Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]2[C:19](=[O:50])[CH:20]([CH:23]([OH:49])[C:24]3[N:25]=[CH:26][N:27]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:28]=3[CH3:29])[CH2:21][CH2:22][C:11]=12)[CH3:9]>N1C=CC=CC=1>[C:1]([O:49][CH:23]([C:24]1[N:25]=[CH:26][N:27]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:28]=1[CH3:29])[CH:20]1[C:19](=[O:50])[N:12]2[C:13]3[C:18]([C:10]([CH2:8][CH3:9])=[C:11]2[CH2:22][CH2:21]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: c1ccncc1
Product: CCc1c2n(c3ccccc13)C(=O)C(C(OC(C)=O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Acetic anhydride (2.0 ml) was added to a solution of 10-ethyl-8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (2.15 g) in pyridine (10 ml). After being stirred at room temperature for 20 hours, the solution was evaporated in vacuo. The residue was dissolved in toluene (30 ml) and the solution was evaporated in vacuo to remove pyridine and acetic anhydride. This operation was repeated further three times to give 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-ethyl-8,9-dihydropyrido-[1,2-a]indol-6(7H)-one as an amorphous powder. This crude product was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C@:12]([C:21]3[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=3)([NH2:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:3][CH2:2]1.[CH3:35][C:36]1[O:37][C:38]([C:44]([F:47])([F:46])[F:45])=[C:39]([C:41](O)=[O:42])[N:40]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C@@:12]([NH:20][C:41]([C:39]3[N:40]=[C:36]([CH3:35])[O:37][C:38]=3[C:44]([F:47])([F:45])[F:46])=[O:42])([C:21]3[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=3)[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:2][CH2:3]1
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC2CC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)N[C@@](Cc2ccccc2)(c2cc(F)cc(OC(F)(F)C(F)F)c2)c2ccc(F)c(OC3CC3)c2)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
To a solution of (R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine, prepared as described in Procedure 109, 110, 111, 112, 113, 114, 161, (24 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was added 2-methyl-5-(trifluoromethyl)-oxazole-4-carboxylic acid (12 mg, 0.06 mmol), followed by PyBrOP (28 mg, 0.06 mmol) and iPr2NEt (9 mg, 0.065 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (Phenomenex Luna 5μ, 30×100 mm, eluting with 10%-90% MeOH/H2O containing 0.1% TFA, gradient time 10 min, flow rate 40 mL/min) to yield (R)—N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methyl-5-(trifluoromethyl)oxazole-4-carboxamide (Example 347) as a white solid (23 mg, 70% yield). HPLC: RT=2.18 min [M+H] 659.5 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.79, s, 1H, 7.10-7.20, m, 3H, 6.90-7.03, m, 5H, 6.70, s, 1H, 6.68, s, 1H, 6.55-6.58, m, 1H, 5.74-6.00, t, J=52; 4.15, 4.19, d, J=16, 1H, 3.66-3.69, d, J=12, 1H, 3.51-3.54, m, 1H, 0.73-0.80, m, 1H, 0.61-0.69, m, 2H, 0.55-0.60, m, 1H.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][CH2:4][C@@H:5]1[CH2:8][CH2:7][C@H:6]1[C:9]([O:11]C)=[O:10].CO.[OH-].[Na+]>O>[F:1][CH:2]([F:13])[O:3][CH2:4][C@@H:5]1[CH2:8][CH2:7][C@H:6]1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)[C@@H]1CC[C@H]1COC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CC[C@H]1COC(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
To a solution of Intermediate 241A (100 mg, 0.515 mmol) in a 1:0.3:1THF:MeOH:water was added NaOH (41.2 mg, 1.030 mmol) and the resulting solution was stirred at RT for 12 h. The volatiles were removed under reduced pressure and the aqueous layer was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 4 by adding an aqueous solution of 1.5 N HCl and extracted with ethyl acetate (3×10 mL) The combined organic layer was dried over Na2SO4 and evaporated under vacuum to afford Intermediate 241B as yellow sticky liquid (80 mg, 86%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 6.35-6.95 (m, 1H), 3.74-3.89 (m, 2H), 2.85 (q, J=8.70 Hz, 1H) 2.63-2.77 (m, 1H) 1.95-2.10 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)ccn1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)ccn1

