Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C[O-].[Na+].[C:22](=O)(OCC)[O:23]CC>C1(C)C=CC=CC=1>[OH:23][C:22]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: CCOC(=O)OCC
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(=O)c2c(ncn2Cc2noc(O)n2)n(C)c1=O
Yield: 82 %

Procedure:
5.04 g. of 2-(theophylline-7-yl)-acetamidoxime, 2.16 g. of sodium methylate, 4.72 g. of diethyl carbonate and 100 cm3 of toluene are heated for 2 hours to boiling, the mixture is then evaporated and the residue crystallized from water. 4.3 g. (82% yield) of 7-[(5-hydroxy-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. M.p.: 206°-207° C.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[CH:3][C:2]=1[CH2:10][OH:11]>O=[Mn]=O.C(Cl)(Cl)Cl>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[CH:3][C:2]=1[CH:10]=[O:11]
Reactant: OCc1cc2n(n1)CCCC2
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2n(n1)CCCC2

Procedure:
MnO2 (activated) (3.36 g) was added to the CHCl3 (44 mL) solution of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)methanol (673 mg) and refluxed for 1 h under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. The filtrate was reduced under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (2/1–1/2). The titled compound was obtained as pale yellow oil (510 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([NH:14][C@@H:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[C:30]([C:34](N(C)OC)=[O:35])[N:31]([CH3:33])[CH:32]=3)=[CH:24][CH:23]=2)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH3:40][Mg]Br>C1COCC1>[C:34]([C:30]1[N:31]([CH3:33])[CH:32]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][C@H:15]([NH:14][C:12]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=3)=[O:13])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:27][CH:26]=2)[N:29]=1)(=[O:35])[CH3:40]
Reactant: CON(C)C(=O)c1nc(-c2ccc(C[C@@H](CCC(=O)O)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1nc(-c2ccc(C[C@@H](CCC(=O)O)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude (4R)-4-[({3-chloro-4-[(1-methylethyl)oxy]phenyl}carbonyl)amino]-5-[4-(1-methyl-2-{[methyl(methyloxy)amino]carbonyl}-1H-imidazol-4-yl)phenyl]pentanoic acid (3.18 mmol) in anhydrous THF (16 mL) under nitrogen at 0° C. was added methylmagnesium bromide (10.6 mL, 10 equiv, 3.0 M in ether) dropwise by syringe. The reaction was stirred for 30 minutes at 0° C. and then carefully quenched with sat. aq. NH4Cl solution (10 mL), followed by 1 N HCl solution (60 mL) such that the pH of the aqueous layer ˜5.5. The product was extracted with EtOAc (4×40 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound, which was used directly in the next reaction. ESMS [M+H]+=512.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]2)=[CH:11][CH:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
In DMF (75 mL) was dissolved 3-nitro-7-hydroxyquinoline (5.0 g, 26.2 mmol.). Under chilling with ice, to the solution was added sodium hydride (1.15 g, 29 mmol.). After 20 minutes, benzyl bromide (3.4 mL, 29 mmol.) was further added for 10 minutes. The mixture was then stirred overnight at room temperature. After the completion of reaction was confirmed, the mixture was poured into a mixture of ice and water. The precipitated crystalline product was collected by filtration, washed with water, and dried, to give the desired compound (7 g) as a white crystalline product (yield 95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:15][C:16]1[C:21]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:9][CH:10]=2)=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: Clc1nccnc1Cl
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-(pyridin-2-ylamino)phenol (14.551 g, 78.14 mmol) and 2,3-dichloropyrazine (11.64 g, 78.14 mmol) in DMSO was added CESIUM CARBONATE (30.55 g, 93.77 mmol). The resulting mixture was heated to 60° C. overnight. Aqueous workup was carried out with DCM extraction and washing with alternating water and brine solutions. Purification by Biotage (0-2%, then 2% MeOH/DCM), followed by washing with EtOAc, produced clean product as solid. MS (ESI, pos. ion) m/z: 298.8 (M+1). IC50 (uM) 0.475.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[C:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=3)[CH:19]=2)[CH2:9][O:10][C:11]([CH3:15])([CH3:14])[O:12][CH2:13]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc(C#Cc2cccc(C#CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)c2)cc(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CCc2cccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 70 %

