Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:33]([O:35]C)=[O:34])#[N:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:32])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:18][CH:19]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:33]([OH:35])=[O:34])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(C(F)(F)F)c4)cc3)c(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of methyl 6-cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylate (0.019 g, 0.0383 mmol) in 3:1 THF/methanol (2 ml) was added 1M sodium hydroxide (0.0459 ml, 0.0459 mmol), and the reaction was stirred at ambient temperature overnight. The reaction was concentrated and partitioned between EtOAc and diluted HCl in water. The aqueous was extracted once with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by preparative thin layer chromatography eluting with 95:5:1 dichloromethane/methanol/acetic acid to yield 10 mg of the title compound (54.2% yield). MS (apci) m/z=480.8 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][CH2:7][C:6]2[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[CH:17][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNCc2cc(Br)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring mixture of 5-bromo-2-nitrobenzaldehyde (0.46 g, 2.0 mmole (prepared according to a reference: Organic Letters (2003), 5(13), 2251-2253) in DCM (4.0 mL) was added p-methoxybenzyl amine (0.32 mL, 2.4 mmol) and three drops of AcOH. The mixture was stirred at RT for 5 min, after which was added NaB(OAc)3H (0.64 g, 3 mmol) and the entire mixture was stirred for additional 2 hrs. The reaction mixture was quenched with NaHCO3 (aq) and diluted with EtOAc (10 mL). The separated aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude residue, which was purified using flash column chromatography (100% hexane to 30% EtOAc/hexanes gradient) to obtain the desired product N-(4-methoxybenzyl)(5-bromo-2-nitrophenyl)methanamine as a pale yellow oil. MS m/e 351 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][NH:3][C:2]1=[O:11].O1CC1C[C:15]1[C:16]([O:34][CH3:35])=[C:17]([O:21][C:22]2C=CC=[C:24](CC3OC3)[C:23]=2[O:32]C)[CH:18]=[CH:19][CH:20]=1.CO>C1(C)C=CC=CC=1>[CH3:35][O:34][C:16]1[CH:15]=[CH:20][CH:19]=[CH:18][C:17]=1[O:21][CH2:22][CH:23]([OH:32])[CH2:24][N:8]1[CH2:7][CH2:6][C:5]2([O:1][C:2](=[O:11])[NH:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: O=C1NCC2(CCNCC2)O1
Reactant: COc1c(CC2CO2)cccc1Oc1cccc(CC2CO2)c1OC
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccccc1OCC(O)CN1CCC2(CC1)CNC(=O)O2
Yield: 86.7 %

Procedure:
A mixture of 3.12 g 1-oxa-3,8-diazaspiro[4.5]decan-2-one, 5.4 g 2,3-epoxypropyl-o-methoxyphenyl ether, 5 ml methanol and 10 ml toluene is heated at reflux for 24 hours. The solvent is evaporated and the residue filtered through 20 g silica gel with 10% methanol/methylene chloride. Evaporation of solvent and crystallization from diethyl ether affords 4.6 g 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 124°-125°.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][CH:5]([CH2:7][CH2:8][CH2:9][CH:10]([CH2:12][CH:13]=[O:14])[CH3:11])[CH3:6]>CN(C)C=O>[CH3:11][C:10](/[CH:9]=[CH:8]/[CH2:7][CH:5]([CH3:4])[CH2:6][CH2:8][CH2:7][CH:5]([CH3:6])[CH3:4])=[CH:12][C:13]([O:2][CH3:1])=[O:14]
Reactant: C[O-]
Reactant: CC(C)CCCC(C)CC=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=C(C)/C=C/CC(C)CCCC(C)C
Reaction time: 3 h

