Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](O)(=O)[CH:11]([CH3:13])[OH:12].C(Cl)Cl>C1(C)C(C)=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([CH:11]([OH:12])[CH3:13])[O:9][C:3]=2[CH:4]=1
Reactant: CC(O)C(=O)O
Reactant: Nc1ccc(F)cc1O
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: CC(O)c1nc2ccc(F)cc2o1
Yield: 61.2 %

Procedure:
A suspension of 2-amino-5-fluorophenol (5.50 g, 43.3 mmol) and 85-92% lactic acid (6 g) in xylene was refluxed overnight while removing off water by-produced as a result of the reaction. After replacing the solvent with methylene chloride, the resultant mixture was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over magnesium sulfate, and then concentrated. The resulting residue was subjected to recrystallization from a mixture of diisopropyl ether and hexane to afford 6-fluoro-2-(1-hydroxyethyl)benzoxazole (4.80 g, yield: 61%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1)=[O:4].CCOCC.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1>[OH:12][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.2 h

Procedure:
25.2 g (154 mmol) of methyl terephthalaldehydate was dissolved in 200 ml of tetrahydrofuran. 51.2 ml(154 mmol) of a 2M ether solution of phenyl magnesium bromide was added dropwise thereto under cooling in a sodium chloride-ice bath with stirring for 12 minutes and the mixture was stirred for further 20 minutes. Dilute hydrochloric acid was added to the resulting reaction mixture, then the obtained mixture was extracted twice with ethyl acetate. After the organic phase was washed with brine and dried (MgSO4), the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1 (v/v)) to obtain 31.7 g (131 mmol) of methyl α-hydroxy-α-phenyl-p-toluate as a pale yellow oily substance. Its spectroscopic data are as follows:
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)Cl.[CH2:6]([N-:8][CH2:9][CH3:10])[CH3:7].[Li+]>C1(C)C=CC=CC=1>[CH2:6]([N-:8][CH2:9][CH3:10])[CH3:7].[CH2:6]([N-:8][CH2:9][CH3:10])[CH3:7].[CH2:6]([N-:8][CH2:9][CH3:10])[CH3:7].[CH2:6]([N-:8][CH2:9][CH3:10])[CH3:7].[Ti+4:1]
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: CC[N-]CC
Agent: [Li+]
Solvent: Cc1ccccc1
Product: [Ti+4]
Temperature: -78 °C

Procedure:
The same apparatus described in Step (1) of Example B is used in this procedure. The 250 mL dropping funnel is charged with 50 mL of toluene and titanium tetrachloride, 7.7 mL (75 mmole), and added to the solution of lithium diethylamide which is chilled to -78° C. over the course of 30 minutes. The mixture is warmed to room temperature then refluxed two hours. All volatiles are removed under vacuum and the residue is extracted twice with 100 mL portions of hexane and filtered from the lithium salts. The combined extracts are reduced in solvent volume then transferred to a small scale distillation apparatus. The complex titanium tetrakis(diethylamide) is distilled from the mixture at 103°-105° C. (0.025 mm Hg) to give approximately 8 g as an orange liquid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:50]([Cl:52])[Cl:51]>>[NH3:1].[CH2:50]([Cl:52])[Cl:51].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N
Product: c1ccc2c(c1)CCN2C1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (112 mg) and 1-piperidin-4-yl-2,3-dihydro-1H-indole*2TFA (194 mg) in DCM (2 mL) was treated with sodium triacetoxyborohydride (150 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (78 mg). 1H NMR (400 MHz, CDCl3): 7.22 (d, J=8.6 Hz, 2H), 7.06–7.00 (m, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.59 (t, J=7.1 Hz, 1H), 6.39(d, J=7.8 Hz, 1H), 4.00 (t, J=6.3 Hz, 2H), 3.48 (s, 2H), 3.41–3.32 (m, 3H), 2.99 (m, 2H), 2.93 (t, J=8.3 Hz, 2H), 2.54 (m, 2H), 2.47 (br, 4H), 2.09–1.98 (m, 4H), 1.79–1.70 (m, 4H), 1.67–1.61 (m, 4H), 1.50–1.43 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:14]([O:21][CH2:22][CH2:23][OH:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CN1CCOCC1>C(Cl)Cl>[Si:14]([O:21][CH2:22][CH2:23][O:24][C:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=1)=[O:10])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[Si](C)(C)OCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 604 mg (3.00 mmol) sample of p-nitrophenoxycarbonylchloride in 3 mL of methylene chloride was added to a solution of 0.528 g (3.00 mmol) of 2-(t-butyldimethylsilyloxy)ethanol and 0.330 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The solution was stirred for 2 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane. The solvent was removed and the product dried to afford 0.453 g of the title compound, which was taken directly to the next step.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[F:11][C:4]1[CH:3]=[C:2]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[O:12])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Oc1ccccn1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-n2ccccc2=O)cc1F
Temperature: 150 °C
Yield: 49.4 %

