Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@:5]([CH3:9])([CH:7]=O)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH3:1][C:2]1([CH3:10])[O:6][C@@:5]([CH3:9])([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: NO
Reactant: CC1(C)OC[C@](C)(C=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@](C)(C=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(R)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde (6.9 g, 48 mmol) was dissolved in 1:1 methanol water (100 mL), and hydroxylamine hydrochloride (3.3 g, 48 mmol) and Na2CO3 (2.5 g, 24 mmol) were added. The reaction was stirred at ambient temperature overnight. The methanol was removed in vacuo and the remaining material was extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford (S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (5.7 g, 36 mmol, 75% yield).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[N:19]=[C:18](Cl)[S:17][N:16]=2)[O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:21][C:22]1[CH:40]=[CH:39][C:25]([CH:26]([N:33]2[CH2:34][CH2:35][N:36]([C:18]3[S:17][N:16]=[C:15]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:8][CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][O:10]4)[N:19]=3)[CH2:37][CH2:38]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: Clc1nc(C(OC2CCCCO2)c2ccccc2)ns1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(C(c2ccccc2)N2CCN(c3nc(C(OC4CCCCO4)c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-[1-phenyl-1-(tetrahydropyran-2-yloxy)methyl]-5-chloro-[1,2,4] thiadiazole (1.56 g, 5.02 mmol) in DMF (25 mL) was added 1-(4-chlorobenzhydryl) piperazine (2.88 g, 10.04 mmol) followed by triethylamine (2.03 g, 20.08 mmol). The resulting mixture was stirred at room temperature for 2 days. Volatile materials were removed in vacuo and the residue was partitionned between dichloromethane and water. The organic layer was collected, dried (sodium sulfate), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (8/2) thereby affording 1 -[(4-chlorophenyl)phenylmethyl]-4-{3-[phenyl-(tetrahydropyran-2-yloxy)methyl]-[1,2,4]thiadiazol-5-yl}-piperazine (1.90 g, 67%) as a white solid and as a mixture of diastereoisomers. 1H-NMR (CDCl3) δ7.55 (d, J=7.8 Hz, 1H), 7.22-7.39 (m, 13H, Ar--H), 5.89 and 5.85 (s, 0.4H and 0.6H each, αH), 4.90 and 4.64 (t, J=3.2 Hz, 0.4H and 0.6H each, OCHO), 4.29 (m, 1H, CH-Ar), 3.60-4.05 (m, 1H, OCH2), 3.50 (m, 5H, 2CH2 +1H, OCH2), 2.49 (m, 4H, 2CH2), 1.50-1.94 (m, 6H, 3CH2).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].Br.Br.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: N#CCCCCl
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 80 %

Procedure:
A mixture of 11 parts of 4-chlorobutanenitrile, 48.5 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 30 parts of sodium carbonate and 270 parts of DMF was stirred and heated overnight at 70° C. The reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized twice from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 2.2 parts (80%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinebutanenitrile; mp. 130.5° C. (90).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.7 %

Procedure:
Ethyl 3-(4-nitrophenyl)acrylate (3 g, 13.56 mmol) was dissolved in methanol/tetrahydrofuran (20 ml), added with 10%-palladium (Pd) (300 mg). The resulting mixture was stirred for one day under hydrogen gas at room temperature and filtered using celite to remove 10%-palladium (Pd). The filtrate was then concentrated under reduced pressure. The residue was then purified by flash column chromatography (hexane:ethylacetate=3:1) to obtain the title compound (2.14 g, yield: 82%, colorless liquid).
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[ClH:1].[NH:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][N:12]1[CH:5]=[C:4]([CH2:3][CH2:2][C:6]2[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=2)[N:14]=[N:13]1
Reactant: [N-]=[N+]=NCc1nc2ccccc2[nH]1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3nc4ccccc4[nH]3)nn2)c[nH]1
Yield: 95.9 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.061 g, 0.361 mmol) was reacted with 2-azidomethyl-1-H-benzimidazole (0.075 g, 0.433 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(1H-Benzoimidazol-2-ylmethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine dihydrochloride (0.066 g, 48%) of a yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.05 (s, 1H), δ 7.68 (m. 2H), δ 7.48 (m, 2H), δ 6.38 (s, 1H), δ 6.15 (s, 2H′), δ 2.90 (t, 2H), δ 2.76 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 147.4, 146.9, 146.8, 131.3, 127.0, 126.4, 124.1, 114.1, 109.2, 44.7, 24.0, 23.9 ppm; HRMS (ESI) calcd for C15H17N8 (M+) 309.1570. found 309.1572.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CCOCC.C1(C)C=CC=CC=1>[C:15]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: O=C1CCCC1
Reactant: c1ccc2occc2c1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C1=C(c2cc3ccccc3o2)CCC1