Procedure:
Sodium methoxide (1.2 g. of sodium and 30 ml. of methanol) is added slowly to a mixture of 5 g. of dihydrocitronellal and 10 g. of diethyl 3-methoxycarbonyl-2-methylprop-2-enyl phosphonate (about 77% trans) in 50 ml. of dimethylformamide, under nitrogen and at about 0°, with stirring. After addition is complete, the reaction is left three hours at room temperature and then worked up by extraction with hexane/ether to yield cis/trans methyl 3,7,11-trimethyldodeca-2,4-dienoate, mostly the trans,trans isomer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C:9]1([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[C:17]1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([CH2:14][CH2:16][CH3:17])[CH2:15][CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCC1(NC(=O)OC(C)(C)C)CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2.20 g of 2,2-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester in 50 ml DCM was added 1.15 ml of benzaldehyde, followed by the addition of 2.61 g of sodium triacetoxyborohydride in small portions. The reaction was stirred at r.t. overnight. To the reaction was then added water. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. 3.30 g (100%) of the title compound were obtained and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH2:23])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:25]([C:27]1[CH:28]=[C:29]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34](=[O:36])[CH3:35])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:25]([C:27]3[CH:28]=[C:29]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:39][CH:38]=4)[CH:30]=[CH:31][C:32]=3[O:33][C:34](=[O:36])[CH3:35])=[O:26])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Product: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 70.5 %

Procedure:
Acetic acid 3-[2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylcarbamoyl]-4′-trifluoromethyl-biphenyl-4-yl ester (45 mg) was prepared from 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (33 mg, 0.1 mmol) and acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (34 mg, 0.1 mmol) following the general procedure M.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].N.[Cl-].[NH4+].[CH3:12][N:13](C=O)C>>[C:12]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])#[N:13]
Reactant: CN(C)C=O
Reactant: Cc1ccncc1Br
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccncc1C#N

Procedure:
3-Bromo-4-methylpyridine (20.0 g, 116 mmol) is dissolved in DMF (100 ml), and thereto is added cuprous cyanide (11.6 g, 30 mmol), and the mixture is heated under reflux for 18 hours. After cooling, a 25% aqueous ammonia (200 ml) and a saturated aqueous ammonium chloride solution (200 ml) are added to the reaction solution, and the mixture is extracted with ethyl acetate (200 ml×5). The organic layer is washed with a saturated brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (11.0 g) as colorless crystals, m.p. 75-78° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[O:35][N:34]=[C:33]([CH:36]([CH3:38])[CH3:37])[N:32]=2)[CH2:27][CH2:26]1)[CH3:24])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:38][CH:36]([C:33]1[N:32]=[C:31]([N:28]2[CH2:27][CH2:26][CH:25]([CH:23]([O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH3:24])[CH2:30][CH2:29]2)[O:35][N:34]=1)[CH3:37]
Reactant: CC(C)c1noc(N2CCC(C(C)OS(C)(=O)=O)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(C(C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1

Procedure:
The title compound (0.212 g, 26%) was prepared as a white foam from 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Steps 1-2, 0.43 g, 1.72 mmol), (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.74 g, 2.32 mmol) and K2CO3 (0.48 g, 3.44 mmol) in DMF (15 mL) in a manner similar to Example 152, Steps 3. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 25% EtOAc/CH2Cl2, followed by chromatography on a silica gel column eluted with 50% EtOAc/hexanes to give (±)-2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.25 (s, 1H), 8.10 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 5.20-5.10 (m, 1H), 4.35-4.20 (m, 2H), 3.15-3.00 (m, 5H), 2.91 (septet, 1H, J=7.0 Hz), 2.00-1.80 (m, 3H), 1.60-1.40 (m, 2H), 1.34 (d, 3H, J=6.1 Hz), 1.28 (d, 6H, J=7.1 Hz); LRMS (ESI), m/z 472 (M+H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:16]([O:34][CH3:35])[CH:15]=2)=[N:8][N:9]([CH3:11])[CH:10]=1)=[O:5].[CH3:37][Mg]Br.Cl>O1CCCC1>[CH3:35][O:34][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27])[CH2:13][O:12][C:7]1[C:6]([C:4](=[O:5])[CH3:37])=[CH:10][N:9]([CH3:11])[N:8]=1
Reactant: C[Mg]Br
Reactant: COc1cc(COc2nn(C)cc2C(=O)N(C)OC)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2C(C)=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of N-methoxy-N-methyl-3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxamide (3.00 g) in tetrahydrofuran (30 mL) was slowly added methylmagnesium bromide (1.0 M tetrahydrofuran solution, 15 mL) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)ethanone (2.65 g, yield 97%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 170-171° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:19]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N=C2NC(=O)CN2C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-methoxyphenylisocyanate (14.91 g, 0.100 mole) is added dropwise over a period of about 15 minutes with cooling. After stirring for 8 hours, the mixture is poured into about 500 ml of ice water to yield white crystals of product which are filtered off, washed with water and purified by recrystallization (twice) from tetrahydrofuran-methanol. The crystalline product is reduced to finer size by adding a solution of the product in minimal DMF to vigorously stirred water (about 1.1 liters) and filtering off the resultant crystals which are then dried at room temperature in vacuo for 24 hours; m.p. 193°-5°C dec.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:3][C:4]1[O:5][CH2:6][C:7](=[O:14])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:6]2[O:5][C:4]([NH:3][N:2]([CH3:1])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]2=[O:14])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NN(C)c2ccccc2)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NN(C)c2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 10.3 %