Procedure:
73.1 To a solution of 10.96 g of 4-bromo-2-fluoro-benzoic acid in 40 ml of DMSO was added subsequently 6.67 g of 2-hydroxypyridine, 1.10 g of 8-hydroxyquinoline, 1.43 g of Cu(I)I and 7.61 g of K2CO3 and the mixture was heated to 150° C. for 18 h. The suspension was diluted with water, filtered, the residue was washed with AcOEt, triturated with MeOH, filtered and dried to give 5.77 g of 2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-benzoic acid. MS: 234.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[N+:18]([O-])=O)[CH3:2].B.C1COCC1.O.C1COCC1>C1COCC1>[NH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[C:11]([NH2:18])[CH:12]=1
Reactant: CCOc1ccccc1-c1ccc(C#N)cc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccccc1-c1ccc(CN)cc1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2′-ethoxy-2-nitrobiphenyl-4-carbonitrile (500 mg, 1.86 mmol) in THF (80 mL) was added a solution of BH3.THF (5.6 mL, 10% wt. in THF, 5.6 mmol) at 0° C. over 30 min. The reaction mixture was stirred at 0° C. for 3 h and then at room temperature for 15 h. The reaction solution was chilled to 0° C., and a H2O/THF mixture (3 mL) was added. After being agitated at room temperature for 6 h, the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 1N HCl (2×100 mL). The aqueous phase was basified with 1N NaOH solution to pH 1 and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (50 mL), dried over Na2SO4, filtered, and evaporated. After drying under vacuum, 4-aminomethyl-2′-ethoxy-biphenyl-2-ylamine was isolated as a brown oil (370 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ 7.28 (dt, J=7.2 Hz, J=1.8 Hz, 1H), 7.09 (dd, J=7.2 Hz, J=1.8 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.96 (dt, J=7.2 Hz, J=0.9 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.66 (d, J=1.2 Hz, 1H), 6.57 (dd, J=7.5 Hz, J=1.5 Hz, 1H), 4.29 (s, 2H), 4.02 (q, J=6.9 Hz, 2H), 3.60 (s, 2H), 1.21 (t, J=6.9 Hz, 3H); HPLC ret. time 1.54 min, 10-100% CH3CN, 5 min gradient; ESI-MS 243.3 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[C:13]1=[O:21].C(N(CC)CC)C.[C:29]([Si:33](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:32])([CH3:31])[CH3:30].O>CN(C)C=O.CN(C)C1C=CN=CC=1>[Si:33]([O:20][CH2:19][CH2:18][C:14]1[C:13](=[O:21])[N:12]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
760 mg (2.64 mmol) of the compound from Example 53A and 0.55 ml (3.9 mmol) of triethylamine are dissolved in 7 ml of anhydrous N,N-dimethylformamide. 16 mg (0.13 mmol) of 4-dimethylaminopyridine and 1.09 g (3.95 mmol) of tert-butyl(chloro)diphenylsilane are added, and the mixture is stirred at RT for 2 h. The mixture is then added to water and, after phase separation, extracted three times with ethyl acetate. The combined organic phases are washed twice with water, dried over sodium sulphate, filtered, and evaporated under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 5:1). This gives 971 mg (58% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29](I)[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[NH:32]1[CH:36]=[CH:35][C:34](B(O)O)=[N:33]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:31])=[N:27][CH:28]=[C:29]([C:36]5[CH:35]=[CH:34][NH:33][N:32]=5)[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Reactant: OB(O)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cc[nH]n2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 35.9 %

