c3ccsc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(O)cc2)c2sccc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 50 ml round bottom flask was added 7-(4-methoxyphenyl)-1-benzothiophene-4-carbaldehyde (420 mg, 1.57 mmol) to CH2Cl2 (8.5 ml) and the solution was cooled to −78° C. To the solution was added BBr3 (3.14 ml of 1.0 M in CH2Cl2, 3.13 mmol) dropwise as the reaction turned dark red in color. The reaction was warmed to ambient temperature as it turned dark green and was complete in 1 h by TLC. After the reaction was quenched with water (15 ml) it was extracted with ether and the organic were combined, dried over anhydrous Na2SO4 and concentrated to 460 mg (>95%) product as a slightly impure green solid. Reverse phase HPLC (CH3CN/water with 0.1% TFA) was used to obtain an analytical sample (120 mg) as a slightly yellow solid: mp 202–204° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.97 (2H, d, J=8.5 Hz), 7.60 (1H, d, J=7.6), 7.64 (2H, d, J=8.5 Hz), 8.10 (1H, d, J=7.6 Hz), 8.14 (1H, d, J=5.6 Hz), 8.38 (1H, d, J=5.6 Hz), 9.92 (1H, s), 10.29 (1H, s); MS (ESI) m/z 253 ([M−H]).
Reaction SMILES: ClC1C=CC(O[C:7]([C:17]([F:20])([F:19])[F:18])([C:13]([F:16])([F:15])[F:14])[C:8]([O:10]CC)=[O:9])=CC=1.[OH-].[K+].CO>O>[F:14][C:13]([F:15])([F:16])[CH:7]([C:17]([F:18])([F:20])[F:19])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(Oc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-(4-chlorophenoxy)-3,3,3-trifluoro2-trifluoromethylpropionate (14.6 g.), 4.5 N-aqueous potassium hydroxide (19.2 ml.) and methanol (35 ml.) is stirred at ambient temperature for 21/4 hours. The resulting solution is diluted with water and washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid, and extracted with ether. The extract is washed with water, dried with sodium sulphate and evaporated. The residue is sublimed twice at 100° C. and 0.3 mm. pressure, and the sublimate is washed with light petroleum (b.p. 30°-40° C.) to give 2-(4-chloropheonxy)- 3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 81°-83° C. (5.1 g.). The acid may be further purified by crystallisation (prisms) from light petroleum (b.p. 60°-80° C.) followed by sublimation, which yields material of m.p. 82°-83° C.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:46]=[CH:45][C:37]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:36][C:35]=5[CH3:47])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:48]4[CH2:51][C:50]([F:53])([F:52])[CH2:49]4)[N:21]=3)[C@H:14]2[CH3:54])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:46]=[CH:45][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=5[CH3:47])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:48]4[CH2:49][C:50]([F:52])([F:53])[CH2:51]4)[N:21]=3)[C@H:14]2[CH3:54])[CH:4]=[C:3]([C:2]([F:56])([F:55])[F:1])[CH:8]=1
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
tert-Butyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3,3-difluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (Step A, 639 mg, 0.805 mmol) was treated with 20 mL of a mixture of dichloromethane and trifluoroacetic acid (2 to 1 by volume) at room temperature for 0.5 hour, and purified on reverse phase HPLC to give the title compound as a white solid, after lyophilization. LCMS (M+H)+: 738.0. 1H NMR (CD3OD, 500 MHz): δ 8.26 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.93 (s, 2H), 7.90 (dd, J=1.5 Hz, 8.0 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 5.87 (d, J=9.0 Hz, 1H), 4.69 (d, J=16.0 Hz, 1H), 4.45 (m, 4H), 4.43 (m, 1H), 4.15 (d, J=16.0 Hz, 1H), 4.00 (s, 3H), 2.38 (s, 3H), 0.73 (d, J=6.5 Hz, 3H). RTA IC50: 9 nM
