Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[N:10]2[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([NH2:21])[C:12]=3[N:22]=[C:9]2[CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl>[NH2:21][C:13]1[C:12]2[N:22]=[C:9]3[CH2:8][O:7][CH2:6][C@H:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[N:10]3[C:11]=2[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: CC(C)C(=O)Cl
Reactant: NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Temperature: 0 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
(11S)-11-(3-Aminopropyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (190 mg, 0.640 mmol) was dissolved in 8 mL of CH2Cl2 and the reaction mixture was cooled to 0° C. under N2. Triethylamine (356 μL, 2.56 mmol) was added followed by iso-butyryl chloride (67 μL, 0.643 mmol). After stirring overnight, the reaction mixture was diluted with 20 mL of CH2Cl2 and was washed successively with saturated NaHCO3 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 10% methanol/CHCl3) gave a white solid. Crystallization from ethyl acetate gave N-{3-[(11S)—6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propyl}-2-methylpropanamide (80 mg) as a white solid, mp 207-208° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([Cl:16])=[CH:10][C:9]=2[Cl:17])=[O:4].[Na+].[NH2:20][CH2:21][C:22]([O-:24])=[O:23]>COCCO>[Cl:16][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:17])[CH:10]=1)[O:7][C:6](=[O:18])[C:5]([C:3]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:4])=[C:14]2[OH:15]
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2cc(Cl)cc(Cl)c2oc1=O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(Cl)c2oc1=O
Yield: 86.9 %

Procedure:
A mixture of 6,8-dichloro-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (400 mg, 1.39 mmol) and glycine sodium salt (674 mg, 6.94 mmol) in 2-methoxyethanol (14 mL) was heated to reflux overnight. Reaction mixture was concentrated and dissolved in water (100 mL). The solution was acidified by 1 N aq HCl to pH=2-3. White precipitate was collected, rinsed with water and methanol and dried to give the title compound (401 mg). MS ESI(−) m/e: 332, 330 (M−1).
Reaction SMILES: ClC1C=CC=CC=1[C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH:15][C:16]1[CH:21]=[C:20]([C:22](=[O:27])[NH:23][CH:24]2[CH2:26][CH2:25]2)[CH:19]=[CH:18][C:17]=1[CH3:28])=[O:14].[B:29]1(B2OC(C)(C)C(C)(C)O2)[O:33]C(C)(C)C(C)(C)[O:30]1.CC([O-])=O.[K+]>CN(C=O)C>[CH:24]1([NH:23][C:22]([C:20]2[CH:19]=[CH:18][C:17]([CH3:28])=[C:16]([NH:15][C:13]([C:9]3[S:10][C:11]([B:29]([OH:33])[OH:30])=[CH:12][CH:8]=3)=[O:14])[CH:21]=2)=[O:27])[CH2:26][CH2:25]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1sccc1-c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(B(O)O)s1
Temperature: 90 °C
Yield: 178.3 %

Procedure:
A solution of 1.0 g (2.64 mmol) of 5-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide (Example 136, Step B), bis(pinacolato)diborane (1.0 g, 3.95 mmol) and KOAc (1.30 g, 13.2 mmol) in DMF (15 mL) was purged with argon and Pd(dppf)2Cl2/CH2Cl2 complex (65 mg, 0.08 mmol) was added followed by heating at 90° C. for 16 h. After cooling to rt, the mixture was partitioned between EtOAc (250 mL) and water (50 mL) and the layers were separated. The organic portion was washed with additional water, then brine, then dried over anhyd Na2SO4, filtered, and concentrated under vacuum to afford 1.62 g of a brown semi-solid as the crude product mixture. This material was triturated with EtOAc and filtered to afford 626 mg of the compound a containing ˜10% of the boronate ester. This material was used as is without any further purification. HPLC Ret time=2.36 min. LCMS [M+H]+ 345.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([F:17])([F:16])[F:15])[C:7]2[CH2:11][O:10][B:9]([OH:12])[C:8]=2[CH:13]=1)([O-])=O.C([O-])(O)=O.[Na+].CCOC(C)=O>CO.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([F:16])([F:17])[F:15])[C:7]2[CH2:11][O:10][B:9]([OH:12])[C:8]=2[CH:13]=1
Reactant: O=[N+]([O-])c1cc2c(c(C(F)(F)F)c1)COB2O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc2c(c(C(F)(F)F)c1)COB2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-nitro-4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXXI) (0.95 g, 3.83 mmol) in MeOH/2M HCl mixture (1:1) (129 mL) was added Zn (dust) (2.5 g, 38.31 nmol). The reaction mixture was stirred at room temperature for 3 hours before it was slowly neutralized by a solution of saturated aq. NaHCO3/EtOAc (1:1, 100 mL/100 mL). Then the reaction mixture was filtered through Celite and washed with EtOAc. The organic layer was washed with 5% NaHCO3, brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to yield 6-amino-4-(trifluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (CXXXII) as a slightly brown crystalline solid (700 mg, 3.22 mmol, 84% yield). ESIMS found for C8H7BF3NO2 m/z 216.4 (M−H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=2[C:9]=1[O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Br)[CH3:26].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][C:15]([O:17][CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:31])=[CH:16][C:10]=2[C:9]=1[O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1sc2ccc(O)cc2c1OC(=O)C(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOC(=O)c1sc2ccc(OCC(=O)OCC)cc2c1OC(=O)C(C)(C)C

