Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:24][NH:25][C@H:26]([CH2:35][C:36]#[N:37])[C:27]([NH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:5]2=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:3]2[CH2:24][N:25]([C@H:26]([CH2:35][C:36]#[N:37])[C:27]([NH:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[O:28])[C:11](=[O:13])[C:10]3=[CH:9][N:8]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[C:5]([C:4]=23)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@H](CC#N)C(=O)NC4CCCC4)c(Cl)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@H](CC#N)C(=O)NC2CCCC2)C3=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-5-chloro-4-((3-cyano-1-(cyclopentylamino)-1-oxopropan-2-ylamino)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid, THF (5 mL), HATU (28.6 mg, 0.075 mmol) and 4-methylmorpholine (19.01 mg, 0.188 mmol) was stirred at room temperature for 2 h. The product was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound. [M+H] calc'd for C25H24ClN5O4S, 526; found, 526.2.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:19]4[N:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.CS(O[CH2:31][C@H:32]([O:34]C1CCCCO1)[CH3:33])(=O)=O>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:19]4[N:24]=[CH:23][C:22]([O:25][CH2:31][C@@H:32]([OH:34])[CH3:33])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Reactant: C[C@H](COS(C)(=O)=O)OC1CCCCO1
Product: C[C@H](O)COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1

Procedure:
Using 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol obtained in Example 6-3) and (2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate, and in the same manner as in Example 26-1) and 26-2), the entitled compound (42 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=3)[S:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COc1ccc2sc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=c1c2cc(O)ccc2sc2c([N+](=O)[O-])ccc(Cl)c12
Reaction time: 48 h