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:33])[N:15]([CH2:20][CH:21]4[CH2:25][CH2:24][CH2:23][N:22]4C(OC(C)(C)C)=O)[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:33])[N:15]([CH2:20][CH:21]4[CH2:25][CH2:24][CH2:23][NH:22]4)[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1Cn1cnc2cc(C#Cc3cccc(F)c3)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2ncn1CC1CCCN1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.6 %

Procedure:
A mixture of tert-butyl 2-((7-((3-fluorophenyl)ethynyl)-4-oxoquinazolin-3(4H)-yl)methyl)pyrrolidine-1-carboxylate (0.74 g) and TFA (4 mL) in dichloromethane (4 mL) was stirred at room temperature for 2.5 h. Then the reaction mixture was adjusted pH to 8-9 with saturated NaHCO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product (0.4 g), which was used for the next step without further purification. MS (ESI): 348 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1.[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[OH:26])=[CH:27][CH:28]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C=O)cc2)c(C)c1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C(O)c3ccccc3)cc2)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-benzaldehyde, prepared as described in Example 52, (100 mg, 0.25 mmol) was dissolved in dry THF and cooled to 0° C. To the solution was added a 1 M solution of PhMgBr in THF (0.63 mL, 0.63 mmol) and the reaction was stirred at 25° C. for 2 h, quenched with water and neutralized with 10% HCl and extracted with EtOAc (100 mL). The EtOAc was washed with brine, dried and stripped in vacuo. The residue was purified by silica gel chromatography (20% EtOAc/hexanes eluent) to give 15 mg {4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-phenyl-methanol as an amorphous solid. mass spec. (AP+): m/z 473 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([Cl:45])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([Cl:45])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1Cl
Yield: 36.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.86 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(3-chloro-4-methoxyphenyl)-1-hexanone (0.82 g) were reacted and treated in the same manner as in Example 172 to give 0.45 g of 4-amino-5-chloro-N-((1-(6-(3-chloro-4-methoxyphenyl)-6-oxohexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([OH:18])=O)(=[O:13])=[O:12].[NH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:18])(=[O:12])=[O:13]
Reactant: COC(=O)CCCN
Reactant: O=C(O)CNS(=O)(=O)c1ccc2ccccc2c1
Product: COC(=O)CCCNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 30 which is concerned with the preparation of starting materials, N-(2-naphthylsulphonyl)glycine was reacted with methyl 4-aminobutyrate to give methyl 4-[2-(2-naphthalenesulphonamido )acetamido]butyrate in 56% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1Br.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[C:24](=[O:34])[NH:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:27]>>[NH2:1][C:2]1[C:3]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:25][C@@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])=[O:34])=[C:18]([F:17])[CH:19]=2)=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CN1CCC(c2cnc(N)c(Br)c2)CC1=O
Reactant: C[C@@H](NC(=O)c1ccc(B(O)O)cc1F)c1ccccc1
Product: C[C@@H](NC(=O)c1ccc(-c2cc(C3CCN(C)C(=O)C3)cnc2N)cc1F)c1ccccc1

Procedure:
Following Step 6 in Scheme 47, using (+/−)-4-(6-amino-5-bromopyridin-3-yl)-1-methylpiperidin-2-one and (R)-(3-fluoro-4-((1-phenylethyl)carbamoyl)phenyl)boronic acid, 4-(2-amino-5-(1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-2-fluoro-N—((R)-1-phenylethyl)benzamide was obtained as a diastereomeric mixture (inseparable) (34%). LCMS (m/z): 447.3 (MH+), 0.58 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.85 (m, 1H), 7.72 (m, 2H), 7.41-7.20 (m, 6H), 7.18 (m, 1H), 5.17 (m, 1H), 3.51-3.29 (m, 3H), 3.13-2.98 (m, 1H), 2.88 (s, 3H), 2.60-2.48 (m, 1H), 2.48-2.30 (m, 1H), 2.10-1.85 (m, 2H), 1.58-1.38 (m, 3H). The diastereomeric mixture was separated by chiral SFC (ChiralPak 5mic AD column, 4.6×100 (mm), 100 mL/min, IPA+0.1%, DEA=40%, 5 ml/min). The polar diastereomer, 4-(2-amino-5-((R)-1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-2-fluoro-N—((R)-1-phenylethyl)benzamide was obtained at Rt=1.67 min. LCMS (m/z): 447.3 (MH+), 0.64 min. The less polar diastereomer, 4-(2-amino-5-((S)-1-methyl-2-oxopiperidin-4-yl)pyridin-3-yl)-2-fluoro-N—((R)-1-phenylethyl)benzamide was obtained at Rt=2.37 min. LCMS (m/z): 447.2 (MH+), 0.64 min. The absolute stereochemistry for both diastereomers was assigned arbitrarily.