Procedure:
Benzofuran was treated with butyllithium in ether followed by cyclopentanone. The resulting alcohol was dehydrated with toluenesulfonic acid in toluene to afford 2-cyclopenten-1-ylbenzofuran. Treatment with maleimide gave a cycloadduct which was aromatized by treatment with tetrachloroquinone. 1H NMR (DMSO-d6) δ 11.29 (s, 1H), 8.60 (d, 1H), 7.82 (d, 1H), 7.66 (t, 1H), 7.52 (t, 1H), 3.23 (m, 4H), 2.30 (quintet, 2H). MS m/e 276 (M−H)−.
Reaction SMILES: C(N(CC)[C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:28])[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH3:18])C.[OH-].[K+].C([OH:36])C.C(O)(=O)C>O>[OH:28][C@H:21]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][NH:19][C@H:17]([CH3:18])[CH2:16][C:12]1[C:11]2[C:15](=[C:7]([O:6][CH2:5][C:4]([OH:29])=[O:36])[CH:8]=[CH:9][CH:10]=2)[NH:14][CH:13]=1
Reactant: CCO
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1cccnc1

Procedure:
A solution of N,N-diethyl-2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetamide (30 mg, 0.071 mmol) and potassium hydroxide (120 mg, 2.1 mmol) in water (1 mL)/ethanol (1 mL) is stirred at 60° C. for 6 hours. After cooling, to the mixture is added acetic acid (0.112 mL), and the mixture is concentrated. The residue is purified by preparative reversed phase HPLC (octadecylsilyl, trade name: Combiprep, ODS-A (YMC), inner diameter: 50×20 mm, particle size: 5 μm, pore size: 120 angstrom (hereinafter, this column is used in preparative reversed phase HPLC column), 0.05% trifluoroacetic acid/water-0.035% trifluoroacetic acid/acetonitrile) to give the desired {3-[(2R)-2-((2R)-2-hydroxy 2-pyridin-3-yl-ethylamino)propyl]-1H-indol-7-yloxy}acetic acid.2 trifluoroacetate (24 mg, yield: 57%).
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3].Br[C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:17]2[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)S(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Yield: 29.5 %

Procedure:
6-{4-[(1-Methylethyl)sulfonyl]phenyl}-3-pyridinol (0.47 g, 29%) was prepared as a tan solid from {4-[(1-methylethyl)sulfonyl]phenyl}boronic acid (1.97 g, 8.62 mmol), 6-bromo-3-pyridinol (1 g, 5.75 mmol), Pd(PPh3)2Cl2 (200 mg, 0.28 mmol), 2M Na2CO3 (5 mL) and DME (5 mL) in a manner similar to Example 21, Step 3. The material was purified by chromatography on a silica gel column eluted with 0 to 5% MeOH/CH2Cl2. 1H NMR (400 MHz, CDCl3): δ 8.36 (d, 1H, J=2.9 Hz), 8.06 (d, 2H, J=8.6 Hz), 7.93 (d, 2H, J=8.6 Hz), 7.68 (d, 1H, J=8.8 Hz), 7.30 (dd, 1H, Ja=8.8 Hz, Jb=2.9 Hz), 3.32-3.16 (m, 1H), 1.30 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 276 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH3:24])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1cccc(C(C)=O)c1

Procedure:
A mixture of m-aminoacetophenone, diisopropylethylamine, methyl chloroformate and dichloromethane was reacted as described in Example 1, giving 33.4 g of (3-acetylphenyl)carbamic acid, methyl ester.
Reaction SMILES: Cl[C@:2]12[C@@H:28]([OH:29])[CH2:27][C@@:26]3([CH3:30])[C@@H:12]([CH2:13][C@@H:14]([CH3:31])[C@@H:15]3[C:16](=[O:25])[CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:33])[CH:4]=[CH:5][C:6](=[O:32])[CH:7]=1>C1(C)C=CC=CC=1>[CH3:31][C@@H:14]1[CH2:13][C@@H:12]2[C@:26]([CH3:30])([CH2:27][C:28](=[O:29])[C@H:2]3[C@H:11]2[CH2:10][CH2:9][C:8]2[C@:3]3([CH3:33])[CH:4]=[CH:5][C:6](=[O:32])[CH:7]=2)[C@H:15]1[C:16](=[O:25])[CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](O)C[C@]2(C)[C@H]1C(=O)COC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@H]1C(=O)COC(=O)C(C)(C)C
Yield: 70.4 %