Procedure:
3.50 g (10 mmol) VII, 2.22 ml (20 mmol) bromoacetic acid ethyl ester and 2.48 g (25 mmol) K2CO3 were heated under reflux for 5 h in 250 ml acetone. The reaction mixture was filtered. The filtrate was freed from the solvent. After recrystallization from n-hexane, VIII was obtained in a yield of 4.00 g (9.2 mmol, 92%).
Reaction SMILES: [C:1]([N:4]([CH3:24])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([C:19](OCC)=[O:20])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[BH4-].[Li+].C(O)C.CC(C)=O>C1COCC1>[C:1]([N:4]([CH3:24])[N:5]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N(C(=O)OC(C)(C)C)N(C)C(C)=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CO)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
tert-Butyl 2-acetyl-1-[4-(ethoxycarbonyl)phenyl]-2-methylhydrazinecarboxylate (2.06 g) was dissolved in THF (60 ml), lithium borohydride (90%, 0.74 g) was added, and ethanol (15 ml) was slowly added dropwise. The obtained mixture was stirred at 80° C. for 3 hr. Acetone (6.0 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 (volume ratio)→1:2 (volume ratio)), and further recrystallized from ethyl acetate to give the title compound (1.22 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][C@@H:24]([OH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C@H:10]([NH:12]C(=O)OCC1C=CC=CC=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[NH2:12][C@H:10]([CH3:11])[CH2:9][N:8]([CH2:23][C@@H:24]([OH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CN(C[C@@H](O)c1ccccc1)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](N)CN(C[C@@H](O)c1ccccc1)C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
2.85 g of (R)-benzyl 1-[tert-butoxycarbonyl{(S)-2-hydroxy-2-phenylethyl}amino]propan-2-ylcarbamate was dissolved in 40 mL of methanol. To the solution, 1.42 g of 20% palladium hydroxide-carbon was added, and the mixture was vigorously stirred at room temperature for 14 hours in a hydrogen gas atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain 1.86 g of the title compound as a colorless oil (96%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH3:12][C:13]1C=C[C:16](S(OCCCC#C)(=O)=O)=[CH:15][CH:14]=1>>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:16][CH2:15][CH2:14][C:13]#[CH:12]
Reactant: COc1ccc(C=O)cc1O
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Product: C#CCCCOc1cc(C=O)ccc1OC
Yield: 83 %