Procedure:
The requisite 1-chloro-7-hydroxy-4-nitrothioxanthone was prepared as follows: To a suspension of 5.0 g of 1-chloro-7-methoxy-4-nitro-thioxanthone in 50 ml of methylene chloride was added 20 ml of boron tribromide in methylene chloride (1M). The mixture was stirred for two days, and an additional 20 ml of boron tribromide was added. The mixture was stirred for three hours at room temperature and heated under reflux for two hours. An additional 20 ml of boron tribromide was added and the mix was heated under reflux for two hours. The mixture was cooled in an ice bath and 50 ml of methanol was added carefully. The solution was heated under reflux for one hour, and the solvent was removed in vacuo. The residue was boiled in about 50 ml of ethanol, collected, and retreated with hot ethanol to provide the product as an orange powder, mp 240°-254° (dec).
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH2:42][C:43]3[CH:52]=[CH:51][C:46]([C:47]([O:49]C)=[O:48])=[CH:45][CH:44]=3)[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)=[CH:9][CH:8]=2)[NH:3]1.[OH-].[Li+].Cl>C1COCC1.O>[O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][N:15]([CH2:42][C:43]3[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:51][CH:52]=3)[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)=[CH:11][CH:12]=2)[NH:3]1
Reactant: COC(=O)c1ccc(CN(CCc2ccc(-c3noc(=O)[nH]3)cc2)CCc2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CN(CCc2ccc(-c3noc(=O)[nH]3)cc2)CCc2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
A solution of 32.7 mg (0.05 mmol) of methyl 4-[({2-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)phenyl]ethyl}-{2-[2-(4′-trifluoromethylbiphenyl-4-ylmethoxy)phenyl]ethyl}amino)methyl]-benzoate from Example 11A in 2 ml of THF and 2 ml of water is mixed with 2.2 mg (0.09 mmol) of lithium hydroxide and stirred at 50° C. for 12 h. After cooling, the THF is stripped off and the aqueous phase is adjusted to pH 4-5 with 1 M hydrochloric acid. It is then extracted three times with ethyl acetate, and the combined organic phases are dried over sodium sulfate. The residue obtained after filtration and concentration is purified by preparative HPLC. 7.4 mg (0.01 mmol, 23% yield) of a colorless oil are obtained.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].[OH-].[Na+].C1COCC1.Cl>CO>[F:35][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][N:17]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(F)(F)F)cn3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ncc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)butyl)amino)benzoate (4.93 g), 1M aqueous sodium hydroxide solution (39.6 mL), THF (40 mL) and methanol (40 mL) was stirred at 70° C. overnight. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:28]([C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([Cl:24])[CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added m-chlorobenzaldehyde (81.8 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (196 mg, 94% yield) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([S:68]([NH:71][CH3:72])(=[O:70])=[O:69])=[CH:64][CH:63]=1>CN(C=O)C>[CH3:72][NH:71][S:68]([C:65]1[CH:66]=[CH:67][C:62]([CH2:61][NH:60][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])=[CH:63][CH:64]=1)(=[O:69])=[O:70]
Reactant: CNS(=O)(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.05 g, 0.2 mmol) in DMF (10 mL) was added PyBOP (0.14 g, 0.30 mmol) and triethylamine (0.07 g, 0.6 mmol) at room temperature. After 15 minutes, 4-aminomethyl-N-methyl-benzenesulfonamide (0.04 g, 0.2 mmol) was added. After 5 hours, the mixture was quenched with water (30 mL) and diluted with ethyl acetate (30 mL). The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.B(F)(F)F.[CH3:20]COCC>CCOC(C)=O>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][CH2:20][O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: OCC(CO)OCc1ccccc1
Agent: C=O
Agent: FB(F)F
Solvent: CCOC(C)=O
Product: c1ccc(COC2COCOC2)cc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
To a mixture of 17 (100 mg, 0.55 mmol) and paraformaldehyde (17 mg, 0.55 mmol) in EtOAc (10 mL), boron trifluoride etherate (70 μL, 0.55 mmol) was added and the reaction mixture was stirred at 23° C. for 4 h. The organic phase was washed with a saturated solution of NaHCO3, dried and the solvent was removed. The residue was purified by flash-chromatography eluting with a 1:4 mixture of EtOAc and hexanes to afford 84 mg (78%) of O-benzyl-1,3-dioxan-5-ol as a colourless oil. The above compound was dissolved in EtOAc (3 mL), Pd/C was added and the resulting suspension was stirred at rt under a hydrogen atmosphere. After 12 h, the catalyst was filtered off, the filtrate was evaporated in vacuo and the residue (39 mg, 100%) was used in the next step without further purification: 1H NMR (CDCl3) δ 4.93 (d, J=6.3 Hz, 1H), 4.76 (d, J=6.3 Hz, 1H), 3.94-3.84 (m, 4H), 3.64-3.61 (m, 1H), 2.78 (bs, 1H). 13C NMR (CDCl3) δ 94.0, 71.7, 64.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=1)[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(CCO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(CCOS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
Methane sulfonyl chloride (2.78 g, 24.3 mmol) was added dropwise to a solution of ethyl[3-(2-hydroxyethyl)phenyl]acetate (Preparation 55) (4.60 g, 22.1 mmol) and triethylamine (3.40 ml, 24.3 mmol) in dichloromethane (250 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature over 1 hour and washed with saturated aqueous sodium hydrogen carbonate (75 ml). The aqueous was washed with dichloromethane (2×100 ml) and the combined organics washed with water (25 ml), dried (sodium sulfate) and the solvent removed in vacuo to furnish the title compound as a colourless oil (6.2 g). 1H NMR (400 MHz, CDCl3): δ=7.29-7.25 (1H, t), 7.17-7.12 (3H, t), 4.41-4.38 (2H, t), 4.16-4.10 (2H, m), 3.58 (2H, s), 3.04-3.00 (2H, t), 2.81 (3H, s), 1.26-1.22 (3H, t) ppm. LRMS (electrospray): m/z [M+H]+ 578, [M−H]− 576.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][NH:28][CH3:29])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]([CH3:29])[C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Reactant: CN(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN(C)C(=O)CN(C)C)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 191, 212 mg, 0.466 mmol) in DCM (4 ml) at 0° C. was added NEt3 (0.103 ml, 0.746 mmol) and 2-(dimethylamino)acetyl chloride (91 mg, 0.49 mmol) and the reaction mixture was stirred for 75 min. Additional NEt3 (0.103 ml, 0.746 mmol) was added and the reaction was continued to stir at 0° C. for 30 min. The reaction mixture was allowed to warm to room temperature and a total of NEt3 (0.206 ml, 1.486 mmol) and 2-(dimethylamino)acetyl chloride (273 mg, 1.469 mmol) and DCM (2 ml) were added stepwise during the next 22 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (3-10%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a brown solid. (UPLC-MS 3) tR 0.90 min, ESI-MS 540.3 [M+H]+. 1H NMR (600 MHz, CDCl3) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.6:0.4) δ 13.92 (s, 0.6H), 13.83 (s, 0.4H), 8.31-8.26 (m, 1H), 7.90-7.85 (m, 1H), 7.38 (s, 0.6H), 7.23 (s, 0.4H), 5.38 (s, 0.6H), 5.33 (s, 0.4H), 4.83-4.72 (m, 3H), 4.02-3.93 (m, 2H), 3.44 (s, 2.4H), 3.42 (s, 3.6H), 3.18 (s, 1.2H), 3.08 (s, 0.8H), 2.92 (s, 1.8H), 2.87 (s, 1.2H), 2.79-2.72 (m, 2H), 2.34 (s, 3.6H), 2.26 (s, 2.4H), 1.98-1.88 (m, 2H), 1.41-1.34 (m, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:14][C:12]=2[CH:13]=1.O1CCCC1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([CH2:21][OH:22])[CH:24]=[CH:25][CH:26]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)O)c3)ccc2o1
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(CO)c3)ccc2o1
Temperature: 60 °C
Yield: 13 %

