Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])[CH:5]=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:35][CH2:34]2)=[CH:28][C:27]=1[CH3:49].Cl.C([O-])(O)=O.[Na+]>C(O)C(F)(F)F.C(Cl)Cl>[C:20]([C:19]1[CH:18]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][CH2:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[O:40])[CH2:37][CH2:38]4)=[CH:28][C:27]=3[CH3:49])[N:7]=2)[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1N
Reactant: N#Cc1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C#N)c3)nc3ccccn23)n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzonitrile (Intermediate Example 5) (0.462 g, 1.39 mmol) and phenylmethyl 4-[(4-amino-3-methylphenyl)oxy]-1-piperidinecarboxylate (0.567 g, 1.67 mmol) were dissolved in 16 mL of trifluoroethanol with stirring in a pressure vessel. HCl (4N in dioxane, 0.17 mL, 0.68 mmol) was added via syringe. The vessel was sealed and placed in an 80° C. oil bath. The reaction was stirred at 80° C. for 40 h and cooled to rt. The reaction was poured into half-saturated NaHCO3 solution and DCM. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.700 g (79%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (br. s., 1H), 8.90 (s, 1H), 8.20 (d, J=5.1 Hz, 1H), 8.04 (s, 1H), 7.96-7.86 (m, 2H), 7.72-7.61 (m, 2H), 7.46-7.21 (m, 7H), 6.93-6.79 (m, 3H), 6.41 (d, J=5.3 Hz, 1H), 5.06 (s, 2H), 4.59-4.50 (m, 1H), 3.77-3.65 (m, 2H), 3.36-3.21 (m, 2H), 2.18 (s, 3H), 1.97-1.86 (m, 2H), 1.61-1.49 (m, 2H).
Reaction SMILES: Br[C:2]1[S:27][C:5]2[C:6]3[CH:14]=[N:13][C:12]([N:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>>[C:23]([N:15]([C:12]1[N:13]=[CH:14][C:6]2[C:5]3[S:27][C:2]([C:36](=[O:37])[NH:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[Cl:28])=[CH:3][C:4]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:11]=1)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sc(Br)cc1CCO2)C(C)(C)C
Product: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sc(C(=O)Nc3ccccc3Cl)cc1CCO2)C(C)(C)C
Yield: 61 %

Procedure:
Following Scheme 4, tert-butyl 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl(tert-butyl)carbamate and 2-chlorophenylisocyanate were reacted to give tert-Butyl tert-butyl(2-(2-chlorophenylcarbamoyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl)carbamate (61%). MS: (ESI+) 528.2
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:38])=[C:5]([CH:35]=[CH:36][CH:37]=1)[C:6]([O:8][C@H:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[CH:21]=1)[CH2:10][C:11]1[C:16]([Cl:17])=[CH:15][N+:14]([O-:18])=[CH:13][C:12]=1[Cl:19])=[O:7])=O.Cl.Cl.[NH2:41][C@H:42]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:43]([O:45][C@@H:46]1[CH:51]2[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]2)[CH2:47]1)=[O:44]>>[CH:6]([OH:8])=[O:7].[OH:38][C:4]1[C:3]([CH2:1][NH:41][CH:42]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:43](=[O:44])[O:45][C@@H:46]2[CH:51]3[CH2:50][CH2:49][N:48]([CH2:53][CH2:52]3)[CH2:47]2)=[CH:37][CH:36]=[CH:35][C:5]=1[C:6]([O:8][C@H:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)[CH:21]=1)[CH2:10][C:11]1[C:16]([Cl:17])=[CH:15][N+:14]([O-:18])=[CH:13][C:12]=1[Cl:19])=[O:7]
Reactant: O=Cc1cccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1O
Reactant: N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccc(CNC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1O
Product: O=CO

Procedure:
The title compound was synthesized from [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl] 3-formyl-2-hydroxy-benzoate and Intermediate 8 via the same method described for Example 1.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][N:6]([CH3:10])[C:5]1=[O:11])([CH3:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH:17]=[C:7]1[N:6]([CH3:10])[C:5](=[O:11])[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]1=[O:9])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: CC(C)N1C(=O)CN(C)C1=O
Product: CC(C)N1C(=O)C(=CN(C)C)N(C)C1=O
Temperature: 100 °C