Procedure:
Isovanillin (0.98 g, 6.4 mmol) was alkylated with pent-4-ynyl 4-methylbenzenesulfonate (2.3 g, 8.3 mmol) according to Procedure 4. The crude product was recystallised from EtOAc/petrol to provide 4-methoxy-3-(pent-4-ynyloxy)benzaldehyde (1.16 g, 83%) as a colourless crystalline solid; mp 73-74° C.; δH (400 MHz, CDCl3) 1.98 (t, J=2.4 Hz, 1H, CCH), 2.06 (p, J=7.0 Hz, 2H, CH2), 2.43 (td, J=7.0, 2.4 Hz, 2H, CH2C≡CH), 3.94 (s, 3H, OCH3), 4.18 (t, J=7.0 Hz, 2H, OCH2), 6.97 (d, J5′,6′=8.0 Hz, 1H, H5), 7.43 (s, 1H, H2), 7.45 (d, J5,6=8.0 Hz, 1H, H6), 9.84 (s, 1H, CHO); δC (100 MHz, CDCl3) 15.1, 27.9, 56.1, 67.3, 69.1, 83.2, 110.6, 110.7, 126.7, 130.0, 148.9, 154.9, 190.9; vmax 1025, 1263, 1584, 1665, 2849, 2936, 3254 cm−1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1[OH:23].[O:24]=[C:25]1[NH:30][C:29]2[N:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[S:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][C@H:4]([OH:23])[C@H:3]([CH2:2][NH:1][CH2:35][C:32]3[CH:33]=[CH:34][C:28]4[S:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=4[N:31]=3)[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNCc4ccc5c(n4)NC(=O)CS5)[C@@H](O)C3)c2n1
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a stirred solution of (±)-cis-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (0.23 g, 0.72 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[1,4]thiazine-6-carboxaldehyde (0.14 g, 0.72 mmole). After 24 h, at RT was added NaBH(OAc)3 (0.23 g, 1.08 mmole). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to afford the title compound (0.24 g, 66%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 4.21 (s, 2H), 4.12 (s, 3H), 3.52 (m, 4H), 3.33 (s, 4H), 3.21 (m, 2H), 3.09 (m, 2H), 2.98 (m, 2H). LC-MS (ES) m/e 499 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][CH:39]=2)=[CH:34][CH:33]=1.CCOC(C)=O.CCCCCC>C1COCC1>[CH3:8][O:9][CH:10]=[CH:44][C:41]1[CH:42]=[CH:43][C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:47])([F:46])[F:30])=[CH:33][CH:34]=2)=[CH:39][CH:40]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To an ambient temperature suspension of potassium tert-butoxide (449 mg, 4.00 mmol) in THF (20 mL) is added (methoxymethyl)triphenylphosphonium chloride (1.37 g, 4.00 mmol) and is stirred at room temperature for 30 min. 4′-trifluoromethyl-biphenyl-4-carbaldehyde (500 mg, 2.00 mmol) is added and the reaction mixture continues to stir at room temperature. After 2 h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction is quenched with saturated aqueous NH4Cl and concentrated. The residue is partitioned between EtOAc (50 mL) and water (20 mL). The aqueous layer is extracted with EtOAc (50 mL) and the combined organic layers are washed with brine (100 mL), dried (MgSO4), filtered, concentrated and chromatographed (40 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (482 mg, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:12]([NH2:15])[CH2:13][CH3:14].C([O-])(O)=O.[Na+].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:12]([NH:15][C:9]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1)=[O:11])[CH2:13][CH3:14]
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)C1(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (Wheeler, T. N.; Ray, J. A. Synthetic Communications 1988, 18(2), 141) (1.52 g, 9.62 mmol) and n-propylamine (0.63 g, 10.58 mmol) in anhydrous DMF (65 mL) at rt, were added NaHCO3 (4.04 g, 48.11 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.21 g, 11.54 mmol) and 1-hydroxybenzotriazole hydrate (1.77 g, 11.54 mmol) under a nitrogen atmosphere. After being stirred at rt overnight, the mixture was partitioned between water (100 mL) and EtOAc (300 mL). The organic phase was separated, washed with water and brine, and was dried over anhydrous MgSO4. The filtrate was evaporated to give 1.65 g (86%) of the crude product which was used in the next step without purification. 1H-NMR (400 MHz, DMSO-d6) δ 8.33 (broad s, 1H), 4.08 (q, J=6.8 Hz, 2H), 3.07 (q, J=6.4 Hz, 2H), 1.43 (hex, J=6.4 Hz, 2H), 1.31 (s, 4H), 1.17 (t, J=6.4 Hz, 3H), 0.85 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].NC1N2C=CN=C2C(C([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:32][CH2:31]2)=O)=CC=1Cl>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:32][CH2:31]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: COCCCN1CCC(NC(=O)c2cc(Cl)c(N)n3ccnc23)CC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NC3CCN(CCCOC)CC3)c2n1

Procedure:
The title compound was prepared according to the procedure described in the step 3 in EXAMPLE 5 using 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 10, Step 2) and 1-[3-(methyloxy)propyl]-4-piperidinamine (EXAMPLE 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([O:32][CH3:33])=[N:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>O1CCCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([O:32][CH3:33])=[N:25][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)nc4OC)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nc(C2CC2)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Ethyl 6-chloro-7-(4-(2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylate (133 mg, 0.241 mmol) was diluted with tetrahydrofuran (2 mL) followed by the addition of aqueous NaOH (603 μL, 1.21 mmol) and ethanol (1 mL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N aqueous HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(2-(6-cyclopropyl-2-methoxypyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (70 mg, 0.134 mmol, 55.5% yield). MS (es+apci, positive) m/z=523.2. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, 2H), 7.42 (s, 1H), 7.35 (d, 1H), 6.96 (d, 2H), 6.54 (s, 1H), 6.47 (d, 1H), 4.25 (dd, 2H), 3.74 (t, 1H), 3.68 (t, 2H), 3.02 (t, 2H), 2.38-2.32 (m, 1H), 2.19-2.08 (m, 2H), 1.13-1.09 (m, 2H), 0.93-0.89 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:17]([NH2:19])=[O:18])=[CH:8]3)[C:4]=2[CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>>[OH:30][C@:26]([C:23]1[N:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:17]([NH2:19])=[O:18])=[CH:8]3)[C:4]=2[CH:3]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1C1CC2C1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)cn2C2CC3C2)no1

