Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[Sn](Cl)(Cl)Cl.[CH2:14]=[O:15].Cl>C1(C)C=CC=CC=1.O>[OH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15]
Reactant: Cc1cccc(O)c1
Reactant: C=O
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C=O)c(O)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
To a stirred solution of 3-methyl-phenol (1 g, 9.2 mmol) in toluene (5 ml) at room temperature under nitrogen was added SnCl4 (241 mg, 0.92 mmol) and tri-nbutylamine (0.6 ml, 2.77 mmol). After 20 min, paraformaldehyde (611 mg, 20.3 mmol) was added and the whole stirred at 100° C. for 16 h. The reaction mixture was diluted with water (20 ml) and acidified with 2N HCl to pH2. The solution was extracted with ether (25 ml), washed with brine (20 ml), dried (MgSO4) filtered and evaporated to a brown oil. This oil was purified by column chromatography using 5% EtOAc in pentane as eluant to provide the title product (319 mg, 25%); 1HNMR (400 MHz, CDCl3) δ: 2.3 (s, 3H), 6.75 (m, 2H), 7.35 (d, 1H), 9.75 (s, 1H), 11.00 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Sc3ccc(N)cc3)ncnc2n1

Procedure:
The product of Example 66 was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) at room temperature for 30 minutes. The solvents were removed under vacuum to provide the title compound as a trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.77 (s, 3 H) 6.65 (d, J=8.46 Hz, 2 H) 6.97 (d, J=8.46 Hz, 1 H) 7.16 (d, J=8.46 Hz, 2 H) 7.30 (m, 2 H) 7.72 (m, 1 H) 7.90 (m, 3 H) 8.05 (s, 1 H) 8.92 (s, 1 H) 9.01 (d, J=8.46 Hz, 1 H) 10.36 (s, 1 H) 11.78 (s, 1 H); MS (ESI+) m/z 557, 559 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([CH:31]=O)[CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:23]2[CH:22]=[N:21][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 376.75 g/mol.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[NH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:17]1([C:23]2[S:27][C:26](B(O)O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].C(#N)C>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.O>[NH2:1][CH:2]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:26]3[S:27][C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)[CH:14]=2)[NH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Reactant: NC(Cc1c[nH]c2ccc(Br)cc12)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(Cc1c[nH]c2ccc(-c3ccc(-c4ccccc4)s3)cc12)C(=O)O
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 19.4 %

Procedure:
2-Amino-3-(5-bromo-1H-indol-3-yl)-propionic acid (0.020 g, 0.071 mmol) was added to a 5 ml microwave vial, which contained 5-phenyl-thiophen-2-boronic acid (0.016 g, 0.078 mmol), Na2CO3 (0.015 g, 0.142 mmol), acetonitrile (1.5 ml)/water (1.5 ml) and dichlorobis(triphenylphosphine)-palladium (3 mg, 0.003 mmol). Microwave vial was capped and stirred at 150° C. for 5 min under microwave radiation. Reaction mixture was cooled, filtered through a syringe filter and then separated by a reverse phase preparative-HPLC using YMC-Pack ODS 100×30 mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were concentrated in vacuum. The product was then suspended in 5 ml of water, frozen and lyophilized to give 5 mg of pure product, 2-amino-3-[5-(5-phenyl-thiophen-2-yl)-1H-indol-3-yl]-propionic acid. 1H-NMR (300 MHz, CD3OD): 3.21-3.26 (m, 2H), 4.25 (q, 1H), 7.15-7.35 (m, 8H), 7.58 (d, 2H), 7.82 (d, 1H).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]([O:13][CH3:14])[NH:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=2[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([CH2:33][C:34]#[N:35])[S:31][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[C:34]([CH2:33][C:30]1[S:31][CH:32]=[C:28]([C:2]2[C:6]3[C:7]([O:13][CH3:14])=[N:8][CH:9]=[C:10]([C:11]#[N:12])[C:5]=3[N:4]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:3]=2)[CH:29]=1)#[N:35]
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
Reactant: COC1NC=C(C#N)c2c1c(Br)cn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(C#N)c2c1c(-c1csc(CC#N)c1)cn2C1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A mixture of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (250 mg) obtained in Step H of Example 33, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl)acetonitrile (292 mg), tetrakis(triphenylphosphine)palladium(0) (90 mg), 2M aqueous sodium carbonate solution (0.781 mL) and DME (3.0 mL) was stirred overnight at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (220 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.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>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccccc1
Temperature: 120 °C

Procedure:
4-Bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.77 g, 2.88 mmol), phenylboronic acid (0.63 g, 5.18 mmol), Pd(PPh3)4 (0.199 g, 0.173 mmol) and Cs2CO3 (1.49 g, 4.6 mmol) were dissolved in DMF (10.7 ml) and heated under microwave irradiation at 120° C. for 20 min. The reaction mixture was then diluted with AcOEt (100 mL) and filtrate. The organic phase was washed twice with 0.5 M HClaqueous, twice with water, sat NaHCO3 and once with sat NaClaqueous. The resulting organic phase was dried over Na2SO4, filtered and concentrated. The crude was finally purified on Biotage Si 50 g Ultra with a gradient of Hexane and EtOAc. The title compound was recovered as dark pink solid (0.53 g, 1.99 mmol, 69.3%) as a dark pink solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH:6]=[CH2:7])(=[O:5])=[O:4].Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.C(N(CC)CC)C>C(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)(=[O:5])=[O:4]
Reactant: C=CS(=O)(=O)NC
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)/C=C/c1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 221.2 %