Procedure:
A mixture of 13.4 g of 3-isopropyl-1-methyl-imidazolidine-2,4-dione and 13.6 ml dimethylformamide dimethylacetal were heated at 100° C. over the weekend. The reaction mixture was cooled to rt and purified by flash chromatography to give 9.9 g of a golden oil. Mass spectrum (EI) m/z 211 M+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C([N:7](C(C)C)C(C)C)C.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16][CH2:15]1>ClCCl>[C:20]([CH:17]1[CH2:18][CH2:19][N:14]([C:1]([NH2:7])=[O:2])[CH2:15][CH2:16]1)#[N:21]
Reactant: N#CC1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: N#CC1CCN(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask containing phosgene (20% wt in toluene, 3.16 mL) and dichloromethane (10 mL) was cooled with an ice bath. A solution of N-ethyl-N-isopropylpropan-2-amine (1.393 mL) and piperidine-4-carbonitrile (0.441 g) in dichloromethane (5 mL) was added via a syringe dropwise. The mixture was stirred at room temperature overnight and then concentrated to dryness. The residue was dissolved in methanol (10 mL) and 2 mL of 7 N NH3 in methanol. The mixture was stirred at 50° C. overnight. The mixture was concentrated and the residual solid was mixed with brine (5 mL) and extracted with ethyl acetate (8×25 mL). The organic solution was dried (MgSO4), filtered and concentrated. The crude material was purified on a silica gel column eluting with 5-10% methanol in CH2Cl2.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][CH3:19])[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH3:19])[C:33](=[O:35])[C:32]3[CH:36]=[CH:37][C:29]([Cl:28])=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=3)[C@H:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)c(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in Example 78 and 4-chloro-3-trifluoromethylbenzoic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([CH:23]=[O:24])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-(3,4-diethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.33 g). To the solution was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-(3,4-diethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.32 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:12]2=[N:11][C:10]=1[C:23]([O:25]CC)=[O:24])[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH:15]3[CH2:16][CH2:17][N:18]([C:12]2=[N:11][C:10]=1[C:23]([OH:25])=[O:24])[CH2:19][CH2:20]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCN2CC1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCN2CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A mixture of ethyl 3-(benzyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-7,10-ethanopyrimido[1,2-a][1,3]diazepine-2-carboxylate (0.5491 g, 1.486 mmol) and LiOH.H2O (0.071 g, 2.97 mmol) in ethanol (12 mL) and water (3.00 mL) was stirred at room temperature for 6 h. The mixture was acidified with concentrated HCl and the product was extracted with ethyl acetate. The organic phase was washed with brine, then dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (0.4521 g, 89% yield). 1H NMR (500 MHz, CD3OD) δ: 7.53-7.49 (2H, m), 7.42-7.36 (3H, m), 5.27 (2H, d, J=15.3 Hz), 4.11-4.00 (4H, m), 3.96 (2H, d, J=14.0 Hz), 3.17-3.13 (1H, m), 2.45-2.39 (2H, m), 2.10-2.03 (2H, m). LCMS (M+H) calcd for C18H20N3O4: 342.14; found: 342.20.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=2[N:12]([CH2:20][C:21]2[C:22]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:23]=3[S:24][CH:25]=2)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+].Cl>CO>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]([CH2:20][C:21]3[C:22]4[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:23]=4[S:24][CH:25]=3)[C:11](=[O:31])[N:10]([C@@H:6]([CH2:7][CH2:8][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:5][C:4]([OH:3])=[O:32])[C:14]=2[CH:15]=1
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccc(C)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(c1)n([C@@H](CCc1ccccc1)CC(=O)O)c(=O)n2Cc1csc2cccc(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 179.4 %