Procedure:
To a 25 mL microwave reactor vial was charged 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodothieno[3,2-c]pyridin-4-amine (150 mg, 0.274 mmol), 1H-pyrazol-3-ylboronic acid (30.7 mg, 0.274 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11.19 mg, 0.014 mmol), and sodium carbonate (58.1 mg, 0.548 mmol) followed by dioxane (5 mL), and water (1 mL). The reaction was heated at 120° C. for 30 min in microwave reactor. Ethyl acetate (20 mL) was added and the layers were separated. The organic layer was washed with brine, concentrated, and the residue purified by silica gel chromatography (0%-100% EtOAc in hexanes). Product came out at 100% EtOAc in 5 minutes, the fractions with the product were combined and evaporated to dryness to afford the title compound as a light gray solid (48 mg). LC/MS (ES) m/z=488.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (s, 1H) 8.36 (s, 1H) 8.12 (d, J=8.1 Hz, 1H) 7.85 (s, 1H) 7.48 (s, 1H) 7.38 (s, 1H) 7.14-7.31 (m, 4H) 6.84 (s, 1H) 5.50 (br. s., 2H) 4.32 (t, J=8.5 Hz, 2H) 3.96 (s, 2H) 3.25-3.32 (m, 2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.[CH:10]1([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:17]=3[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:10]1([N:14]2[CH2:15][CH2:16][C:17]3[CH:24]=[CH:23][C:22]([O:25][C:2]4[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=4)=[CH:21][C:18]=3[CH2:19][CH2:20]2)[CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(Br)s1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 2-bromo-5-nitrothiophene (478 mg, 2.3 mmol), 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (500 mg, 2.3 mmol) and potassium carbonate (765 mg, 5.5 mmol) in dimethylformamide (10 ml) was stirred at 80° C. for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with water, brine and dried (sodium sulfate). Concentration in vacuo and purification of the resulting residue by column chromatography 0.880 ammonia:methanol:dichloromethane (1:8:300) afforded the title compound (E211); MS (ES+) m/e 345 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-])=O)[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[H][H]>O1CCOCC1.[C].[Pd]>[ClH:1].[NH2:21][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O
Yield: 190.7 %

Procedure:
4-[3-(4-Chlorophenylsulfonyl)propyl]-2-nitrophenol (10.00 g, 28.11 mmol) was dissolved in 1,4-dioxane (100 ml), 4 N hydrochloric acid solution in 1,4-dioxane (8.43 ml, 33.73 mmol) and 10% palladium-carbon (1.0 g) were added, and the mixture was stirred for 4 hours in an atmosphere of hydrogen gas under 1 atmospheric pressure. The crystals precipitated in the reaction solution were dissolved by adding methanol, the reaction mixture was filtered, and then the resulting filtrate was concentrated under reduced pressure. By crystallizing the resulting residue from acetonitrile-ether, 2-amino-4-[3-(4-chlorophenylsulfonyl)propyl]phenol hydrochloride (9.71 g, 95%) was obtained.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1.C[N:31](C=O)C>>[NH2:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH2:23][N:22]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:21]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)CNC2
Product: Nc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2

