Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[N:10][N:11]2[C:16]([C:17]3[CH:18]=[C:19]([NH:23][C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])[CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:14]=[N:13][C:12]=12)=[O:7].[H-].[Na+].[CH3:31]I>CN(C)C=O.C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[N:10][N:11]2[C:16]([C:17]3[CH:18]=[C:19]([N:23]([CH3:31])[C:24]([CH:26]4[CH2:28][CH2:27]4)=[O:25])[CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:14]=[N:13][C:12]=12)=[O:7]
Reactant: CI
Reactant: O=C(c1ccco1)c1cnn2c(-c3cccc(NC(=O)C4CC4)c3)ccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN(C(=O)C1CC1)c1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 3.85 g sample of N-[3-[3-(2-furanylcarbonyl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]cyclopropanecarboxamide in 40 ml of dimethylformamide is added 0.384 g of 60% sodium hydride in oil. The mixture is stirred at room temperature under argon for one hour and then 0.65 ml of methyl iodide is added. After stirring overnight at room temperature, several drops of acetic acid are added, the mixture poured onto ice-water and extracted with dichloromethane. The extracts are washed with water, dried over sodium sulfate and the solvent removed under reduced pressure. The residue is dissolved in dichloromethane, filtered through a short pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and hexane added. Cooling gives the desired product as crystals, mp 207°-209° C.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6](=[O:23])[CH:7]([O:20][CH2:21][CH3:22])[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[F:18])[C:9]1=[O:19].[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[C:28]([C:26]1[CH:25]=[CH:24][C:3]([CH2:4][NH:5][C:6](=[O:23])[CH:7]([O:20][CH2:21][CH3:22])[N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:18])[C:9]2=[O:19])=[C:2]([NH:1][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[F:30])[CH:27]=1)#[N:29]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1N)N1C(=O)c2cccc(F)c2C1=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOC(C(=O)NCc1ccc(C#N)cc1NCc1ccccc1F)N1C(=O)c2cccc(F)c2C1=O
Reaction time: 6 h
Yield: 76 %

Procedure:
(RS)-N-(2-amino-4-cyano-benzyl)-2-ethoxy-2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide (0.060 g) was treated in MeOH (1 ml) successively with 2-fluoro-benzaldehyde (56 mg) and 1 ml of a MeOH-solution containing scrupulously dried ZnCl2 (83 mg) and NaCNBH3 (29 mg). The reaction mixture was stirred for 6 h at 50–55° C., poured onto crashed ice and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, hexane/AcOEt=6/4) to yield (RS)-N-[4-cyano-2-(2-fluoro-benzylamino)-benzyl ]-2-ethoxy-2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide (58 mg) as yellow oil, MS 505.4 ([M+H]+).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.C(O)(=O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CN2CCC(C(=O)O)CC2)cccc1-c1cnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.5 %

Procedure:
A solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D92) (150 mg), ethyl 4-piperidinecarboxylate (63.0 mg) and acetic acid (0.1 mL) in dichloromethane (DCM) (10 mL) was stirred at room temperature for 15 min, then sodium triacetoxyborohydride (255 mg) was added. The mixture was stirred at room temperature for 2 h, then formaldehyde (0.11 mL) was added. The mixture was stirred at room temperature overnight. After concentration, the residue was partitioned between ethyl acetate and water, washed with saturated brine. The organic phase was collected and evaporated, the residue was dissolved in DMF (5 mL) and 2M NaOH (2 mL) solution was added. The mixture was stirred at 50° C. for 1 h, then cooled to room temperature. This reaction mixture was acidified with 2M HCl to pH 5-6, extracted with ethyl acetate for three times. The combined organic phase was concentrated and the residue purified by Mass Directed AutoPrep to afford 1-[(3-{2-[3-cyano-4-(2-methylpropyl)phenyl]-1,3-thiazol-5-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylic acid (E42) (40 mg) as a TFA salt. δH (DMSO-d6, 400 MHz): 0.92 (6H, d), 1.02 (3H, t), 1.78 (2H, m), 1.98 (2H, m), 2.07 (2H, m), 2.73 (2H, d), 2.83 (2H, m), 3.19 (2H, m), 3.46 (2H, m), 4.41 (2H, m), 7.48 (2H, t), 7.63 (2H, m), 7.96 (1H, s), 8.22 (1H, dd), 8.35 (1H, d), 9.23 (1H, br s), 12.58 (1H, br s). δF (DMSO-d6, 376 MHz): −74.2. MS (ES): C29H33N3O2S requires 487. found 488.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[C:11]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[C:11]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:18][CH:17]=1)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)CCc1ccc(-c2ccc(C(=O)O)nc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to 4 ml 1,2-dimethoxyethane are added 5-bromo-pyridine-2-carboxylic acid (93 mg, 0.46 mmol), 4-(2-carboxyethyl)benzeneboronic acid (106 mg, 0.55 mmol), 0.51 ml of a 2M aqueous sodium carbonate solution and dichlorobis-(triphenylphosphin) palladium (II) (20 mg, 0.03 mmol). The mixture is stirred at 90° C. overnight, cooled and quenched with water. Ethyl acetate is added and the mixture adjusted to pH=2 with 1M hydrochloric acid. After threefold extraction with ethyl acetate, the combined organic layers are dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue is purified by silica gel chromatography (eluent:dichloromethane/methanol 5:1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:29]([Si:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OCCN1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.4 %