Procedure:
The title compound, MS: m/e=281.0 (Me) was obtained as a light yellow solid (10% yield) by the reaction of 4-bromo-pyridine-2-carboxylic acid methyl ester with 3,4-dichlorophenyl boronic acid.
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:12]([O:14][CH3:15])=[O:13]>O1CCOCC1>[CH3:15][O:14][C:12]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:13]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To (S)-2-amino-3-methylbutanoic acid (57 g, 487 mmol) dissolved in dioxane (277 mL) was added a 2N aqueous sodium hydroxide solution (803 mL, 1606 mmol) followed by the dropwise addition of methyl chloroformate (75 mL, 973 mmol) over 1 hr which caused warming of the solution to occur. After the addition, the mixture was heated at 60° C. for 22 hrs, then cooled and extracted with dichloromethane (400 mL). The resultant aqueous layer was cooled in an ice bath then 12N hydrochloric acid was added dropwise until the pH was 2. The resultant mixture was stirred at 0° C. for 2 hrs then the resultant solid was vacuum filtered and dried in a vacuum oven to provide 80 g (94%) of the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 12.50 (bs, 1H), 7.34 (d, J=8.6 Hz, 1H), 3.84 (dd, J=8.6, 6.0 Hz, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.86 (t, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[C:1]([O:7][CH2:8][N:9]1[CH:13]=[C:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:20][CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[O:19])[N:11]=[N:10]1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)C(=O)OCn1cc(CCCC(=O)O)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)CCCc2cn(COC(=O)C(C)(C)C)nn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-(1-((pivaloyloxy)methyl)-1H-1,2,3-triazol-4-yl)butanoic acid (1.63 g, 6.05 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.212 g, 6.05 mmol) in DMF (10 mL) was added Huenig's Base (3.17 mL, 18.16 mmol) followed by T3P® 50% in DMF (7.07 mL, 12.11 mmol) at RT. The reaction mixture was allowed to stir at RT for 20 hours. The DMF was removed under reduced pressure and the residue dissolved in EtOAc and washed with a saturated solution of sodium bicarbonate, a saturated solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product;
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])[CH2:8][CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:7]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1cccc(N)c1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Product: CCCCc1cccc(NC(=O)CC(C)=O)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
3.9 g of diketene were added to a mixture of 6.9 g of m-(n-butyl)-aniline and 70 ml of benzene and the mixture was stirred for 2 hours at 30° C. The benzene was evaporated under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 mixture of methylene chloride and ethyl acetate yielded 8.5 g of m-(n-butyl)-acetylacetanilide in the form of an oil with a refractive index of nD 20 = 1.5355.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][CH2:5][CH:4]([S:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:3]1.N>[Ni].C(O)C>[CH3:1][C:2]1([CH3:18])[CH2:7][CH2:6][CH2:5][CH:4]([S:8][CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=2)[CH2:3]1
Reactant: CC1(C)CCCC(SCc2ccc(C#N)cc2)C1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC1(C)CCCC(SCc2ccc(CN)cc2)C1
Yield: 98.6 %

Procedure:
To a slurry of Raney Nickel (0.25 g, 50% in water) in ethanol (40 mL) add a solution of 4-[(3,3-dimethylcyclohexyl)thiomethyl]-benzonitrile (0.4 g, 1.54 mmol) in ethanol (5 mL) followed by aqueous ammonia (0.88 M, 2.5 mL) and hydrogenate the mixture in a Parr shaker at 60 psi for 3 h. Filter the mixture through Celite® washing the filter cake with ethanol. Remove the solvent in vacuo to obtain the title compound as an oil (0.4 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][NH:17][C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.[H-].[Na+].[CH3:26]I.Cl>O1CCCC1.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[CH2:18][N:17]([CH3:26])[C:16]4=[O:22])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1
Reactant: CC1(C)CNC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CC(C)(C)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C1=O
Reaction time: 0.5 h

Procedure:
A mixture of 0.254 g (0.65 mmol) of 1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one from Example 429, and 50.0 mg (1.25 mmol) of 60% sodium hydride dispersion in mineral oil in 2 ml of tetrahydrofuran and 2 ml of dimethylformamide was stirred for 20 min. 0.062 ml (1.00 mmol) of methyl iodide was added in one portion to the above mixture. The mixture was stirred for 30 min and poured into 10 ml of 1 N aq hydrochloric acid. The mixture was extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuum. The residue was triturated with hexane and the resulting precipitate was filtered and washed with hexane. Yield 260 mg (98%). MS(ESI+): 408.1
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]([CH:20]([OH:28])[CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]([OH:13])[CH:20]([OH:28])[CH2:21][N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(C)C[C@H]1C(C(O)CN2CCOCC2)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@H](N)C(O)C(O)CN1CCOCC1
Yield: 73.1 %

