Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[F:8][C@@H:9]1[C@@H:14]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@@H](F)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@@H](F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Triethylamine (0.95 mL, 6.8 mmol) was added to a 0° C. solution of (3S,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (500.0 mg, 2.28 mmol) and methanesulfonyl chloride (0.27 mL, 3.4 mmol) in dichloromethane (9 mL), and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL). Additional dichloromethane (10 mL) was added, and the layers were separated. The organic layer was washed with 1M aqueous citric acid (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified directly via column chromatography on silica gel (Biotage 50 g column, gradient elution with 20-30% ethyl acetate in hexanes) to afford tert-butyl (3S,4S)-3-fluoro-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (629 mg, 93%) as a colorless oil that solidified to a white solid upon standing. 1H NMR (300 MHz, CDCl3) δ ppm 1.46 (s, 9H), 1.73-1.87 (m, 1H), 2.15-2.25 (m, 1H), 2.97-3.12 (m, 2H), 3.08 (s, 3H), 3.85-3.95 (m, 1H), 4.39-4.46 (m, 1H), 4.55-4.62 (m, 1H), 4.65-4.78 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:6]=2[O:7][C:8]=1[CH3:9])(=O)[CH3:2].Cl.[NH2:18][OH:19].C(=O)(O)[O-].[Na+].O>C(O)C>[OH:19][N:18]=[C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:6]=2[O:7][C:8]=1[CH3:9])[CH3:2]
Reactant: NO
Reactant: CC(=O)c1c(C)oc2c([N+](=O)[O-])cccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1c(C)oc2c([N+](=O)[O-])cccc12
Yield: 72.5 %

Procedure:
A mixture of 3-acetyl-2-methyl-7-nitrobenzo[b]furan (413 mg), hydroxylamine hydrochloride (393 mg) and sodium bicarbonate (792 mg) in ethanol (10 ml) was refluxed for 30 minutes. The reaction mixture was cooled and water was added to the solution. The separated solid was collected, washed with water and dried to give 3-(1-hydroxyiminoethyl)-2-methyl-7-nitrobenzo[b]furan (320 mg).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][C:8]1=[O:18])[CH:2]1OCC[CH2:3]1>C(Cl)(Cl)Cl.C(O)C>[CH2:1]([N:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][C:8]1=[O:18])[CH2:2][CH3:3]
Reactant: O=C1CCCc2c1ccc(=O)n2CC1CCCO1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCCn1c2c(ccc1=O)C(=O)CCC2

Procedure:
1-tetrahydrofurfuryl-7,8-dihydro-2,5(1H,6H)-quinolinedione oil, Rf-value: 0.58 (Polygram silica gel plates SIL G/UV254 of Messrs. Machery-Nagel, system: chloroform/ethanol=19/1 by volume).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C(Cl)Cl.[CH2:25]([N:27](CC)CC)C>CC(N(C)C)=O.[C-]#N.[Zn+2].[C-]#N>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:25]#[N:27])=[CH:3][N:4]=[C:5]4[N:10]=[N:9]3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCN(CC)CC
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 85 °C
Yield: 88 %