Procedure:
To 2-piperazin-1-yl-ethanol (2 g, 15.36 mmol) in CH2Cl2 (70 mL) and pyridine (1.85 mL, 23.04 mmol) was added DMAP (188 mg, 1.53 mmol) and TBDPS chloride (3.37 mL, 18.44 mmol) and the reaction mixture stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and the crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 10% MeOH/CH2Cl2 to obtain 1-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-piperazine as a colourless oil (1.1 g, 21%).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:22]4[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH2:30][C:31]5([OH:39])[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]5)=[CH:24][C:23]=4[CH3:40])[CH:19]=[CH:20][CH:21]=3)=[CH:13][C:8]=2[O:7][CH2:6]1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[OH:39][C:31]1([CH2:30][O:29][C:25]2[CH:26]=[C:27]([CH3:28])[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][O:14][C:12]4[CH:11]=[CH:10][C:9]5[C@H:5]([CH2:4][C:3]([OH:41])=[O:2])[CH2:6][O:7][C:8]=5[CH:13]=4)[CH:17]=3)=[C:23]([CH3:40])[CH:24]=2)[CH2:32][CH2:33][S:34](=[O:37])(=[O:38])[CH2:35][CH2:36]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCC5(O)CCS(=O)(=O)CC5)cc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCC2(O)CCS(=O)(=O)CC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of methyl[(3S)-6-({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.482 g, 0.830 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.358 g, yield 76%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:27]([C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[O:28])[CH2:16]3)[CH2:12]2)[N:4]=1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1ccccc1-c1ccccn1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4ccccc4-c4ccccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 39 and 2-pyridin-2-yl-benzoic acid. MS (ESI) mass calcd. for C24H25N5O3, 431.49; m/z found, 432.2 [M+H]+. 1H NMR (CDCl3): 8.49 (d, J=3.9 Hz, 1H), 7.69-7.49 (m, 3H), 7.48-7.29 (m, 3H), 7.15-7.04 (m, 1H), 5.32 (s, 1H), 3.92-3.61 (m, 8H), 3.60-3.40 (m, 2H), 3.35-3.15 (m, 3H), 2.98-2.65 (m, 3H).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH2:12][C:13]#[CH:14])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].N1C=CC=CC=1>C(O)C>[C:1]([CH:5]1[CH2:10][CH2:9]/[C:8](=[N:16]/[OH:17])/[CH:7]([CH2:12][C:13]#[CH:14])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCC1CC(C(C)(C)C)CCC1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C#CCC1CC(C(C)(C)C)CC/C1=N/O
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A mixture of 4-tert-butyl-2-prop-2-ynyl-cyclohexanone (50 mg, 0.26 mmol) (prepared as described in Dufey, P.; Bull. Soc. Chim. Fr.; 1968, 4653-4662) in 1.0 mL of ethanol was refluxed with hydroxylamine hydrochloride (25 mg, 0.36 mmol) and pyridine (0.25 mL, excess) for 3 h. The mixture was then allowed to cool to room temperature and partitioned between ethyl acetate and 3N aq. HCl. The organic layers were washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered and concentrated to give the titled compound as a light yellow solid (50 mg, 93% yield).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Cl:7][C:8]1[C:13]2[CH:14]=[CH:15][N:16]([CH3:17])[C:12]=2[C:11]([C:18]([OH:20])=O)=[CH:10][N:9]=1>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:13]2[CH:14]=[CH:15][N:16]([CH3:17])[C:12]=2[C:11]([C:18]([N:9]2[CH2:2][CH2:1][CH2:12][CH2:13][CH2:8]2)=[O:20])=[CH:10][N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2c(Cl)ncc(C(=O)O)c21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)ncc(C(=O)N3CCCCC3)c21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of oxalylchloride (3.43 ml) in DCM (40 ml) was cooled to 0° C. and 4-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (3.75 g) was added portionwise followed by the addition of DMF (4 drops). The reaction mixture was stirred at 0° C. for 90 min, DCM (5 ml) was added and stirring continued for a further 30 min. The reaction mixture was evaporated and the residue dissolved in dichloromethane (20 ml) and dimethylformamide (10 ml). N-ethylmorpholine (9.09 ml) followed by piperidine (3.53 ml) were added and the mixture stirred at 0° C. for 45 min. The reaction mixture was evaporated and the residue dissolved in EtOAc (150 ml). The organic layer washed with water (100 ml), sodium bicarbonate (3×100 ml) and brine (30 ml) then dried (MgSO4) and evaporated to a yellow oil. The oil was triturated with diethyl ether, and the solid filtered and dried at 60° C. under vacuum, to afford the title compound (3.95 g).
