Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.[C:25](Cl)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[F:24][C:22]1[CH:21]=[CH:20][C:16]2[CH2:17][CH2:18][CH2:19][C:12]3[S:11][C:10]([NH:9][CH:6]4[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25](=[O:27])[CH3:26])[CH2:4][CH2:5]4)=[N:14][C:13]=3[C:15]=2[CH:23]=1
Reactant: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.5 %

Procedure:
To a stirred, septum capped solution of trans-N2-[4-(aminomethyl)cyclohexyl]-9-fluoro-5,6-dihydro-4H-benzo-[6,7]cyclohepta-[d][1,3]thiazol-2-amine (0.165 g, 0.394 mmol) in 3.0 ml anhydrous pyridine was added 0.034 ml (0.038 g, 0.48 mmol) acetyl chloride dropwise. Stirring at room temperature was continued for 90 minutes and the solution was then poured into 50 ml water and extracted with EtOAc (2×50 ml). The combined extracts were evaporated to yield 0.126 g of the crude product as a viscous golden oil. The oil was chromatographed on preparative TLC eluting with EtOAc to yield 28% (0.042 g) of the desired product as a white solid: 1H-NMR (CDCl3) δ 1.13 (4H, m), 1.43 (1H, m), 1.80 (2H, m), 1.98 (3H, s), 2.05 (2H, m), 2.21 (2H, m), 2.80 (4H, m), 3.10 (2H, t, J=6.5 Hz), 3.24 (1H, m), 5.00 (1H, d, J=7.8 Hz), 5.75 (1H, m), 6.81 (1H, dt, J=2.8, 8.2 Hz), 7.04 (1H, m), 7.69 (1H, dd, J=2.7, 10.8 Hz); m.p. 88-91° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C@H:4]([CH3:18])[NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1.[Li+].[OH-]>O1CCOCC1.O>[N+:14]([C:10]1[CH:9]=[C:8]([CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:19])=[O:2])[CH3:18])=[O:17])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: COC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Reaction time: 4 h

Procedure:
The title compound was prepared by dissolving 9.27 g (0.0348 mols) of the N-(3-nitrophenylacetyl)-L-alanine methyl ester in 60 mL of dioxane and 15 mL of H2O and adding LiOH (3.06 g, 0.0731 mol) that has been dissolved in 15 mL of H2O. After stirring for 4 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4×100 ml), the combined organics were dried over Na2SO4 and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/isooctane giving 7.5 g (85%). C11H12N2O5 requires C, 52.38 H, 4.80 N, 11.11. Anal found C, 52.54 H, 4.85 N, 11.08.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])[O:29][C:30](Cl)(Cl)Cl)Cl.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[O:29][CH2:30][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[Cl:36]
Reactant: OCc1ccccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4Cl)c(Cl)c3)c2cc1OC
Yield: 106.1 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-chlorophenyl)methanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 93%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.[C:19]1(S)[CH:24]=[CH:23]C=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][C:18]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Sc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(Sc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, thiophenol and DBU in DME. ES-MS m/e (%): 295 (M+H+, 100).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:16][CH:15]([CH2:17]I)[O:14][C:13]2=[O:19])[CH:9]=[CH:8][C:7]=1[N:20]1[CH2:28][CH:27]2[CH:22]([O:23][CH2:24][CH2:25][N:26]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]1>CN(C)C=O>[N:1]([CH2:17][CH:15]1[O:14][C:13](=[O:19])[N:12]([C:10]2[CH:9]=[CH:8][C:7]([N:20]3[CH2:28][CH:27]4[CH:22]([O:23][CH2:24][CH2:25][N:26]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:21]3)=[C:6]([F:5])[CH:11]=2)[CH2:16]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCOC2CN(c3ccc(N4CC(CI)OC4=O)cc3F)CC21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC2CN(c3ccc(N4CC(CN=[N+]=[N-])OC4=O)cc3F)CC21
Temperature: 60 °C
Reaction time: 3 h
Yield: 124.3 %