Procedure:
A mixture of the product of Step B (0.09 g, 0.17 mmol) and 10% Pd/C (0.04 g) in EtOH (10 ml) was stirred for 36 h at room temperature under H2. The catalyst was removed by filtration through Celite pad and the filtrate was evaporated to dryness to give the title product (0.063 g; 70%), as colourless paste. 1H-NMR (CDCl3) 1.41 (s, 3H); 1.42 (s, 3H); 1.46 (s, 9H); 1.92-1.98 (m, 2H); 2.49-2.55 (m, 2H); 2.81-2.86 (m, 4H); 7.18 (tr, 1H, J=7.59 Hz). 3.67 (d, 2H, J=11.72 Hz); 3.80 (s, 6H); 3.83 (s, 3H); 3.88 (d, 2H, J=11.65 Hz); 5.01 (broad s, 1H); 6.37 (s, 2H); 6.98-7.01 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(C)(C)C.Cl>CC(O)C.C(Cl)Cl>[NH2:7][CH2:8][CH:9]([NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCC(NC(=O)c1ccc(-c2ccncc2)cc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: NCC(NC(=O)c1ccc(-c2ccncc2)cc1)c1ccccc1

Procedure:
The title compound was prepared by BOC cleavage of the compound obtained in Example 3 with HCl in 2-propanol/DCM at room temperature.
Reaction SMILES: [CH:1]1([C:4]2[C:19]([O:20][CH2:21][C@@H:22]([NH:27]C(=O)OC(C)(C)C)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:7]3[N:8]([CH3:17])[C:9](=[O:16])[C:10]4[C:15]([C:6]=3[CH:5]=2)=[CH:14][CH:13]=[N:12][CH:11]=4)[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:27][C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:21][O:20][C:19]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[N:8]([CH3:17])[C:7]=2[CH:18]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1C1CC1)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)COc1cc2c(cc1C1CC1)c1ccncc1c(=O)n2C
Yield: 17.1 %