Procedure:
53.7 mg of (4S,5RS)-3-benzyloxycarbonyl-2,2-dimethyl-5-[(1RS)-1-hydroxy-2-morpholinoethyl]-4-isobutyloxazolidine was dissolved in 0.8 ml of ethanol, and palladium black was added thereto. Then, hydrogenation was conducted at room temperature at atmospheric pressure. The catalyst was removed by filtration, and the solvent was distilled off to obtain 23 mg of (2RS,3RS,4S)-4-amino-6-methyl-1-morpholino-2,3-heptanediol as colorless oily substance.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:14][S:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([O:8][CH2:7][C:6]([OH:25])=[O:5])=[CH:10][C:11]=3[S:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
3.89 g (9.3 mmol) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid tert-butyl ester in 35 ml CH2Cl2 were added 17 ml TFA at 0° C. The solution was stirred at RT for 2 h, concentrated and triturated with ether to yield 3 g (89%) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid as white solid, MS: 362 (M−H,1Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:41][C:42]([CH2:46][CH2:47][OH:48])=[C:43]([CH3:45])[N:44]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[C:55]([CH3:56])=[CH:54][C:53](O)=[CH:52][C:51]=1[CH3:58]>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:41][C:42]([CH2:46][CH2:47][O:48][C:53]4[CH:54]=[C:55]([CH3:56])[C:50]([Cl:49])=[C:51]([CH3:58])[CH:52]=4)=[C:43]([CH3:45])[N:44]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(O)cc(C)c1Cl
Reactant: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Product: COc1cccc(CN(C(=O)C2=C(c3nc(C)c(CCOc4cc(C)c(Cl)c(C)c4)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C

Procedure:
This compound is prepared from compound E2 and 4-chloro-3,5-dimethylphenol, according to the above-described procedure A. LC-MS: tR=1.27 min, ES+: 821.24.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6]>CCO.[Pd]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([OH:2])[C:4]=1[C:5]#[N:6]
Reactant: COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Product: N#Cc1c(N)cccc1O
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 2-methoxy-6-nitrobenzonitrile (Example 1290 (1.11 g, 6.76 mmol) in EtOH (120 mL) was hydrogenated over a catalytic amount of 10% Pd/C (0.15 g) at room temperature under hydrogen (1 atm). After 2 h, the mixture was filtered and the catalyst was washed with EtOAc (150 mL). The combined extract was evaporated, to give 1.11 g (100%) of the title compound as a brown solid. The crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (broad s, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.12-6.17 (m, 1H), 6.01-6.05 (m, 1H), 5.77 (broad s, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:17]4[C:23]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=6)=[C:27]([Cl:40])[CH:26]=5)=[N:22][CH:21]=[N:20][C:18]=4[S:19][C:12]=3[C:11]=2[CH:10]=[N:9]1)(=O)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:23]2[N:22]=[CH:21][N:20]=[C:18]3[S:19][C:12]4[C:11]5[CH:10]=[N:9][N:8]([CH2:7][CH2:6][N:41]6[CH2:46][CH2:45][O:44][CH2:43][CH2:42]6)[C:16]=5[CH2:15][CH2:14][C:13]=4[C:17]=23)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3c-5cnn3CCN3CCOCC3)cc2Cl)c1
Temperature: 70 °C
Yield: 58.6 %

Procedure:
To 2 mL CH3CN were sequentially added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethyl methanesulfonate (80 mg, 0.13 mmol), morpholine (18 mg, 0.20 mmol), and diisopropylethylamine (35 mg, 0.27 mmol). The reaction mixture was then heated up to 70° C. for 14 h. Upon cooling down, the crude was purified by HPLC to afford the desired product as an off-white solid (45 mg, 54%). 1H-NMR (DMSO-d6) δ 8.38 (s, 1H), 7.80 (d, 1H), 7.53 (s, 1H), 7.44 (dd, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.04 (td, 1H), 6.98 (d, 1H), 6.95 (s, 1H), 5.13 (s, 2H), 4.18 (t, 2H), 3.63 (t, 4H), 3.35 (t, 2H), 3.14 (t, 2H), 2.78 (t, 2H), 2.45 (t, 4H); LCMS RT=2.72 min; [M+H]+=591.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:21]1(C)C=CC(S(O)(=O)=O)=C[CH:22]=1>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc2oc(-c3ccc(Cl)cc3)nc2c1