Procedure:
To a suspension of 6-[(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl]quinoline (1.0 g, 2.93 mmol) in DMAC (70 ml) were added zinc cyanide (413 mg, 3.52 mmol). The reaction mixture was degassed then PdCl2(dppf).CH2Cl2 (240 mg, 0.29 mmol) was added followed with triethylamine (0.828 ml) at R.T. The reaction mixture was degassed again. After heating at 85° C., the reaction mixture was filtered through a celite pad and washed with 5.0 ml of CH2Cl2. The solvents were concentrated under reduced pressure. The resulting residue was purified via flash column chromatography eluted with 1-3% 7N N3 in MeOH:CH2Cl2 to give the desired product (740 mg, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.28 (s, 2H) 7.55 (dd, J=8.34, 4.29 Hz, 1H) 7.81 (dd, J=8.72, 2.15 Hz, 1H) 7.99-8.04 (m, 2H) 8.33-8.37 (m, 1H) 8.91 (dd, J=4.04, 1.77 Hz, 1H) 9.41 (s, 1H) APCI (Mz+1) 288.2
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].N[CH2:35][C@@H](O)C.CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH3:35])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: C[C@H](O)CN
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@H](C)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 57 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (S)-(+)-1-amino-2-propanol (0.16 mL 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (387.8 mg, 57%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=1.6 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.92 (m, 1H), 3.32 (m, 2H), 2.19 (s, 3H), 1.18 (d, 3H, J=6.4 Hz); ES-HRMS m/z 508.0661 (M+H C22H21BrF2N3O4 requires 508.0678).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[CH2:33]([O:35][C:36](=[O:47])[CH:37]([NH2:46])[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34].CN1CCOCC1>C1COCC1>[CH2:33]([O:35][C:36](=[O:47])[CH:37]([NH:46][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: CCOC(=O)C(N)C(=O)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)c1cc2cc(Cl)ncc2[nH]1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (100 mg, 0.51 mmol) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (183 mg, 0.66 mmol) were dissolved in THF (20 ml). After 5 min, 2-amino-3-oxo-3-phenylpropionic acid ethyl ester hydrochloride (Tetrahedron Lett., 1993, 34(2), 211–214; 124 mg, 0.51 mmol) and 4-methylmorpholine (56 μl, 0.51 mmol) were added and the reaction mixture stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between water (40 ml) and EtOAc (3×30 ml). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19). This material was further triturated with methanol:diethyl ether (1:19) to give the title compound as a pale yellow solid. m/z (ES+)=386 [M+H]+; RT=3.56 min.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([OH:20])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][O:24][CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([N:23]([O:24][CH3:25])[CH3:22])=[O:20])[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CNOC
Reactant: COc1ccc(-c2c(C(=O)O)cnn2C(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C(=O)N(C)OC)cnn2C(C)(C)C)cc1
Yield: 92.5 %

Procedure:
A solution of the compound (300 mg, 1.09 mmol) obtained in step 2, N,O-dimethylhydroxylamine monohydrochloride (160 mg, 1.64 mmol), HOBt (222 mg, 1.64 mmol), WSC (314 mg, 1.64 mmol) and TEA (0.228 mL, 1.64 mmol) in DMF (5 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and aqueous sodium hydrogen carbonate solution and dried, and the solvent was evaporated under reduced pressure to give a crude product 1-tert-butyl-N-methoxy-5-(4-methoxyphenyl)-N-methyl-1H-pyrazole-4-carboxamide (320 mg, 1.008 mmol, 92%) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7](Cl)[C:6]=2[C:13]#[N:14].[CH2:15]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>COC(O)CC>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:16][CH2:17][CH3:18])[C:6]=2[C:13]#[N:14]
Reactant: CCCCNCCCC
Reactant: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Agent: CCC(O)OC
Product: CCCCN(CCCC)c1ccc2cc(Cl)cnc2c1C#N
Yield: 82.3 %

Procedure:
22.3 g of 3,7-dichloro-8-cyanoquinoline and 26 g of di-n-butylamine in 300 ml of methoxypropanol were refluxed for 12 hours, the solution was cooled, and the precipitated solid was filtered off under suction and recrystallized from a mixture of naphtha and toluene. 26 g of 3-chloro-8-cyano-7-di-n-butylaminoquinoline of melting point 112° C. were obtained. Yield: 82.5% of theory.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:17]([NH:16][C:2]3[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=4)[N:3]=3)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)=[N:30][CH:31]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccc(Br)cn2)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc(Br)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32; 2,6-dichloro-quinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-bromo-pyridin-2-yloxy)-phenyl]-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CCN(CC)CC.[C:18](Cl)([CH3:20])=[O:19]>C(Cl)Cl>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:18](=[O:19])[CH3:20])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a white suspension of 1-(2-aminophenyl)ethanone (25 g, 185 mmol) and Et3N (33.4 mL, 240 mmol) in DCM at 0° C. was added dropwise AcCl (15.70 mL, 222 mmol) in 25 mL DCM. The reaction mixture was then stirred at r.t. for 2 h. After the reaction went to completion as monitored by LC-MS, the reaction mixture was cooled to 0° C., and was then quenched with H2O (100 mL). The organic phase was isolated; the aqueous layer was extracted with DCM. The organic phases were combined, and washed with H2O and brine. The resulting organic phase was dried over anhydrous MgSO4, filtered and concentrated to dryness to give crude N-(2-acetylphenyl)acetamide, which was used in the next step without further purification (30 g, yield 92%). MS (m/z): 136 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C1C(=O)N([Br:22])C(=O)C1>>[Br:22][C:8]1[CH:7]=[C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCCC(=O)O)cc1
Product: COc1ccc(CCCC(=O)O)cc1Br
Reaction time: 20 h
Yield: 99.6 %