Procedure:
To a solution of (S)-tert-butyl (1-((9-cyclopropyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (60 mg, 0.129 mmol) in MeOH (4 mL), at 0° C. was added a 4M solution of HCl in 1,4-dioxane (2 mL, 8 mmol). The resultant solution was stirred for 2 h at RT. The methanol was removed under reduced pressure and the residue was extracted with ethyl acetate (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (2×5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column (MeOH—CHCl3) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-9-cyclopropyl-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (8 mg, 0.022 mmol, 17% yield) as an off-white solid. LC/MS (ESI) m/z 366.2 [(M+H)+, calcd for C22H28N3O2 366.2]; LC/MS retention time (method B): tR=1.34 min. HPLC retention time (method B): tR=4.87 min and HPLC retention time (method A): tR=9.18 min. 1H NMR (400 MHz, CDCl3) δ ppm 9.47 (s, 1H), 8.75 (d, J=5.7 Hz, 1H), 8.28 (d, J=5.7 Hz, 1H), 7.96 (s, 1H), 7.06 (s, 1H), 4.27 (m, 1H), 4.06-4.15 (m, 1H), 3.84 (s, 3H), 3.38-3.48 (m, 1H), 2.23-2.38 (m, 1H), 1.83-1.94 (m, 1H), 1.56-1.67 (m, 1H), 1.46-1.55 (m, 1H), 1.00-1.08 (m, 6H), 0.79-0.94 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:43][C@@H:44]([C:50]1[CH:51]=[C:52]2[C:57](=[CH:58][CH:59]=1)[N:56]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:55][CH2:54][CH2:53]2)[CH2:45][C:46]([O:48][CH3:49])=[O:47]>CN(C)C=O>[C:60]([N:56]1[C:57]2[C:52](=[CH:51][C:50]([C@H:44]([NH:43][C:7]([C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[O:9])[CH2:45][C:46]([O:48][CH3:49])=[O:47])=[CH:59][CH:58]=2)[CH2:53][CH2:54][CH2:55]1)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]
Reactant: COC(=O)C[C@@H](N)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)O)no1
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: COC(=O)C[C@@H](NC(=O)c1cc(C)on1)c1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 5-methyl-isoxazole-3-carboxylic acid (65 mg) in dimethylformamide (30 ml) was treated successively with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg), diisopropylethylamine (1 ml) and methyl (R) 3-amino-3-(1-boc-1,2,3,4-tetrahydro-quinolin-6-yl)-propionate (200 mg, Reference Example 14). After standing at room temperature overnight the mixture was evaporated to low bulk and the residue partitioned between ethyl acetate and dilute hydrochloric acid. The layers were separated and the organic layer was washed with sodium carbonate solution, dried, and evaporated. The residue was purified by flash chromatography to give the title compound as an orange gum, 310 mg.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cccc(Oc3ccccc3)c12
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A mixture of 1-cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (322 mg, 1.0 mmol), glycine (1.51 g, 20.1 mmol), and a 0.5 M sodium methoxide solution in methanol (38.2 mL) was refluxed for 31 h before it was cooled to room temperature and concentrated in vacuo. Water (75 mL) was added and the pH of the yellow suspension was adjusted to 10 with aqueous 1 N HCl. A clear yellow solution was obtained after 5 minutes of sonication. The solution was washed with dichloromethane (2×50 mL). The remaining aqueous layer was acidified to pH=3 with aqueous 1 N HCl. The white precipitate formed was separated by filtration, washed with water and dried in vacuo to give the title compound as a white solid (354 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.86 (bs, 1H), 9.56 (t, 1H), 8.09 (m, 1H), 7.88 (t, J=8.2 Hz, 1H), 7.47 (m, 2H), 7.21 (m, 4H), 4.05 (d, J=5.8 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.BrBr.N>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]2[S:11][C:10]([NH2:12])=[N:9][C:4]=2[CH:3]=1
Reactant: NC(=S)Nc1cc(Br)cc(Br)c1
Agent: BrBr
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc2cc(Br)cc(Br)c2s1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
To a solution of (3,5-dibromo-phenyl)-thiourea (35 g, 0.11 mol) in CHCl3 (600 mL) at −55-60° C. was added dropwise a solution of Br2 (40.40 g, 0.25 mol, in 100 ml of CHCl3) over a period of 1 h. The reaction mixture was stirred at −55-60° C. for 15 min followed by refluxing at 70-75° C. for 3 h. The reaction mixture was cooled to room temperature and filtered to get the crude residue that was washed with hexane and diethyl ether. The solid thus obtained was dissolved in H2O, basified with aqueous ammonia solution to pH 10-12 and stirred for 30 min. The solid thus obtained was filtered and washed with water to get the desired product (34.0 g, 98%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:20][C@H:21]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:23](=[CH:24][CH:25]=[C:26]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@H:31]([CH3:34])[CH2:32][OH:33])[C:22]1([CH3:45])[CH3:44])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:12]([O:20][C@H:21]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:23](=[CH:24][CH:25]=[C:26]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@@H:31]([CH2:32][O:33][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH3:34])[C:22]1([CH3:44])[CH3:45])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)[C@H]2CC[C@H]3C4=CC=C5C(C)(C)[C@@H](OC(=O)c6ccccc6)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 0.573 g toluene-4-sulfonylchloride in 4 ml pyridine was added drop by drop to a solution of 0.926 g (20S)-4,4,20-trimethyl-pregna-5,7-dien-3β,21-diol 3-benzoate in 15 ml pyridine while cooling on an ice-bath. The reaction mixture was stirred for 1 h at 0-3□C. and overnight at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layers were combined, washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.0 g of (20S)-4,4-dimethyl-20-[((toluene-4-sulfonyl)oxy)methyl]-pregna-5,7-dien-3β-ol benzoate which could be further purified by crystallization from methanol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].C([O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37](O)=[O:38])=[CH:34][CH:35]=3)[C:30]([CH3:40])=[C:29]2[CH3:41])=[CH:23][CH:22]=1)=[O:14])(C)(C)C>>[CH3:41][C:29]1[N:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]3[C:15]([C:13]([OH:14])=[O:12])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:22][CH:23]=2)[C:36]2[C:31]([C:30]=1[CH3:40])=[CH:32][C:33]([C:37](=[O:38])[NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[CH:34][CH:35]=2
Reactant: NCc1cccs1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccs3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 2-thiophenemethylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[CH:3]=1.[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:9][O:13][C:10](=[O:12])[CH3:11])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Br)cc[n+]1[O-]
Solvent: ClCCl
Product: CC(=O)OCc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-methylpyridine-1-oxide (4.00 g, 21.40 mmol) in DCM (20 mL) is added acetic anhydride (6 mL). The mixture is stirred at room temperature for 1 hour and then heated at reflux overnight. The solvent is removed under vacuum and the crude product is filtered through a silica plug, eluting with DCM to afford the title compound as an orange oil (815 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC.Cl>C1(C)C=CC=CC=1.CCOCC.C(Cl)Cl.[Cu]I>[ClH:1].[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:19]3[CH:20]=[CH:21][C:22]4[C:23]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][C:24]=5[N:25]([CH3:28])[C:26]=4[CH:27]=3)[C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1cc(OCc2ncc(Cl)cc2Cl)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ncc(Cl)cc5Cl)cc4=O)cc31)CCNCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A suspension of 4-((3,5-dichloropyridin-2-yl)methoxy)pyridin-2(1H)-one (103 mg, 0.380 mmol), tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (131 mg, 0.345 mmol), Cs2CO3 (124 mg, 0.380 mmol), CuI (79 mg, 0.41 mmol) and trans-1,2-bis(methylamino)cyclohexane (33 mg, 0.23 mmol) in toluene (10 mL) was degassed by bubbling N2 through the suspension for 45 min. The suspension was put under N2 and heated at reflux for 2 d. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a viscous oil. 2 N HCl in Et2O (100 mL) was added to a solution of the viscous oil in CH2Cl2 (10 mL) under N2, and the resulting suspension was stirred at 25° C. for 16 h. The suspension was filtered, and the solid was washed with Et2O and put in a vacuum oven at 40° C. for 3 h to afford 59 mg (34%) of the title compound as a white powder: mp 178-180° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.14 (br s, 2H), 8.69 (s, 1H), 8.37 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.09 (dd, J=7.5, 2.5 Hz, 1H), 6.01 (s, 1H), 5.30 (s, 2H), 3.69 (s, 3H), 3.42-3.30 (m, 4H), 3.28-3.22 (m, 2H), 3.17-3.09 (m, 2H); ESI MS m/z 469 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=2[CH3:18])[CH:7]=1.[C:20]([O:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[CH2:38][O:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33]Br)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]1([C:20]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=2[CH2:38][O:39][C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH2:33][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:9]=3[CH3:18])[CH:7]=2)=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(-c2cc(O)ccc2C)c(C)c1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)ccc2C)c(C)c1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 2.24 g (8.7 mmol) of methyl 5′-hydroxy-2,2′-dimethylbiphenyl-4-carboxylate with 4.20 mg (9.6 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 1.26 g (9 mmol) of potassium carbonate, the desired product is obtained in the form of a colourless oil (m=5.34 g; Y=99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:11]=1[O:12][CH3:13]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:11]=1[O:12][CH3:13]
Reactant: COC(=O)c1cc(Cl)c(OC)c2c1OCCO2
Agent: [Na+]
Agent: [OH-]
Product: COc1c(Cl)cc(C(=O)O)c2c1OCCO2
Yield: 2.6 %