Procedure:
A mixture of N-methylethenesulphonamide (45 g), 5-bromoindole (60 g), palladium acetate (0.9 g), tri-o-tolylphosphine (18.6 g) and triethylamine (90 mL) in isopropanol (300 mL) was heated at 85° under nitrogen for 18 h. The reaction mixture was cooled to ambient temperature, filtered and the filter-cake washed with isopropanol (30 mL). The combined washings and filtrate were concentrated in vacuo to give a yellow-brown solid (160 g). This material was purified by column chromatography on silica gel. Eluting initially with ethyl acetate/cyclohexane (1:1) followed by ethyl acetate provided the product (26.4 g, 36% of theory) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8]2)[NH:3]1.[CH2:15]1[O:17][CH2:16]1>C(O)CCCCCCC>[OH:17][CH2:16][CH2:15][N:3]1[CH:4]2[CH:9]([CH2:8][CH:7]([CH3:13])[CH2:6][CH2:5]2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:14])[CH3:1]
Reactant: CC1CCC2NC(C)(C)CC(C)C2C1
Reactant: C1CO1
Solvent: CCCCCCCCO
Product: CC1CCC2C(C1)C(C)CC(C)(C)N2CCO
Temperature: 200 °C

Procedure:
1-(2'-hydroxyethyl)-2,2,4,6-tetramethyl decahydroquinoline was prepared. 50 grams of 2,2,4,6-tetramethyl decahydroquinoline and 50 milliliters of 1-octanol were placed into a reactor vessel equipped for heating and agitation and he mix heated to 200° C. Ethylene oxide was then slowly added to the reactor over a period of 7 hours. The reaction mixture was then distilled to yield a liquid product boiling at 106° C. at 0.5 mm Hg. The NMR and infrared spectra were consistent with the desired product. Calculated contents and analyzed contents of the product (formula of C15H29NO) were respectively: 75.26% carbon, 74.36% carbon found; 12.21% hydrogen, 12.24% hydrogen found; and 5.85% nitrogen, 6.04% nitrogen found.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1.[CH3:12]O>>[CH3:12][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][N:7]=1)=[O:11]
Reactant: CO
Reactant: O=C(O)c1ccc(O)cn1
Agent: Cl
Product: COC(=O)c1ccc(O)cn1
Reaction time: 48 h
Yield: 70 %