Procedure:
Sodium azide (1.21 g) was added to the compound tertbutyl 6-{2-fluoro-4-[5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (2 g) obtained from example 02 above in dimethyl formamide (30 mL) and the reaction mixture was stirred at 60° C. for 3 hrs. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (2.1 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.[ClH:16].CO>C(Cl)Cl.CO>[ClH:16].[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NCCc1cccc(O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-methoxyphenyl)ethylamine (10.0 g, 66.2 mmol) in dry CH2Cl2 (100 mL) at −78° C. was added a 1M solution of BBr3 in CH2Cl2 (200 mL, 3 eq.) and the solution was allowed to slowly warm to RT. After stirring for 3 h at RT the resulting precipitate was filtered off, washed with CH2Cl2 (200 mL) and dried. The off-white solid was dissolved in cold H2O (50 mL) and the insoluble material was filtered off. The acidic filtrate (pH 1.2) was made basic (pH 13.0) with 10 N NaOH and the resulting yellow solution was extracted with ether (100 mL) and the organic layer was discarded. The aqueous layer was re-acidified with conc. HCl to pH 1.5 and then made alkaline (pH 9–10) with conc. NH4OH. The aqueous layer was then extracted with n-butanol (2×150 mL), dried (K2CO3) and concentrated to dryness to afford a viscous oil. The oily residue was then dissolved in MeOH (10 mL) and a solution of saturated HCl/MeOH was added. The solution was concentrated to small volume and ether was added to give a precipitate. The ether was decanted off to afford the desired compound as an off white solid (6.5 g, 57%). 1H NMR (D2O) 2.79 (t, 2H, J=7.2 Hz), 3.08 (t, 2H, J=7.2 Hz), 6.60–6.78 (m, 3H), 7.11 (t, 1H, J=7.7 Hz).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:33](OC)=[O:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.O1CCCC1.CO.[BH4-].[Li+]>O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][CH2:33][OH:34])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CCO)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]acetate (400 mg), tetrahydrofuran (10 mL) and methanol (2 mL) was added lithium borohydride (85 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give the title compound as a crude product from a fraction eluted with hexane-ethyl acetate-methanol (1:4:0-0:95:5, volume ratio), the crude product was subjected to preparative HPLC to give the title compound (150 mg, yield 39%) as a pale-yellow amorphous solid. MS: 481 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH2:19][N:18]([CH:23]2[CH2:25][CH2:24]2)[CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH:23]1([N:18]2[CH2:17][C:16]([CH3:26])([CH3:27])[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:10][CH:9]=4)[CH:14]=3)[CH2:19]2)[CH2:24][CH2:25]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CN(C2CC2)Cc2ccc(C#Cc3ccc(CC(=O)O)cc3)cc21

Procedure:
Following general procedure J and using [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6ylethynyl)-phenyl]-acetic acid methyl ester (Compound 23, 0.01 g, 0.027 mmol), methanol (1 mL), tetrahydrofuran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate (0.042 g, 1 mmol) the title compound was obtained as a pale yellow solid foam (0.0065 g, 68%).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:14][CH3:15])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]([CH3:35])[CH2:31][C:32]([OH:34])=O)[CH:26]=[CH:27][C:28]=1[Cl:29].C(N(CC)CC)C>ClCCl>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]([CH3:15])[C:32](=[O:34])[CH2:31][N:30]([C:25]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=2)[CH3:35])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
[1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (50 mg, 0.18 mmol) was added to a solution of N-(3,4-dichlorophenyl)-N-methylglycine (49 mg, 0.21 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexaflurophosphate (BOP) (118 mg, 0.27 mmol) and triethylamine (TEA) (54 mg, 0.54 mmol) in dichloromethane (DCM) (2.0 mL), The reaction mixture was stirred at room temperature for 3 h and was then concentrated in vacuo. To the residue was added 4 mL of saturated solution of Na2CO3 and then extracted by ethyl acetate (2×3 mL). The combined organic layers were concentrated in vacuo to give a brown solid, which was purified by using a Gilson preparative HPLC system (Phenomenex 75×30 mm column, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to yield the title compound (52 mg, 58%). MS (ES) m/e 496 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[N:13][C:14]([C@@H:24]([NH2:26])[CH3:25])=[C:15]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=3)[CH:16]=2)[CH:11]=[CH:10]1.[Cl:27][C:28]1[C:33]([C:34]#[N:35])=[C:32](Cl)[N:31]=[C:30]([S:37][CH3:38])[N:29]=1.CCN(CC)CC>C1COCC1>[Cl:27][C:28]1[C:33]([C:34]#[N:35])=[C:32]([NH:26][C@H:24]([C:14]2[N:13]=[C:12]3[CH:11]=[CH:10][N:9]([CH3:8])[C:17]3=[CH:16][C:15]=2[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=2)[CH3:25])[N:31]=[C:30]([S:37][CH3:38])[N:29]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine 2,2,2-trifluoroacetate (1562 mg, 4.23 mmol) in THF (27.5 mL) along with 4,6-dichloro-2-(methylthio)pyrimidine-5-carbonitrile (931 mg, 4.23 mmol) and Et3N (1297 μL, 9.31 mmol) were added to a pear-shaped flask. The resulting mixture was stirred at room temperature for 2 hours and then concentrated to give the title compound, which was used in next step without further purification. ESI-MS m/z [M+H]+ calc'd for C20H19ClN8S, 439.11. found 439.4.
Reaction SMILES: [O:1]=[C:2]([NH:32][C:33]1[CH2:34][O:35][C:36](=[O:38])[CH:37]=1)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[CH:17][CH:16]=2)[CH:6]=1)=[O:4]>CN(C=O)C.[Pd].O.C(O)C>[O:1]=[C:2]([NH:32][C:33]1[CH2:34][O:35][C:36](=[O:38])[CH:37]=1)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][CH:20]=2)[CH:6]=1)=[O:4]
Reactant: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(CC(=O)OCc4ccccc4)cc3)c3ccccc23)CO1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(Cn2cc(C(=O)C(=O)NC3=CC(=O)OC3)c3ccccc32)cc1
Yield: 64.8 %