Procedure:
A mixture of intermediate (2) (0.138 mol) in a 2N NaOH solution (500 ml) was stirred and refluxed for 1 hour, then cooled and washed with DCM. The mixture was separated into its layers. The aqueous layer was acidified with a concentrated HCl solution until pH=2. The solid was filtered off, washed with water and dried in vacuo. A part (2.5 g) of this fraction was crystallized from methanol. The precipitate was filtered off and dried, yielding 0.88 g of 7-chloro-2,3-dihydro-8-methoxy-1,4-benzodioxin-5-carboxylic acid (intermediate 3, mp. 172° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH:25]4[CH2:27][CH2:26]4)=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:28][C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1>>[C:7]([C:6]1[CH:9]=[C:2]([N:30]2[C@H:29]([CH3:28])[CH2:33][O:32][C:31]2=[O:34])[CH:3]=[CH:4][C:5]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH:25]3[CH2:27][CH2:26]3)=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])#[N:8]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2C#N)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2C#N)CC1

Procedure:
By reaction and treatment in the same manner as in Example 110 and using 5-bromo-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (425 mg) described in Preparation Example 194 and (R)-4-methyloxazolidin-2-one. (121 mg) described in Preparation Example 25, the title compound (363 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:13]2[CH2:14][CH2:15][C:16]3[C:6]4[CH:5]=[C:4]([O:18][CH3:19])[C:3]([O:2][CH3:1])=[CH:8][C:7]=4[O:9][C:10](=[O:17])[C:11]=3[CH2:12]2)=[CH:23][CH:22]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: O=Cc1ccc(Cl)cc1
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(Cc1ccc(Cl)cc1)C3
Yield: 48 %

Procedure:
Prepared by the procedure of Example 3 from 8,9-dimethoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]-pyridin-5-one* and 4-chlorobenzaldehyde. Yield 48%; mp 173°-175° C.