Procedure:
Gaseous hydrogen chloride was passed through a solution of 5 g of dry 5-hydroxy-2-pyridinecarboxylic acid in 100 ml methanol for 5 hours at 70° C. The mixture was kept for 2 days at room temperature and the solvent removed in vacuo. The residue was taken up in a minimum amount of water and neutralized with ammonium hydroxide. The precipitate was removed by filtration and the ester was separated in 70% yield from the acid by recrystallizing from isopropyl alcohol; m.p. 188°-190°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18]1[NH:23][CH:22]([CH3:24])[CH2:21][NH:20][CH2:19]1>CS(C)=O.O>[CH3:24][CH:22]1[NH:23][CH:18]([CH3:17])[CH2:19][N:20]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:21]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CNCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1CN(c2ccc([N+](=O)[O-])cc2)CC(C)N1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a suspension of 1-fluoro-4-nitrobenzene (2.12 mL, 20 mmol) and potassium carbonate (3.5 g, 25 mmol) in DMSO (10 mL) was added 3,5-dimethyl-piperazine (2.5 g, 22 mmol). The mixture was stirred at 100° C. for 2 hours. After cooing down, the mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried with sodium sulfate (Na2SO4), and concentrated in vacuo to afford a yellow solid. Recrystallization from EtOAc/hexanes gave 3.9 g of 3,5-dimethyl-1-(4-nitro-phenyl)-piperazine, which was reduced via hydrogenation to give the title compound (purple solid, 3 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 6.80 (d, J=8.8 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 3.40 (br, 2H), 3.32 (d, J=9.5 Hz, 2H), 3.05 (m, 2H), 2.19 (t, J=10.5 Hz, 2H), 1.12 (s, 3H), 1.10 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]2[NH:26][CH:27]=[C:28]([NH:29][C:30](=[O:35])[C@H:31]([O:33][CH3:34])[CH3:32])[C:17]=12>CCCCO.O>[CH3:34][O:33][C@H:31]([CH3:32])[C:30]([NH:29][C:28]1[C:17]2[C:18](=[N:19][CH:20]=[C:21]([C:22]([F:25])([F:23])[F:24])[C:16]=2[N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)[NH:26][CH:27]=1)=[O:35]
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: O
Solvent: CCCCO
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(C(F)(F)F)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Yield: 41 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (456 mg, 2.28 mmol) and N,N-diispropylethylamine (294 mg, 0.396 mL, 2.28 mmol) were added to a suspension of (R)—N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (244 mg, 0.759 mmol) in n-BuOH (3 mL). The resulting mixture was heated in a sealed tube under a nitrogen atmosphere at 160° C. for 24 hours. The cooled mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated to an oil, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-80% CH3CN/water, 25CV) to give tert-butyl (R)-1-(3-((R)-2-methoxypropanamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (151 mg, 41%) as a solid. LCMS (APCI+) m/z 386.1, 486.1 (M+H)+, Retention time=3.85 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][C:3]=1[F:23].Cl[C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26]>CCOC(C)=O.C([O-])(O)=O.[Na+].O>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][C:3]=1[F:23])[CH2:29][CH3:30]
Reactant: CCCOC(=O)Cl
Reactant: CCn1c(-c2ccc(N)c(F)c2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOC(=O)Nc1ccc(-c2c(C#N)c3ccc(OC)cc3n2CC)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
A biphasic mixture of 2-(4-amino-3-fluorophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (74 mg, 0.24 mmol), prepared as described in example 1Gb, and propyl chloroformate (0.033 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 10-40%) gives 60 mg (63%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamic acid propyl ester as an off-white solid.
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:19]3[CH3:29])=[CH:14][CH:13]=2)[CH2:7]1)(=O)=O.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][C:19]1[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH:8]3[CH2:9][CH2:10][CH:6]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:7]3)=[CH:13][CH:14]=2)[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(OS(C)(=O)=O)C2)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(N3CCCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
3-[4-({3-[(methylsulfonyl)oxy]cyclopentyl}oxy)phenyl]-2-methyl -4(3H)-quinazolinone (550 mg, 1.33 mmol), pyrrolidine (474 mg, 6.7 mmol) and potassium carbonate (277 mg, 2.0 mmol) were mixed in dimethylformamide (10 mL) and stirred at 80° C. overnight. Distilled water was added, and the mixture extracted with ethyl acetate. The organic phase was dried by anhydrous magnesium sulfate, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain the title compound (143 mg) as a colorless solid. 2-methyl-3-[4-{[3-(1-pyrrolidinyl)cyclopentyl]oxy}phenyl]-4(3H)-quinazolinone (trans isomer)
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:48])([F:47])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[C:43]([CH2:45][NH2:46])[CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:46][CH2:45][C:43]1[CH:42]=[CH:41][N:40]=[C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:48])([F:31])[F:47])=[CH:34][CH:35]=2)[CH:44]=1)=[O:7])[CH3:2]
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)c(F)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
Acid 4G (500 mg, 1.7 mmol) was dissolved in 20 ml of THF and at rt DEPC (1.3 equiv, 0.34 ml) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv., 476 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 mL) and washed with water (1×20 mL) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (EtOAc 1/petroleum ether 1) afforded 120 mg of a white solid. Yield=24% 1HNMR (DMSO, 200 MHz) δ 1.09 (3H, t, J=7.2 Hz), 3.45 (2H, q, J=6.8 Hz), 4.51 (2H, d, J=6 Hz), 5.31 (1H, s), 6.17 (1H, s), 7.38 (1H, dd, J=4.8 Hz, J′=1.2 Hz), 7.68 (2H, t, J=8.8 Hz), 7.83 (d, 3H), 8.02 (s, 1H), 8.32 (d, 2H, J=7.8), 8.67 (d, 1H, J=5.8), 8.93 (t, 1H). [M+1] 525.11 (C24H20F5N3O3S requires 524.98).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[CH:14]=1)=O)(=O)[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].C([NH2:27])(=O)C.B(F)(F)F.CCOCC>C(OCC)(=O)C>[Cl:23][C:15]1[CH:14]=[C:13]([C:11]2[N:27]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9][CH:10]=2)[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: COC(=O)CCC(=O)OCC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A stirred solution of 2-(3-chloro-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (Reference Example 35, 1.10 g, 3.12 mmol), acetamide (0.921 g, 15.59 mmol) and boron trifluoride diethyl etherate (0.565 g, 3.98 mmol) was heated at 140° C. for 2 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to provide methyl 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.401 g, 39%) as a yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Br)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (843 mg, 0.005 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.64 g, 0.020 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (1.50 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(3-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (490 mg, 25%) as yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29](O)=[O:30])=[CH:21]1.C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)Cl>CN(C=O)C>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:30])=[CH:21]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1c[nH]c2ccccc12
Reaction time: 18 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (49.2 mg, 0.196 mmol), indole-3-carboxylic acid (37.9 mg, 0.235 mmol) and 1M DCC in CH2Cl2 solution (0.235 ml, 0.235 mmol) were mixed in DMF (2 ml) and the pH adjusted to 9.0 with triethylamino (32.7 μl, 0.235 mmol). The reaction was stirred 18 hrs. at 25° C., the DMF removed in vacuo, and the residue chromatographed on a Waters Semi-Prep C-18 30×0.9 cm column (gradient elution of 5 to 95% CH3CN in H2O) to give the title compound as a white solid from MeOH/ether: (m.p. 265°-268°).