Reaction SMILES: C([NH:8][S:9]([C:12]1[C:13]2[CH2:28][CH2:27][CH2:26][CH2:25][C:14]=2[C:15]2[NH:16][C:17](=[O:24])[C:18](=[O:23])[N:19]([OH:22])[C:20]=2[CH:21]=1)(=[O:11])=[O:10])(C(OCC)=O)=O>Cl>[OH:22][N:19]1[C:20]2[CH:21]=[C:12]([S:9](=[O:10])(=[O:11])[NH2:8])[C:13]3[CH2:28][CH2:27][CH2:26][CH2:25][C:14]=3[C:15]=2[NH:16][C:17](=[O:24])[C:18]1=[O:23]
Reactant: CCOC(=O)C(=O)NS(=O)(=O)c1cc2c([nH]c(=O)c(=O)n2O)c2c1CCCC2
Agent: Cl
Product: NS(=O)(=O)c1cc2c([nH]c(=O)c(=O)n2O)c2c1CCCC2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
A suspension of 6-ethoxalylaminosulfonyl-7,8,9,10-tetrahydro-4-hydroxybenzo[f]quinoxaline-2,3(1H,4H)-dione (0.20 g, 0.5 mmol) in 7 ml of conc. hydrochloric acid was heated to reflux with stirring for 1.5 h. The mixture was cooled to 0° C. and filtered. The isolated product was washed with water and dried to give 0.14 g (66%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21](OB(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:23]2[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:17]([O:16][CH3:15])=[O:18])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.1 %

Procedure:
3-(tert-Butoxycarbonylamino)piperidine (200 mg, 1.00 mmol), 3-(methoxycarbonyl)phenylboric acid (360 mg, 2.00 mmol) and molecular sieves 4 Å (100 mg) were suspended in dichloromethane (10 mL). To this suspension, copper (II) acetate (182 mg, 1.00 mmol) and triethylamine (0.280 mL, 2.00 mmol) were added and the mixture was stirred at room temperature for 15 hours. Subsequently, the reaction mixture was filtered through Celite and a saturated aqueous sodium bicarbonate solution was added to the filtrate. This mixture was extracted with ethyl acetate and the extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1->5:1) to give a colorless oil. This product was further purified by silica gel column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.) hexane:ethyl acetate=10:1) to give 154 mg (46%) of the desired compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:25][N:26]2[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]2)[S:5][C:6]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[O:9][N:8]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:25][N:26]2[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]2)[S:5][C:6]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)[O:9][N:8]=1
Reactant: COC(=O)C1CN(Cc2cc(C)c(-c3noc(-c4ccc(Oc5ccccc5)cc4)n3)s2)C1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)cc2)n1
Yield: 85.1 %

Procedure:
The title compound (0.16 g) was synthesized in a yield of 85% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-({4-methyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylate (0.20 g, 0.42 mmol) that was obtained in Example 12 (12b) and a 1 N aqueous solution of sodium hydroxide (1.3 mL, 1.3 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:21]([NH:23][CH3:24])=[O:22]>>[CH2:25]([C:20]([NH:19][C:14]([C:12]1[CH:11]=[CH:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:21](=[O:22])[NH:23][CH3:24])[CH2:27][CH3:28])[CH3:26]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Product: CCC(CC)(NC(=O)c1ccc(OC)c(-c2cccc(Cl)c2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=390.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1([C:13]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[[[13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepin-10-yl]carbonyl/amino]-cyclopentanecarboxylic acid. 1-(Tert-butoxycarbonyl)cyclopentanecarboxylic acid (3.37 g, 14.7 mmol) was dissolved in DMF (40 mL) and treated with Cs2CO3 (5.28 g, 16.2 mmol) and benzyl bromide (1.1 mL, 16.2 mmol), the mixture was stirred at rt overnight and then at 70° C. for 3 h. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (250 mL). The organic phase was washed with water (100 mL) and brine (100 mL); dried over Na2SO4, filtered and concentrated to afford benzyl 1-(t-butoxycarbonyl)cyclopentanecarboxylate as a white solid. A portion of the solid (1.4 g) was dissolved in CH2Cl2 (40 mL) and treated with TFA (5 mL) and stirred at rt overnight. The reaction mixture was concentrated in vacuo to afford the TFA salt of benzyl 1-aminocyclopentanecarboxylate as an off-white solid. LCMS: m/e 220 (M+H)+, ret time 1.30 min, column 3, 2 minute gradient. This solid was then dissolved in THF (20 mL) and dimethyl-4-morpholinyl]carbonyl]-N-[(methylamino)sulfonyl]-,7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-, (1.4 g, 4.2 mmol) was added followed by DMAP (1.54 g, 1.27 mmol) and HATU (2.4 g, 6.3 mmol). The mixture was stirred at rt for 48 h. Solvent was removed in vacuo. Water (100 mL) and AcOEt (100 mL) were added. The organic phase was separated, dried over Na2SO4 and purified using silica gel (AcOEt/Hex 10%-70%) to afford the benzyl protected cyclopentanecarboxylic acid, 1-[[[13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepin-10-yl]carbonyl]amino]-, as a bright yellow solid (1.4 g). LCMS: m/e 700 (M+H)+, ret time 2.46 min, column 3, 2 minute gradient. The benzyl protected compound (578 mg, 0.8 mmol) was dissolved in a 1:1 mixture of THF/MeOH (10 mL) and treated with 1N NaOH (2 mL). The mixture was stirred at rt for 18 h. Same procedure was repeated with 822 mg of the benzyl protected compound and the reactions were reunited. HCl (1N) was added to pH=5 and the precipitated formed was collected by filtration to afford the title compound as a pale yellow solid (650 mg). A small portion was purified using reverse phase HPLC. 1HNMR (500 MHz, DMSO) δ 8.33 (br s, 1H), 8.30 (br s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.60-7.50 (m, 5H), 6.92 (br s, 1H), 5.15 (br s, 1H), 4.37 (br s, 1H), 4.22-3.05 (m, 6H), 2.75 (m, 1H), 2.50-1.10 (m, 24H). LCMS: m/e 610 (M+H)+, ret time 2.35 min, column 3, 2 minute gradient.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:3]1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.CCOC(C)=O.C(=O)(O)[O-].[Na+]>[N:28]([C@H:6]1[C@@H:2]([CH3:1])[CH2:3][N:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:5]1)=[N+:29]=[N-:30]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Yield: 60.1 %

Procedure:
(+/−)-(trans)-benzyl 3-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate (5.00 g, 12.84 mmol) and sodium azide (2.087 g, 32.1 mmol) in DMF (10 mL) was heated under argon at 85° C. for 18 h. The resulting mixture was cooled and diluted with EtOAc and sat. sodium bicarbonate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give a tan oil which was purified via preparative chromatography using Hexanes/EtOAc mixtures as the eluant and 40 g silica cartridge. Fractions containing the major product were combined and concentrated to afford the title compound as a near colorless oil (2.01 g, 7.72 mmol, 60%). HPLC (method B) retention time=3.30 min. LCMS (m+Na)=283.2. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.41-7.30 (m, 5H), 5.15 (d, J=6.2 Hz, 2H), 4.00 (t, J=4.3 Hz, 1H), 3.76-3.55 (m, 3H), 3.16-3.02 (m, 1H), 2.47-2.30 (m, 1H), 1.13 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([NH2:31])[CH:26]=[C:25]2[CH3:32])(=[O:21])=[O:20].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:18][S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([NH:31][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH:26]=[C:25]2[CH3:32])(=[O:21])=[O:20]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: Cc1cn(N)c2ccc(S(C)(=O)=O)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C)c2cc(S(C)(=O)=O)ccc21
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 13.7 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (1.77 mmol) and 5-methanesulfonyl-3-methyl-indol-1-ylamine (452 mg, 1.95 mmol) in DMF (15 mL) is stirred at rt for 1 h. The mixture is treated with DMTMM (538 mg, 1.95 mmol) and stirred at 60° C. for 1.5 h. The mixture is diluted with EtOAc (50 mL), and washed with saturated aqueous Na2CO3 (50 mL). The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-100% EtOAc in heptane, and then by triturating in Et2O to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-methanesulfonyl-3-methyl-indol-1-yl)-amide (106 mg, 14%). MS: 439 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.37 (d, 1H), 8.24 (m, 2H), 7.82 (m, 1H), 7.59 (d, 1H), 7.54 (m, 1H), 7.34 (s, 1H), 7.29 (m, 1H), 3.13 (s, 3H), 2.83 (s, 3H), 2.42 (s, 3H).