Procedure:
To a solution of (S)-3-[6-Methyl-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (0.12 g, 0.23 mmol) in MeOH (5 mL) was added 2N NaOH (2 mL). The reaction mixture was stirred at room temperature for 2 h. When the reaction was complete, the reaction mixture was treated with 1N HCl and extracted with CH2Cl2 (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1 CH2Cl2:MeOH as an eluent to afford 0.1 g of the title compound as a white solid. LCMS (ESMS): m/z 485.54 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C@H:10]2[O:22][C@@H:21]([CH2:23][O:24]C(=O)C)[C@H:16]([O:17]C(=O)C)[C@@H:11]2[O:12]C(=O)C)[N:6]=1)=O.[NH3:28]>>[C@@H:10]1([N:7]2[CH:8]=[N:9][C:5]([C:3]([NH2:28])=[O:2])=[N:6]2)[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]1[OH:12]
Reactant: COC(=O)c1ncn([C@H]2O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Reactant: N
Product: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate (62 g, 161 mmol) was placed in a steel bomb and treated with freshly prepared methanolic ammonia (350 ml, prepared by passing dry HCL gas into dry methanol at 0° C. until saturation) at 0° C. The steel bomb was closed and stirred at room temperature for 18 h. The steel bomb was then cooled to 0° C., opened and the content evaporated to dryness. The residue was treated with dry ethanol (100 ml) and evaporated to dryness. The residue obtained was triturated with acetone to give a solid, which was filtered and washed with acetone. The solid was dried overnight at room temperature and dissolved in a hot EtOH (600 ml) and water (10 ml) mixture. The volume of the EtOH solution was reduced to 150 ml by heating and stirring on a hot plate. The hot EtOH solution on cooling provided colorless crystals, which were filtered, washed with acetone and dried under vacuum. Further concentration of the filtrate gave additional material. The total yield was 35 g (89%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([Cl:35])=[CH:33][C:32]([Cl:36])=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:35][C:34]1[C:25]([NH:24][C:22]2[C:21]([Cl:37])=[CH:20][N:19]=[C:18]([NH:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=4[CH:12]=3)[N:23]=2)=[C:26]([CH:31]=[C:32]([Cl:36])[CH:33]=1)[C:27]([NH:29][CH3:30])=[O:28]
Reactant: CNC(=O)c1cc(Cl)cc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cc(Cl)cc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
3,5-Dichloro-2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,5-dichloro-N-methyl-benzamide in an analogous manner to Example 303c. Product isolated as an off-white foam (47 mg, 25%). LCMS (m/e) 549 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.69 (s, 1H), 7.61 (s, 1H), 7.47 (s 1H), 7.15 (s, 1H), 7.01-6.89 (m, 2H), 6.87 (s, 1H), 6.01-5.92 (m, 1H), 3.56 (t, 2H, J=5.5 Hz), 3.39 (s, 3H), 2.92-2.84 (s, 2H), 2.81-2.65 (m, 8H), 2.75 (d, 3H, J=4.4 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:10]1[N:14]([CH3:15])[N:13]=[C:12]([CH2:16][CH2:17][CH3:18])[C:11]=1[NH:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25]C=1)(=[O:9])[NH2:8].[C:31](#N)C>>[C:7]([C:10]1[N:14]([CH3:15])[N:13]=[C:12]([CH2:16][CH2:17][CH3:18])[C:11]=1[NH:19][C:20](=[O:30])[CH2:21][C:22]1[CH:23]=[CH:28][C:27]([CH2:31][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:26][CH:25]=1)(=[O:9])[NH2:8]
Reactant: C1COCCN1
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)CCc1ccc(Br)cc1
Reactant: CC#N
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)Cc1ccc(CN2CCOCC2)cc1

Procedure:
Morpholine (0.3 ml, 0.00344 mol) was added to a solution of N-(5-carbamoyl-1-methyl-3-propyl-1H-4-pyrazolyl)-2-(4-bromobenzyl)acetamide (400 mg, 0.001 mol) in acetonitrile (3 ml) and the reaction stirred at reflux for 2 hours. On cooling, the reaction was concentrated under reduced pressure.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[C:42]([Br:48])[CH:41]=1)C1C=CC=CC=1.Cl.[H][H]>C1COCC1.CO.[Pd]>[Br:48][C:42]1[CH:41]=[C:40]([C@@H:10]2[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]2[OH:8])[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=1
Reactant: [H][H]
Reactant: COc1cc(Br)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Br)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Yield: 58.9 %

Procedure:
5% palladium/carbon (1.0 g) was added to a solution of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(3-bromo-5-methoxyphenyl)-D-glucitol (10.0 g) in THF-methanol (ratio: 1:1, 100 ml). Two drops of a 1 M aqueous solution of hydrochloric acid was further added to the mixture, followed by stirring for 30 minutes in a hydrogen atmosphere. After filtrating the reaction mixture, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-(3-bromo-5-methoxyphenyl)-D-glucitol (2.9 g).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:31])[C:22]=2[CH3:21])[CH2:11][CH2:10][N:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)N2CCN(C(=O)OC(C)(C)C)[C@@H](Cc3ccccc3)C2)c1C