Procedure:
One gram of 9α-chloro-11β-hydroxy-16α-methyl-21-trimethylacetoxy-1,4-pregnadiene-3,20-dione is stirred in 4 ml of "Marlotherm" S for 5 minutes at an oil bath temperature of 300° C. under argon. After cooling, the mixture is diluted with toluene and chromatographed on silica gel, thus obtaining 650 mg of 16α-methyl-21-trimethylacetoxy-1,4-pregnadiene-3,11,20-trione; mp 201°-202.5° C. (acetone-hexane).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1>C(O)(C)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:32][C@H:33]4[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1

Procedure:
1-Benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (50.0 g, 148 mmol) was suspended in isopropanol (400 mL) and DIPEA (35.0 mL, 207 mmol) was added, followed by trans-4-aminocyclohexanol (18.7 g, 163 mmol). The mixture was heated at reflux for 2 hours, then cooled and concentrated under vacuum. The residue was dissolved in dichloromethane and washed with water (added 1 N HCl to bring pH to 6-7). The organic layer was dried (Na2SO4) and concentrated under vacuum. The residual foam was taken up in ethanol and the resulting precipitate collected to give 65.0 g (quant) of crude trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 9.03 (d, 1H), 8.19 (dd, 2H), 7.62 (m, 2H), 7.52 (m, 2H), 6.71 (d, 1H), 3.95 (m, 1H), 3.79 (m, 1H), 3.78-3.67 (m, 2H), 2.22 (m, 2H), 2.08 (m, 2H), 1.59 (m, 1H), 1.54 (m, 4H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[C:12](=[CH:23][NH:24][C:25]=3[CH3:26])[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1.[C:29](=O)([O-])[O-:30].[Na+].[Na+]>CN(C)C=O>[Cl:6][C:7]1[CH:28]=[CH:27][C:10]2[C:11]3[C:12](=[C:23]([CH:29]=[O:30])[NH:24][C:25]=3[CH3:26])[CH2:13][N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:9]=2[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=O)c2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 1 h

Procedure:
By means of a syringe 0.6 ml (6.5 mmol) of phosphorous oxychloride was added to a solution of 0.7 g (2.0 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine in 8 ml of dimethylformamide which was cooled to 0°. The mixture was stirred at 0° for 1 hr, poured into 50 ml of saturated aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a red amorphous solid. Purification by column chromatography (silica gel, 20 g; 4% ether in methylene chloride, eluent) gave an off-white solid. Recrystallization from a mixture of methylene chloride and ethyl acetate gave off-white crystals, mp 274°-276°.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:22][NH:23][O:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:23]([O:24][CH2:25][CH3:26])[CH3:22])=[O:20])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(Oc3ccc(N=C=O)cc3)ccc2O1
Reactant: CCONC
Solvent: Cc1ccccc1
Product: CCON(C)C(=O)Nc1ccc(Oc2ccc3c(c2)CC(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.5 %

Procedure:
1.8 g of 4-(2,3-dihydro-2,2-dimethyl-5-benzofuranyloxy)phenyl isocyanate was dissolved in 20 ml of toluene, and 2.0 g of N-methyl-O-ethylhydroxylamine dissolved in 5 ml of toluene, was dropwise added thereto over a period of 20 minutes at room temperature. The mixture was stirred at room temperature for 2 hours, and then the solvent was distilled off. The residue was purified by silica gel column chromatography by using a solvent mixture of ethyl acetate/n-hexane=1/4 as the developer, to obtain 2.2 g of compound No. 29 as identified in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:21][CH2:22]O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([O:15][CH2:21][CH3:22])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cn(C)c2cc(Cl)ccc2c1=O

Procedure:
A solution of 7-chloro-1-methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.50 g, 2.10 mmol) and SOCl2 (2.0 mL) in EtOH (15.0 mL) was heated to 78° C. for 6 h. After the completion of reaction (TLC monitoring), EtOH was distilled off, added water and extracted with EtOAc (3×70 mL). The combined organics was washed with saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated to obtain the desired product in quantitative yields.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:21])[CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:18](=[O:19])[CH2:17][C:16](=[O:21])[NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: Cc1ccccc1
Product: O=C1CC(=O)N(c2ccc(Cl)cc2)c2ccccc2N1
Yield: 60.7 %