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[SH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[Si:5]([O:4][CH2:3][CH2:2][S:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C(O)c1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCSc1cccc(C(=O)O)c1
Reaction time: 2 h

Procedure:
(2-Bromoethoxy)(tert-butyl)dimethylsilane (1.48 mL) was added dropwise to a suspension of 3-mercaptobenzoic acid (1.07 g) and potassium carbonate (1.91 g) in DMF (15 mL). The resulting suspension was stirred for 2 h. The reaction was carefully acidified by dropwise addition of aqueous HCl (2M, 10 mL) and poured into water (100 mL). The resulting aqueous was extracted with ethyl acetate (3×100 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 2.8 g.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.CN1CCOCC1.[C:25]1([CH2:31][S:32](Cl)(=[O:34])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:31]([S:32]([NH:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:34])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of 3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (960 mg, 4.0 mmol), as prepared in the preceding step, and N-methylmorpholine (840 μL, 8.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonyl chloride (765 mg, 4.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Additional methylene chloride (50 mL) was added. The resulting methylene chloride solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. The solvent was concentrated to give a solid which was washed with ethyl acetate/hexane (1:2, 60 mL) to give the title compound as a white solid (1.4 g, 89%). 1H-NMR (300 MHz, CDCl3) δ7.35 (d, J=7.5 Hz, 1H), 7.31 (m, 5H), 7.20 (s, 1H), 6.02 (d, J=7.4 Hz, 1H), 4.75 (s, 2H), 4.31 (s, 2H), 2.27 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])C>C(O)=O>[CH2:1]([O:8][NH:9][CH:10]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
O-benzylhydroxylamine (4.63 g, 37 mmol) was dissolved into 89% formic acid (80 ml), and 30 ml of acetic anhydride was added dropwise thereto with keeping the temperature at 50 to 60° C. After adding acetic anhydride, the solution was stirred for 2 hours at room temperature. The organic layer was rinsed and dried, and the solvent was evaporated. The residue was then purified with silica gel chromatography to obtain 3.05 g of N-benzyloxyformamide (yield: 60%). The proton NMR spectrum of the compound is 4.82 bs, 4.93 bs (2H); 7.20-7.47 m (5H); 7.93 bs, 8.30 bs (1H) (solvent: CDCl3).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5](N)[C:4]=2[N:3]=1.[CH2:17]([C@H:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([CH:24]1[NH:25][CH2:26][CH2:27][N:28]([N:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[CH:5][C:4]3[N:3]=[C:2]([CH3:1])[S:11][C:10]2=3)[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Product: Cc1nc2c(s1)N(N1CCNC(Cc3ccccc3)C1)c1ccccc1N=C2
Yield: 35.1 %

Procedure:
By a similar method to Example 460, using 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.703 g, 3.0 mmol) and (S)-2-benzyl-piperazine (0.538 g, 3.0 mmol) give 0.410 g of the title compound as a yellow solid: mp 250–252° C.; mass spectrum (ion spray): m/z=390 (M+1); Analysis for C22H23N5S(0.6 H2O): calcd: C, 66.01; H, 6.09; N, 17.49; found: C, 65.94; H, 5.66; N, 17.8 1.