Procedure:
The product from Example 144 (167 mg, 0.48 mmol) was dissolved into 1 M BH3 in tetrahydrofuran (2 mL, 2 mmol), stirred at room temperature overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc. The organic phase was separated and washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO4), concentrated, and chromatographed through a short column of silica with a gradient of 0 to 5% MeOH/CH2Cl2, and through a second short column of silica with a gradient of 0 to 5% MeCN/CH2Cl2, collecting and concentrating the material with a mass ion corresponding to a borane complex. This residue was dissolved in methanol (1.5 mL), treated with 0.1 M aqueous hydrochloric acid (0.3 mL), heated at 60° C. for three hours, treated with more 0.1 M aqueous hydrochloric acid (0.1 mL), heated at 60° C. for one hour, concentrated, and chromatographed through a short column of silica with a gradient of 2 to 10% 2 M NH3 in MeOH/CH2Cl2 to provide the title compound as a white powder (13% yield). MS (ESI APCI) m/z 336 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.18 (s, 3 H), 1.38-1.53 (m, 1 H), 1.73-1.87 (m, 2 H), 1.94-2.08 (m, 1 H), 2.24-2.36 (m, 1H), 2.41-2.60 (m, 2 H), 2.94-3.14 (m, 2 H), 3.19-3.34 (m, 2 H), 4.68 (s, 2 H), 6.60 (s, 1 H), 7.28-7.34 (m, 1 H), 7.40 (dd, 1 H), 7.46-7.49 (m, 2 H), 7.52 (ddd, 1 H), 7.62 (s, 1 H), 7.73 (dd, 1 H).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:12]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3ccncc3)ccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3ccncc3)ccc2O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.094 g) in ethyl acetate (2.5 mL) and methanol (3.5 mL), 10% palladium-carbon (19 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. To the reaction mixture, 10% palladium-carbon (19 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and the residue was washed with ethyl acetate and tetrahydrofuran. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), PSQ100B(spherical), eluent: 65-45% hexane/ethyl acetate] to obtain tert-butyl 2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[O:42])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (75.2 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.83 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2) to provide the titled compound (48.5 mg, 46%) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:12]1[CH:13]=[C:8]([C:6](=[O:7])[C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=[CH:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccc(F)cc1)c1cc[n+]([O-])cc1
Product: O=C(c1ccc(F)cc1)c1ccnc(Cl)c1

Procedure:
0.88 g 4-(4-fluorobenzoyl)-pyridine N-oxide and 50 ml POCl3 are refluxed for 2 hrs. Excess POCl3 is distilled at normal pressure. The crude is treated with slightly alkaline cold water and then extracted with methylene chloride. Working as usual affords 0.80 g of title product, identical with that obtained by the Friedel-Crafts process (see Ex. 3d).
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=2[CH:4]=1)=O.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.CC(O)=O.C([BH3-])#N.[Na+]>CO>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][CH2:1][C:3]2[CH:23]=[CH:22][C:6]3[NH:7][C:8]([C@@H:10]4[CH2:14][CH2:13][CH2:12][N:11]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=3[CH:4]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(C=O)ccc2[nH]1
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CNc3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of the product from Example 95A (1.0 g, 3.17 mmol), 4-fluoroaniline (304 μL, 3.17 mmol) and AcOH (150 μL) in MeOH (30 mL) was added sodium cyanoborohydride (199 mg, 3.17 mmol). The mixture was stirred at rt overnight, and was then quenched with aqueous 1N HCl followed by stirring for 5 minutes. A few drops of aqueous NH4OH were added, and the mixture was diluted with EtOAc and washed with saturated aq. NaHCO3, H2O, and brine. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound (1.3 g, 100%). MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[CH3:20]>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[C:14]([CH3:20])[CH:15]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(O)ccc1Br
Product: Cc1cc(O)ccc1-c1ccc(C#N)cc1
Yield: 60 %

Procedure:
4-Cyanophenylboronic acid and 4-bromo-3-methylphenol were processed as described in Example 167A to provide the title compound (60% yield). 1HNMR (300 MHz, CDCl3) δ2.20 (s, 3H), 4.68 (bs, 1H), 6.78 (m, 2H), 7.15 (m, 1H), 7.42 (m, 2H), 7.76(m, 2H); MS (CDI) m/z 227 (M+NH4)+.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([CH:14]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][NH:16][CH2:17][CH:18]([CH2:23][CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[CH3:13]>C(#N)C>[CH2:23]([CH:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:17][N:16]([CH2:15][CH:14]([CH2:12][CH3:13])[CH2:25][CH2:26][CH2:27][CH3:28])[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])[CH3:24]
Reactant: CCCCC(CC)CNCC(CC)CCCC
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)c1ccccc1C(=O)O
Yield: 100.2 %

Procedure:
To 200 ml of acetonitrile were added 14.8 g of phthalic anhydride and 24.2 g of di(2-ethylhexyl)amine and the mixture was refluxed for 2 hours and then concentrated to provide 39.0 g of oily 2-{N,N-di(2-ethylhexyl)carbamoyl}-benzoic acid.