Procedure:
9-Bromo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide (0.15 g) was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 24.2 mg of 9-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide following reverse phase hplc purification. MS (Q1) 390.1 (M)+. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.84 (s, 1H), 7.52 (s, 1H), 7.30 (s, 2H), 7.09 (s, 1H), 6.72 (s, 1H), 4.98-4.88 (m, 1H), 3.78-3.68 (m, 1H), 3.15-3.02 (m, 2H), 2.62 (s, 3H), 1.85 (s, 3H), 1.66 (d, J=11.9 Hz, 2H).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=1>>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:22][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(Cl)c2)cc(C)n1
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)c2cc(-c3ccnc(Cl)c3)cc(C)n2)nc1

Procedure:
The title compound, was prepared from 2′-Chloro-6-methyl-[4,4′]bipyridinyl-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-amino-5methylpyridine instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=339.2, 341.1 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:28]1(I)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC(C)=O>CN(C)C=O>[CH:28]1([N:16]2[CH:17]=[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:13][CH:12]=3)=[N:15]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: IC1CCCC1
Reactant: CC(C)(C)OC(=O)c1c[nH]nc1-c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cn(C2CCCC2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
To tert-Butyl 3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxylate (156 mg, 0.46 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride, 60% in mineral oil (20.8 μg, 0.52 mmol). After the gas evolution ceased (about 5 minutes), cyclopentyl iodide (59 μL, 0.51 mmol) was added dropwise and the mixture was stirred for 16 hours at room temperature. EtOAc was added and the crude mixture was washed with a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc (3 times). The combined organic extracts were washed with water and brine. The organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with petroleum ether/DCM) to afford the title compound as a white solid (0.131 g, 69% yield). MS (ES+) m/e=405. 1H NMR (CDCl3) δH 1.51 (9H, s), 1.70-1.80 (2H, m), 1.85-2.00 (2H, m), 2.02-2.13 (2H, m), 2.18-2.30 (2H, m), 4.71 (1H, quint.), 7.06 (4H, d), 7.12 (1H, t), 7.35 (2H, t), 7.76 (2H, d), 7.95 (1H, s).
Reaction SMILES: [CH3:1][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:11])[CH:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([O:35][CH3:36])[C:26]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([O:35][CH3:36])[C:26]=1[C:27]([NH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:2]([CH3:1])([N:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH3:11])=[O:28]
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Reactant: COc1cc(Cl)cc(Cl)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)cc(Cl)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 0.03 h
Yield: 72.4 %

Procedure:
To a solution of (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (0.10 g; 0.459 mmol) and triethylamine (0.15 ml; 1 mmol) in DCM (3 ml) was added a solution of 2,4-dichloro-6-methyloxybenzoyl chloride (0.13 g; 0.540 mmol) in DCM (2 ml). After 1 h. saturated aqueous sodium hydrogen carbonate (8 ml) was added and the mixture shaken for 2 minutes. The organic layer was passed through a phase separation cartridge and the solvent removed under reduced pressure. The residue was dissolved in the minimum of DCM and applied to a 10 g silica gel column. Elution with 0-100% ethyl acetate in pentane gradient and removal of solvent under reduced pressure afforded the title compound as a colourless gum (0.14 g: 72%). 1H NMR (CDCl3) δ: 0.91 (3H, s), 0.96 (3H, s), 1.60-1.80 (4H, m), 2.55-2.75 (4H, m), 3.82 (3H, s), 4.76 (1H, d, J=2.4 Hz), 6.81 (1H, d, J=1.6 Hz), 7.02 (1H, d, J=1.6 Hz), 7.20-7.50 (6H, m). Mass spectrum (Electrospray LC/MS). Found 421 (MH+). C22H2635Cl2N2O2 requires 420. Ret. Time: 1.97 min.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1C=CCCC1
Product: O=C1CCCC(c2ccccc2)C1

Procedure:
The title compound was obtained using a procedure analogous to that described in Step 1 of Example 10 using cyclohex-2-enone (1.0 g, 10.4 mmol) and phenylboronic acid (1.3 g, 10.4 mmol) to afford the title compound as a colorless oil. MS m/z: 175(M+1).