Procedure:
According to the procedure described in the synthesis method of Intermediate 3 in Reference Example 1 (Step g) with the modifications that the reaction was carried out under ice cooling for 30 minutes and at room temperature for 20 hours, 4-(4-methoxyphenyl)butyric acid (11.64 g, Ald) and NBS (11.21 g) were reacted and treated to obtain the title compound (Intermediate 11, 16.30 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:11][C:12]1[C:20]([O:21]C2CCCCO2)=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][N:16]2C1CCCCO1)[CH2:9][CH3:10].[OH-].[Na+]>ClCCl>[CH2:8]([O:11][C:12]1[C:20]([OH:21])=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2)[CH2:9][CH3:10]
Reactant: CCCOc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1c(O)ccc2[nH]ncc12
Reaction time: 2.5 h
Yield: 74384.8 %

Procedure:
Under a nitrogen atmosphere, trifluoroacetic acid (5.5 ml) was added to a solution of 4-propoxy-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (852.6 mg) in dichloromethane (16.5 ml) at room temperature. After 2.5 hours, the reaction solution was poured onto ice, adjusted to pH 7 with an aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The extract solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The residue purified was concentrated under reduced pressure and the resulting residue was washed with diethyl ether/hexane by repulping to obtain 4-propoxy-1H-indazol-5-ol (338.2 g, 80%, two steps).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:10][C:9]2[C:8]([N:11]3[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]3)=[N:7][C:6]([C:19]3[CH:24]=[C:23]([F:25])[C:22](F)=[CH:21][C:20]=3[F:27])=[N:5][C:4]=2[CH2:3]1.[CH3:29][S:30](C)=O.C[S-].[Na+]>O>[F:27][C:20]1[CH:21]=[C:22]([S:30][CH3:29])[C:23]([F:25])=[CH:24][C:19]=1[C:6]1[N:7]=[C:8]([N:11]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]2)[C:9]2[CH2:10][S:2](=[O:28])(=[O:1])[CH2:3][C:4]=2[N:5]=1
Reactant: O=C1CCN(c2nc(-c3cc(F)c(F)cc3F)nc3c2CS(=O)(=O)C3)CCN1
Reactant: CS(C)=O
Agent: C[S-]
Agent: [Na+]
Solvent: O
Product: CSc1cc(F)c(-c2nc3c(c(N4CCNC(=O)CC4)n2)CS(=O)(=O)C3)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 500 mg of 1-[6,6-dioxido-2-(2,4,5-trifluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]-1,4-diazepan-5-one and 5 ml of DMSO, 89 mg of sodium thiomethoxide was added, the mixture was stirred at ambient temperature for 1 hour, here was then added 21 mg of sodium thiomethoxide, and the mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added 50 ml of water, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure. The filtrate was separately extracted with a mixture of EtOAc and THF, the organic phase obtained was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the solid obtained was combined with the former solid. The mixture was purified by silica-gel column chromatography (chloroform-MeOH) to yield 352 mg of 1-{2-[2,5-difluoro-4-(methylthio)phenyl]-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl}-1,4-diazepan-5-one.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][NH:12][C:13]1[N:17]([C@@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=1)(O)=[O:2].Cl.[NH2:41][CH2:42][C:43]([NH2:45])=[O:44].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:43]([CH2:42][NH:41][C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][C:33]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][NH:12][C:13]1[N:17]([C@@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=1)=[O:2])(=[O:44])[NH2:45]
Reactant: O=C(O)CCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)CCCOc1cc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.6 %

Procedure:
2-[3-(3-Carboxypropoxy)-4-phenylbenzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (50 mg), glycinamide hydrochloride (17 mg), 1-hydroxybenzotriazole (29 mg) and triethylamine (47 mg) were suspended in N,N-dimethylformamide (2 mL) at room temperature. To the mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (36 mg), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (23 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[CH3:17][O:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH2:28])[C:22]2=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH:28][C:14]([C:10]3[C:11]([CH3:13])=[N:12][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][CH:9]=3)=[O:16])[C:22]2=[CH:21][CH:20]=1
Reactant: COc1ccc2c(n1)c(C)cn2N
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)c(C)cn2NC(=O)c1cnc(-c2ccccn2)nc1C
Yield: 46.6 %