Procedure:
To a solution of ethyl 2-(2-methyl-2-phenylhydrazinyl)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.053 g, 0.36 mmol) in ethanol (10 mL), L-proline (0.020 g, 0.17 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and hexane then dried to afford the titled compound as solid (0.015 g, y. 10%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:20]=[N:19][NH:18][C:17]=2[NH2:21])(=[O:15])=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO.FC(F)(F)C(O)=O.[CH3:34][C:35]([CH3:45])=[CH:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O>>[CH2:1]([CH:8]1[CH2:12][CH2:11][N:10]([S:13]([C:16]2[CH:20]=[N:19][N:18]3[C:35]([CH3:45])([CH3:34])[CH:36]=[C:37]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[NH:21][C:17]=23)(=[O:15])=[O:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CC(=O)c1ccccc1
Reactant: Nc1[nH]ncc1S(=O)(=O)N1CCC(Cc2ccccc2)C1
Solvent: COCCO
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C=C(c2ccccc2)Nc2c(S(=O)(=O)N3CCC(Cc4ccccc4)C3)cnn21

Procedure:
A 2 mL ethanol solution containing 0.079 g (0.247 mmol) of 3 was treated with 0.013 mL (0.27 mmol) of hydrazine monohydrate and heated to reflux for 5 h. The reaction was concentrated in vacuo to give crude 4-(3-benzylpyrrolidine-1-sulfonyl)-2H-pyrazol-3-ylamine. The crude pyrazole thus obtained was dissolved in 2 mL of 2-methoxyethanol containing 0.044 g (0.27 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 0.038 mL (0.49 mmol) of trifluoroacetic acid was added. The mixture was refluxed for three days then concentrated and purified by flash chromatography eluting with 60% hexanes/AcOEt to give 3-(3-benzylpyrrolidine-1-sulfonyl)-7,7-dimethyl-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine that was found to be only 90% pure by HPLC analysis. This material was then dissolved in 1 mL of 1:1 THF:ethanol and 0.010 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 90 min at room temperature, the catalyst was removed via filtration and the filtrate concentrated to an oil. Purification by flash chromatography eluting with 75% hexanes/AcOEt gave 0.024 g (20% from 3) of the title compound as a light yellow oil. 1H NMR (CDCl3) δ 1.55-1.66 (m, 7H), 1.94-2.03 (m, 1H), 2.08-2.16 (m, 2H), 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H), 2.90-2.97 (m, 1H), 3.18-3.27 (m, 1H), 3.31-3.42 (m, 2H), 4.53-4.60 (m, 1H), 5.71 (s, 1H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.40 (m, 7H), 7.53 (s, 1H). MS Calcd.: 450. Found: 451 (M+H).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([NH:18][C:19]([C:21]1[C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20])[CH:12]=2)=[O:7])C>C(O)C.O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([C:22]2[C:21]([C:19]([NH:18][C:13]3[CH:12]=[C:11]4[C:16]([CH:17]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]4)=[CH:15][CH:14]=3)=[O:20])=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:32][CH:31]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(C)(C)C)cc3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccccc2C(=O)Nc2ccc3cc(C(=O)O)cnc3c2)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Lithium hydroxide (20.0 mg, 0.48 mmol) was added to a mixture of 7-[(4′-tert-butyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (99 mg, 0.22 mmol) in 6 ml ethanol and 3 ml water. The reaction mixture was heated under reflux for 1.5 hr, then cooled to room temperature. The ethanol was removed in vacuo and aqueous hydrochloric acid solution was added (0.46ml of 0.961M solution, 0.44 mmol) to the resulting aqueous solution. The precipitate that formed was filtered, washed with water and air dried to yield the title compound as a white solid (75.1 mg, 80.8% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])[CH2:17][Zn+].Cl>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[C:22]([F:23])([F:24])[F:25])[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1cc(C[Zn+])ccc1C(F)(F)F