Procedure:
A solution of benzyl {4-[(3-{oxo[(5-oxo-2,5-dihydro-3-furanyl)amino]acetyl}-1H-indol-1-yl)methyl]phenyl}acetate (300 mg) in DMF (10 ml) is hydrogenated at room temperature and pressure in the presence of 10% palladium on charcoal (60 mg of a 50% wt/wt suspension in water). After 3 h30′ the catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue obtained is suspended in absolute ethanol and recovered by filtration, to give {4-[(3-{oxo[(5-oxo-2,5-dihydro-3-furanyl)amino]acetyl}-1H-indol-1-yl)methyl]phenyl}acetic acid (160 mg).
Reaction SMILES: [C:1]([N:5]([C:13]1[N:23]=[CH:22][C:21]2[C:20]3[S:24][C:25]([C:27](=[O:36])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])=[CH:26][C:19]=3[CH2:18][CH2:17][O:16][C:15]=2[CH:14]=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:37]I.[H-].[Na+]>>[C:1]([N:5]([C:13]1[N:23]=[CH:22][C:21]2[C:20]3[S:24][C:25]([C:27](=[O:36])[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])[CH3:37])=[CH:26][C:19]=3[CH2:18][CH2:17][O:16][C:15]=2[CH:14]=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(c1cc2c(cn1)-c1sc(C(=O)Nc3ccccc3Cl)cc1CCO2)C(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN(C(=O)c1cc2c(s1)-c1cnc(N(C(=O)OC(C)(C)C)C(C)(C)C)cc1OCC2)c1ccccc1Cl
Yield: 78 %

Procedure:
Following Scheme 4, tert-butyl tert-butyl(2-(2-chlorophenylcarbamoyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl)carbamate, methyl iodide and sodium hydride were reacted to give tert-butyl tert-butyl(2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-8-yl)carbamate (78%). MS: (ESI+) 542.3
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[NH:20][C:12]3=[N:13][CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=[C:11]3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[H][H]>[Pd].CO>[NH2:17][C:15]1[CH:16]=[C:11]2[CH:10]=[C:9]([C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])[NH:20][C:12]2=[N:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(c1cc2cc([N+](=O)[O-])cnc2[nH]1)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2[nH]c(C(=O)N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
An autoclave is charged with 313 mg (1.13 mmol) of the morpholino(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanone formed during the preceding stage, 100 mL of methanol and 31 mg of palladium on charcoal at 10%. The autoclave is placed under 20 bar of hydrogen and the solution is stirred at room temperature for 18 hours, The solution is then filtered on Celite, the Celite is rinsed with 50 mL of methanol and the filtrate is evaporated under reduced pressure. 280 mg of a white solid is recovered, and is used in the next stage without further purification (quantitative raw yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[CH:5][C:6]=1[C:7](=[O:23])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:3]1[C:4]([CH3:24])=[CH:5][C:6]([C:7](=[O:23])[C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[C:2]1[CH3:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)[nH]1
Product: Cc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)n1Cc1ccccc1