Procedure:
A solution of 2-pyridin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.69 mmol), 5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.69 mmol), DIPEA (5.01 mmol) and HATU (2.03 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 16 h. DMF is evaporated in vacuo. The residue is dissolved in EtOAc (40 mL), and washed with water (3×10 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-15% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (295 mg) as a solid. MS: 375 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.40 (s, 3H), 2.84 (s, 3H), 4.02 (s, 3H), 6.70 (d, H), 7.13 (s, H), 7.41 (m, H), 7.50 (d, H), 7.85 (t, H), 8.51 (m, 2H), 8.78 (s, 2H), 10.57 (br, N—H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([S:31]([N:12]2[C:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:11]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)#[N:24]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(C#N)c2)c1)C(=O)OC(C)(C)C

Procedure:
By an operation similar to that in Reference Example 32 and using tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (305 mg), and 3-cyanobenzenesulfonyl chloride (318 mg), the title compound was obtained as a colorless oil (yield 447 mg, 95%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[CH:21][CH:22]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[CH:21][CH:22]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc[nH]1
Agent: O=C(Nc1ccc(O)cc1)c1ccccn1
Product: O=C(Nc1ccc(O)cc1)c1ccc[nH]1

Procedure:
This compound was prepared from 1H-pyrrole-2-carboxylic acid (4-benzyloxy-phenyl)-amide (2.5 g, 8.55 mmol), using the same method used to prepare of pyridine-2-carboxylic acid (4-hydroxyphenyl)amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 7.5% methanol in DCM, to give the product as a colorless solid, 1.47 g (85%). MS m/z 203 (MH+). 1H NMR(DMSO-d6) δ 6.14 (m, 1H), 6.72 (d, 2H), 6.92 (m, 1H), 6.99 (d, 1H), 7.47 (d, 2H), 9.19 (s, 1H). Anal. calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.15; H, 4.83; N, 13.81.
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]=[C:17]([F:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1>>[Cl:21][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:18]=[C:17]([F:19])[C:16]=1[OH:20]
Reactant: Oc1c(F)cc(Br)cc1Cl
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(F)c(O)c(Cl)c2)cc1
Yield: 48 %

Procedure:
4-Cyanophenylboronic acid and 4-bromo-2-chloro-6-fluorophenol were processed as described in Example 167A to provide the title compound (48% yield). 1HNMR (300 MHz, MeOD) δ7.40 (m, 1H), 7.52 (m, 1H), 7.78 (s, 4H); MS (CDI) m/z 248 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7]2[C:12]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[C:25]5[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=5[CH:23]=[CH:22][CH:21]=4)[CH:14]=3)=[CH:11][CH:10]=[C:9]([C:33]([F:36])([F:35])[F:34])[N:8]=2)[CH2:2]1.[CH3:37][C:38]([CH3:40])=O>>[CH:38]([N:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7]2[C:12]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([O:19][C:20]4[C:25]5[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=5[CH:23]=[CH:22][CH:21]=4)[CH:14]=3)=[CH:11][CH:10]=[C:9]([C:33]([F:36])([F:34])[F:35])[N:8]=2)[CH2:2]1)([CH3:40])[CH3:37]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NC4CCNC4)ncn3)cccc2s1
Reactant: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)nc4NC4CCN(C(C)C)C4)ncn3)cccc2s1

Procedure:
N-(4-(6-(2-(Pyrrolidin-3-ylamino)-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide, Example 3(c), (30 mg, 0.06 mmol) was reacted with acetone (1 mL, 136 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 558 (M+1). Mp: 140-141° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][C@H:29]2[CH2:30][CH2:31][C@@H:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@H]1CC[C@@H](c2ccccn2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@H]3CC[C@@H](c4ccccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (180 mg, 0.649 mmol), cis-3-(2-pyridyl)cyclopentylamine (158 mg, 0.973 mmol) and triethylamine (0.200 mL, 0.976 mmol) in anhydrous DMSO (3 mL) was stirred at 80° C. for 8 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/3) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[cis-3-(2-pyridyl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (diastereomer mixture, 55.6 mg, 20%) as a yellow powder.