Procedure:
A suspension of 2-(p-chlorophenyl)-5-benzoxazolylacetic acid (26 g.) and p-toluene sulphonic acid (4.6 g.) in dry benzene (156 ml.) and dry absolute ethanol (78 ml.) was refluxed for 38 hours. Evaporation gave a solid which was dissolved in ethyl acetate (2 l) and washed with an aqueous saturated sodium bicarbonate solution (6 × 50 ml.). Evaporation of the organic phase gave ethyl 2-(2-p-chlorophenyl-5-benzoxazolyl)acetate as a solid (24.1 g.); m.pt. 133° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[F:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[F:33]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N45-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 96.4%, 424.0482 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([N:6]([CH3:18])[CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:5].[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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.COCCOC.O>[CH3:18][N:6]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:5])[C:3]1[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=1[C:26]1[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1ccncc1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1Br
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: O
Solvent: COCCOC
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1-c1ccncc1
Yield: 32.8 %

Procedure:
A solution of 2-bromo-N-methyl-N-[(1-methyl-1H-indol-2-yl)methyl]benzamide (0.30 g, 0.84 mmole), pyridine-4-boronic acid (0.20 g, 1.63 mmole), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmole), and Cs2CO3 (1.10 g, 3.38 mmole) in 10:1 DME/H2O (25 mL) was degassed, then was heated under N2 overnight. The resulting mixture was concentrated in vacuo, and the residue was taken up in 10% NaOH solution. The mixture was extracted with CH2Cl2, and the combined organic extracts were washed with brine and dried (MgSO4). Flash chromatography on silica gel (3% MeOH/CH2Cl2) followed by preparative TLC (3% MeOH/CH2Cl2) gave the title compound (98 mg, 33%) as a white solid: 1H NMR (300 MHz, CDCl3) indicated an approximately 5:1 mixture of amide rotamers; for the major rotamer: 6 8.50-8.65 (m, 2H), 7.00-7.60 (m, 10H), 6.27 (s, 1H), 4.50-5.00 (m, 2H), 3.62 (s, 3H), 2.49 (s, 3H); for the minor rotamer: δ 8.65-8.75 (m, 2H), 7.00-7.60 (m, 10H), 6.12 (s, 1H), 4.50-5.00 (m, 2H), 3.41 (s, 3H), 2.86 (s, 3H); MS (ES) m/e 356 (M+H)+. Anal. Calcd for C23H21N3O.0.10H2O: C, 77.33; H, 5.98; N, 11.76. Found: C, 77.07; H, 5.98; N, 11.56.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:11][O:10][C:9](=[O:12])[N:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)=O.CS(OCC1COC(=O)N1[C:31]1[CH:36]=[CH:35][C:34](Cl)=[CH:33][CH:32]=1)(=O)=O>>[C:13]1([N:8]2[CH:7]([CH2:6][O:5][C:31]3[CH:32]=[CH:33][C:34]([C:9]([O:10][CH3:11])=[O:12])=[CH:35][CH:36]=3)[CH2:11][O:10][C:9]2=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)OCC1COC(=O)N1c1ccccc1
Reactant: CS(=O)(=O)OCC1COC(=O)N1c1ccc(Cl)cc1
Product: COC(=O)c1ccc(OCC2COC(=O)N2c2ccccc2)cc1
Yield: 60 %

Procedure:
The same procedure of Example 22 was repeated except that 3-phenyl-2-oxooxazolidin-4-ylmethyl methanesulfonate obtained in Reference Example 20 was used in lieu of 3-(4-chlorophenyl)-2-oxooxazolidin-4-ylmethyl methanesulfonate to give the title compound (compound 177) in a yield of 60%.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32]I)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32][S:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCCC(CI)C1
Reactant: Sc1nc(-c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CSc2nc(-c3ccccc3)cs2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
2-Mercapto-4-phenylthiazole (304 mg, 1.54 mmol) and potassium carbonate (261 mg, 1.85 mmol) were added to 1-(tert-butoxycarbonyl)-3-iodomethylpiperidine (500 mg, 1.54 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 30 min. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was then washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=40:1->10:1) gave 598 mg (99%) of the desired compound as a colorless oil.