Procedure:
The title compound was prepared according to the procedure described for Example 1, Step A except using 2(S)-benzyl-1-tert-butoxycarbonylpiperazine (0.292 g, 1.06 mmol), 2,3-dimethyl-benzoic acid (0.159 g, 1.06 mmol), HOBT (0.157 g, 1.02 mmol), EDC.HCl (0.213 g, 1.11 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a thick oil (0.416 g). NMR (DMSO-d6, 300 MHz) δ 7.15 (2H, m), 6.06 (1H,m), 4.42 (1H,m), 3.6-4.2 (2H, m), 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=2[CH3:33])=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:36])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (38 mg, 28%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].O[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][O:9][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]
Reactant: OCC1CC2CCC1C2
Reactant: O=Cc1cccc(O)c1
Product: O=Cc1cccc(OCC2CC3CCC2C3)c1

Procedure:
Condensation of bicyclo[2.2.1]heptan-2-ylmethanol with 3-hydroxybenzaldehyde (11) under Mitsunobu conditions was performed following the method given in Example 2. The product was purified by flash chromatography (5 to 30% EtOAc/hexane gradient) to give 3-(bicyclo[2.2.1]heptan-2-ylmethoxy)benzaldehyde as a colorless oil. Yield (0.88 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.38-7.50 (m, 3H), 7.22-7.28 (m, 1H), 4.01 (m, 1H), 3.88-3.93 (m, 1H), 3.70-3.80 (m, 1H), 2.15-2.29 (m, 2H), 1.67-1.90 (m, 1H), 1.40-1.52 (m, 2H), 1.24-1.40 (m, 2H), 1.05-1.21 (m, 2H), 0.75 (ddd, J=2.3, 5.1, 12.1 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[NH2:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CS(C)=O>[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:22]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:17])[CH:23]=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: Nc1cc(Cl)ccn1
Reactant: CNC(=O)N1CCc2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=O)N1CCc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 160 °C
Reaction time: 12 h
Yield: 4.6 %

Procedure:
Sodium hydride (202 mg, 3.89 mmol, 60% in oil) was suspended in dimethyl sulfoxide (5.0 ml), then 5-hydroxy-2,3-dihydro-1H-indole-1-carboxylic acid methylamide (971 mg, 5.06 mmol) and 2-amino-4-chloropyridine (500 mg, 3.89 mmol) were added at room temperature under nitrogen atmosphere, and the reaction mixture was heated and stirred at 160° C. for 12 hours under nitrogen atmosphere. After naturally cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300; eluent: ethyl acetate, ethyl acetate:methanol=85:10 in this order). The fractions containing the desired compound were concentrated, and the residue was further purified by silica gel column chromatography (Fuji Silysia NH, eluent; from ethyl acetate to ethyl acetate:methanol=90:10). The obtained crystals were suspended in diethyl ether:acetone=3:1, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (51 mg, 0.18 mmol, 4.6%) as pale green crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH2:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([O:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:33](=[O:34])[CH2:32][O:31][C:28]4[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=4)[C@@H:15]([CH2:19][O:20][CH2:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=C(O)COc1ccc(Cl)nc1
Reactant: CCOCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Product: CCOC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)COc1ccc(Cl)nc1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-aminoquinazoline-7-ylmethyl)-3-ethoxymethyl-piperazine-2-one, EXAMPLE 79 and, (6-chloro-pyridin-3-yloxy)-acetic acid, prepared similary to the procedure described in EXAMPLE 29. 1H NMR (d6-DMSO, 300 MHz) δ9.73 (bs, 2H), 8.81 (s, 1H), 8.37 (m, 1H), 8.10 (m, 1H), 7.61 (m, 2H), 7.40 (m, 2H), 4.98 (m, 2H), 4.65 (m, 2H), 4.50 (m, 1H), 3.91 (m, 1H), 3.75 (m, 1H), 3.59 (m, 2H), 3.31 (m, 2H), 1.07 (m, 3H). MS (ion spray), m/z, 485, 487 (M+H), (Cl pattern).