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccc(C(F)(F)F)c(F)c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of methyl 2-chloroisonicotinate (5.15 g, 30 mmol) and Pd(PPh3)4 (0.693 g, 0.60 mmol) in tetrahydrofuran (40 mL) under nitrogen in a dried flask was added freshly prepared (3-fluoro-4-(trifluoromethyl)benzyl)zinc(II) bromide (12.55 g, 38.91 mmol) in tetrahydrofuran (50 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 20 min, then cooled to room temperature. The reaction was quenched by the addition of 10% NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 150 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 200 mL, then hydrogen chloride (7.50 mL, 30.00 mmol) (4M in dioxane) was added dropwise. A colorless precipitate formed. The resulting suspension was stirred for ca. 1 h, then sonicated for 2 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10% K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinate (8.26 g, 88%) was isolated as a pale orange oil. 1H NMR (400 MHz, cdcl3) δ 3.94 (s, 3H), 4.24 (s, 2H), 7.06-7.18 (m, 2H), 7.52 (t, 1H), 7.69-7.75 (m, 2H), 8.68-8.75 (m, 1H). MS m/z 314 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[N:28][C:27]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:37][CH2:36][C:27]2[N:28]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[O:30][C:26]=2[CH3:25])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(-c4cccs4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester using the procedure of Example 74. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J=3.52 Hz), 7.36 (d, 1H, J=5.08 Hz), 7.17-7.13 (m, 3H), 7.08-6.99 (m, 1H), 6.82 (d, 2H, J=8.60 Hz), 6.62-6.59 (m, 1H), 6.52-6.46 (m, 2H), 4.19 (t, 2H, J=6.65 Hz), 3.75 (s, 3H), 3.24 (d, 1H, J=14.08 Hz), 3.16 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.45 (s, 3H); HRMS (ES+) m/z exact mass calcd for C27H28NO6S 494.1637, found 494.1642.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:18]3[N:19]([CH3:34])[C:20](=[O:33])[N:21]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([CH3:32])([CH3:31])[C:29]#[N:30])=[CH:24][CH:23]=4)[C:17]=3[C:16]3[CH:15]=[C:14]([C:35]4[CH:36]=[N:37][C:38]5[C:43]([CH:44]=4)=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:13]=[CH:12][C:11]=3[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[C:18]2[N:19]([CH3:34])[C:20](=[O:33])[N:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:32])([CH3:31])[C:29]#[N:30])=[CH:24][CH:23]=3)[C:17]=2[C:16]2[CH:15]=[C:14]([C:35]3[CH:36]=[N:37][C:38]4[C:43]([CH:44]=3)=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COc1ccc(CNc2nc3ccc(-c4cnc5ccccc5c4)cc3c3c2n(C)c(=O)n3-c2ccc(C(C)(C)C#N)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc5ccccc5c4)ccc3nc(N)c21
Reaction time: 5 h

Procedure:
110 mg (0.182 mmol) of 2-{-4-[4-(4-methoxy-benzylamino)-3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-phenyl}-2-methyl-propionitrile (Example 109a) in 1.1 ml TFA are stirred at rt for 24 h and then at 35° C. for 5 h. The reaction mixture is purified by preparative HPLC to provide the title compound as an off-white solid. ES-MS: 485 (M+H)+; analytical HPLC: tret=2.86 minutes (Grad 1).
Reaction SMILES: [CH3:1][C@H:2]([CH:9]=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH:12](Cl)[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[Li+].[I-]>C1COCC1>[CH3:1][C@H:2](/[CH:9]=[CH:12]/[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[C@H](C)C=O
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](C)/C=C/B1OC(C)(C)C(C)(C)O1

Procedure:
Following the same procedure for the preparation of pinacol boronates, the reaction of ethyl (S)-3-methyl-4-oxobutanoate (S)-3 (0.057 g, 0.40 mmol) with CrCl2 (0.39 g, 3.18 mmol), 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 5 (0.168 g, 0.80 mmol) and LiI (0.21 g, 1.59 mmol) in THF (6 mL) afforded, after purification by column chromatography (silica gel, 97:3 hexane/ethyl acetate), 69 mg (65%) of a colourless oil identified as ethyl (3S,4E)-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoate (S)-4.