Procedure:
136 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 200 mg of isoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 130 mg of the target compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:42])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[N:27]=[C:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[Cl:41])[O:29][C:30]=3[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:28]1[O:29][C:30]([C:31]([F:34])([F:32])[F:33])=[C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([C@H:10]3[CH2:9][CH2:8][C@H:7]([CH2:6][C:5]([OH:43])=[O:4])[CH2:12][CH2:11]3)=[CH:18][CH:17]=2)=[O:42])=[O:25])[N:27]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4Cl)oc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4Cl)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (108 mg, 2.7 mmol) was added to trans-{4-[4-(3-{[2-(2-chlorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (160 mg, 0.27 mmol) dissolved in THF/MeOH/water (25 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH of 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. Acetonitrile was added thereto and cooled to obtain a filtrate, and the filtrate was filtered and separated to obtain the desired compound (130 mg, 83%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH:29]=[N:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:30][CH:29]=[N:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cncs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
In THF (5.0 ml)/methanol (10 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (0.50 g). To the solution was added 1N sodium hydroxide solution (5.0 ml), and the mixture was stirred at room temperature for 16 hours. pH was adjusted to approximate 5 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate/THF, and the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane ethyl acetate (8/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(1,3-thiazol-5-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (385 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2.[H][H]>C(O)C.C1COCC1.[Pd]>[NH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]2
Reactant: [H][H]
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2cc(N)ccc2[nH]1
Yield: 99.6 %

Procedure:
A solution of 2-methyl-5-nitroindole (1 g, 5.7 mmol) in ethanol (25 ml) and THF (25 ml) containg 10% palladium on charcoal (128 mg) was hydrogenated until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to give 5-amino-2-methylindole (830 mg, quant.).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][CH2:21][C:22]#[N:23].CCN(C(C)C)C(C)C>CN(C=O)C.ClCCl>[C:21]([CH2:22][NH:23][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)=[O:3])#[N:20]
Reactant: N#CCN
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCNC(=O)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0° C. was added oxalylchloride (5.9 mL, 66 mmol) dropwise. When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 40° C. for three hours by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 0° C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 mL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na2SO4) filtered and concentrated under reduced pressure to afford 4-(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87%). 1H NMR (300 MHz, d6-DMSO): 9.18 (br. t, J=5.1 Hz, 1H), 7.8-7.9 (m, 4H), 4.31 (d, J=5.4 Hz, 2H); LC-ESI-MS (method B): rt 0.9 min.; m/z 203.3 [M−H]−.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C1C=CC=CC=1.C1CCCCC=1>[Pd].C(O)C>[OH:8][CH2:9][CH2:10][O:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(COCCOCc1ccccc1)OCC
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOP(=O)(COCCO)OCC

Procedure:
Palladium on carbon (10%, 100 mg) was added to a solution of diethyl 2-(benzyloxy)ethoxymethylphosphonate prepared in this manner (0.9 g,2.8 mmol) and cyclohexene (2.0 ml, 20 mmol) in 20 ml ethanol under a nitrogen atmosphere. The resulting slurry was heated to reflux overnight. The catalyst was filtered off and the solution concentrated under vacuum to yield 0.5 g of diethyl 2-hydroxyethoxymethylphosphonate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][C:4]=1C)#[CH:2].[C:17](O)(=O)C1C=CC=CC=1.[CH2:26]([O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33](I)=[CH:32][CH:31]=1)[CH3:27]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([O:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:33]3[CH:34]=[CH:35][C:30]([C:29]([O:28][CH2:26][CH3:27])=[O:37])=[CH:31][CH:32]=3)=[CH:8][C:7]=2[CH3:17])[CH2:10][CH2:11]1)([CH3:14])[CH3:15]
Reactant: O=C(O)c1ccccc1
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 159.2 %

Procedure:
Using General Procedure F; 4-ethynyl-1-(1-isopropoxycyclopropyl)-3-methyl-benzene (Intermediate 81, 80.0 mg, 0.13 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (91 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 75.0 mg (56%) of the title compound as an orange solid.