Procedure:
To a stirred refluxing solution of N1-(4-chlorophenyl)benzene-1,2-diamine (100.0 mg, 0.46 mmol) in toluene (20 mL) was added dropwise a solution of malonyl dichloride (65.00 mg, 0.46 mmol). After addition was completed, the reaction mixture was refluxed for 1 h. The solvent was removed in vacuo, the mixture was stirred with water (20 mL), extracted with DCM (10 mL*3), and then was purified by Prep-TLC (DCM:MeOH=30:1) to give 1-(4-chlorophenyl)-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (80.00 mg, 60%) as a white solid. LRMS (M+H+) m/z: calcd 286.05. found 286.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[C-:19]#[N:20].[K+].[CH2:22]([N:29]1[CH2:33][CH:32]([C:34]2[S:35][CH:36]=[C:37]([Br:39])[CH:38]=2)[CH:31]([CH2:40]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O.O>[CH2:22]([N:29]1[CH2:33][CH:32]([C:34]2[S:35][CH:36]=[C:37]([Br:39])[CH:38]=2)[CH:31]([CH2:40][C:19]#[N:20])[CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CC2c2cc(Br)cs2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1CN(Cc2ccccc2)CC1c1cc(Br)cs1
Temperature: 80 °C
Yield: 44 %

Procedure:
18-Crown-6 (5.3 g, 0.020 mol) and potassium cyanide (1.3 g, 0.020 mol) were added, respectively, to a solution of the product from step c) (6.7 g, 0.013 mol) in 50 mL of DMSO. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, diluted with water (150 mL) and extracted with ethylacetate (3×150 mL). The combined organic extracts were washed with brine (200 mL), dried with MgSO4, and evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using 1-100% ethylacetate-hexane gradient to give the subtitle compound (2.1 g, yield: 44%). MS calculated for C17H17BrN2S +H: 361, observed: 361 and 363.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:19]=[CH:18][N:17]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:16]3[CH:21]=[C:20]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Reaction time: 2 h

Procedure:
A solution of 4-(2-nitro-5-(piperidin-1-yl)phenyl)-6-(3-(trifluoromethyl)phenoxy)pyrimidine in a mixture of methanol and ethyl acetate was treated with 35 mg of 5% Pd/C and stirred for 2 h under a hydrogen atmosphere. The mixture was filtered and the solvent was evaporated. The residue was purified by chromatography to give the product as 170 mg of a yellow syrup.
Reaction SMILES: [CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+]>C(O)C>[ClH:36].[CH:1]1([N:6]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:7]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24](=[NH:41])[NH2:25])=[CH:22][CH:23]=4)=[N:15][C:11]=3[CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Yield: 65 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 65% of theory, C28H35N5O3 (489.6); EKA mass spectrum: (M+H)+=490.
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:24][CH2:23]1>CN(C)C=O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][N:9]2[C:7](=[O:8])[CH2:6][C:4]3([CH2:5][CH2:1][CH2:2][CH2:3]3)[CH2:12][C:10]2=[O:11])[CH2:27][CH2:26]1
Reactant: O=C1CC2(CCCC2)CC(=O)N1
Reactant: Fc1ccccc1N1CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A mixture of 3,3-tetramethylene glutarimide (6.9 mg) and potassium carbonate (40 mg) in dimethylformamide (0.5 mL) was stirred at room temperature for 30 minutes. 1-(2-Chloroethyl)-4-(2-fluorophenyl)piperazine (10.0 mg) was added and the resulting solution was heated at 120° C. for 3 hours. The solvent was removed and the residue was purified by thin-layer chomatography (silica gel, eluting with hexane/ethyl acetate, 1:1), giving the title compound as a white solid (6.2 mg, 40%). 1H NMR (300 MHz, CDCl13) δ7.07-6.87 (m, 4H), 3.96 (t, 2H, J=6.6 Hz), 3.05 (t, 4H, J=4.8 Hz), 2.67 (t, 4H, J=4.7 Hz), 2.59 (s, 4H), 2.54 (t, 4H, J=6.6 Hz), 1.73-1.68 (m, 4H), 1.55-1.50 (m, 4H). ESI-MS m/z 374 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:9]([O:13][C:14]([N:16]1[CH2:19][C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([N:4]2[CH2:5][CH2:6][O:7][C:2]([CH3:8])([CH3:1])[CH2:3]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC1(C)CNCCO1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCOC(C)(C)C2)C1
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of 2,2-dimethylmorpholine (260 mg, 2.26 mmol) and 3-oxoazetidine-1-carboxylic acid tert-butyl ester (464 mg, 2.71 mmol) in DCE (15 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (957 mg, 4.52 mmol). The resulting mixture was stirred for 16 h, then diluted with DCM and washed with H2O. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 0-40%) affording the title compound as an oil (492 mg, 81%). 1H NMR (CDCl3, 300 MHz): δ 3.95-3.85 (m, 2 H); 3.80-3.71 (m, 4 H); 3.07-2.88 (m, 1 H); 2.32-2.22 (m, 2 H); 2.14-2.06 (m, 2 H); 1.44 (s, 9 H); 1.25 (s, 6 H).