Procedure:
Likewise, using 2,5-dimethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole as compound "E" in this general reaction with benzyl chloride as "R-X" yields N-benzyl-2,5-dimethyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (a compound according to Formula X wherein: m is 0; n is 1; R is benzyl; Y is H; and X and Z are each methyl).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:25][CH2:24][CH2:23][O:22]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO.O1CCCC1>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:25][CH2:24][CH2:23][O:22]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(OCC3CCCO3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(OCC3CCCO3)cc12
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89.9 %

Procedure:
Cyclohexyl[3-methyl-5-(tetrahydrofuran-2-ylmethoxy)-1-benzofuran-2-yl]methanone (260 mg) synthesized above was dissolved in methanol (0.5 mL)-tetrahydrofuran (2.5 mL), and sodium tetrahydroborate (90%) (64 mg) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (235 mg, 90%) as a colorless oil.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])=[CH:21][CH:22]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.0 g. of adamantane carboxylic acid chloride 1.6 g. (10 mmoles) of p-trifluoromethylaniline and 5.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from a mixture of methylene chloride-hexane to obtain the product of this Example, m.p. 189°-193° C.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]3[C:14](=[O:17])[O:15][CH2:16][C:12]=3[CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH:30]([CH3:33])[CH:31]=O)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH:30]([CH3:33])[CH2:31][N:5]2[CH2:6][CH2:7][N:2]([CH2:8][CH2:9][C:10]3[CH:11]=[C:12]4[C:13](=[CH:18][CH:19]=3)[C:14](=[O:17])[O:15][CH2:16]4)[CH2:3][CH2:4]2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: COc1cc(C(C)C=O)ccc1C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: Cl
Product: COc1cc(C(C)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc1C#N

Procedure:
2-Methoxy-4-[1-methyl-2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile. LC-MS (IE, m/z): 420.5 [M+1]+. (0.28 μM)
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]2[CH2:10][CH2:11][CH2:12][C:2]1=2.C1COCC1.CCO.O.[Li+].[OH-].Cl>O>[S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]2[CH2:10][CH2:11][CH2:12][C:2]1=2
Reactant: COC(=O)c1cc2c(s1)CCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(s1)CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of methyl 4H,5H,6H-cyclopenta[b]thiophene-2-carboxylate (1 g, 5.49 mmol, 1.00 equiv) in a THF/EtOH/water (10/10/10 mL) mixture was added LiOH (660 mg) at room temperature. The resulting solution was stirred for 3 h at 50° C. in an oil bath and then diluted with 20 mL of water. The pH value of the solution was adjusted to 5 with 2 M aqueous hydrochloric acid. The precipitate was collected by filtration and dried in an oven under reduced pressure to give the desired 4H,5H,6H-cyclopenta[b]thiophene-2-carboxylic acid (0.84 g, 91%) as an off-white solid.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([F:14])=[CH:9][N:8]=1.[OH-].[Na+].[CH3:17][O:18][CH2:19]Cl>O.C(OCC)C>[Cl:6][C:7]1[C:12]([O:13][CH2:17][O:18][CH3:19])=[CH:11][C:10]([F:14])=[CH:9][N:8]=1
Reactant: COCCl
Reactant: Oc1cc(F)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(F)cnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A DMF (10 ml) solution of 2-chloro-5-fluoro-3-hydroxypyridine (500 mg) was cooled to 0° C. Sodium hydroxide (60% oil dispersion: 149 mg) was added to the reaction solution, and the obtained mixture was stirred at 0° C. for 15 minutes. Chloromethyl methyl ether (293 ul) was added to the reaction solution at the same temperature as described above, and the obtained mixture was heated to room temperature and stirred for 1 hour. Diethyl ether and water were added to the reaction solution, and the organic layer was successively washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1 to 7:3), so as to obtain the title compound (598 mg).