Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)=[CH2:36]>C(O)C(O)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:43][C:40]1[CH:41]=[CH:42][C:37](/[CH:35]=[CH:36]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:12])[C:5](=[O:11])[NH:6]3)=[CH:38][CH:39]=1
Reactant: C=Cc1ccc(O)cc1
Reactant: O=C1Nc2cccc(I)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(O)CO
Solvent: CC#N
Product: O=C1Nc2cccc(/C=C/c3ccc(O)cc3)c2C1=O
Temperature: 100 °C
Yield: 13 %

Procedure:
A mixture of 1.0 g (3.6 mmol) of 4-iodo-1H-indole-2,3-dione (Snow, et al., Journal of the American Chemical Society 1977, 99, 373444), 0.42 g (4.2 mmol) of TEA, 0.06 g (0.27 mmol) of palladium(II) acetate, 0.16 g (0.54 mmol) of trio-tolylphosphine and 5.0 g (4.2 mmol) of a 10% solution of 4-vinylphenol in propylene glycol was suspended in 15 mL of dry acetonitrile in a pyrex sealed tube and heated to 100° C. for 4 h. The mixture was cooled to rt, quenched with 50 mL of 10% hydrochloric acid and extracted with two 100 mL-portions of EtOAc. The combined extracts were dried over MgSO4 and concentrated to give a brown solid, which was subjected to chromatography on silica gel, eluting with hexane:EtOAc (3:1), to yield 0.125 g (13%) of trans4-[2-(4-hydroxyphenyl) vinyl]-1H-indole-2,3-dione as a red solid: 1H NMR (DMSO-d6): δ 6.6-7.6 (m, 8H), 7.77 (d, J=16.4 Hz, 1H), 9.85 (bs, 1H), 11.00 (bs, 1H); APCI−MS m/z 264 (M−1)−. Condensation of trans4-[2-(4-hydroxyphenyl)vinyl]-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 27% yield as an orange solid: 1H NMR (DMSO-d6): δ 6.78 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.26 (t, J=7.8 Hz, 1H), ), 7.29 (s, 2H), 7.36 (d, J=16.5 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), ), 7.81 (d, J=8.7 Hz, 2H), 8.03 (d, J=16.5 Hz 1H), 9.78 (s, 1H), 11.17 (s, 1H), 13.02 (s, 1H); APCI−MS m/z 433 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].CCCCCC>O1CCCC1.C(OCC)C>[C:30]1([O:29][C:27](=[O:28])[NH:11][C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:2]=3[F:1])[N:10]=[CH:9][N:8]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.8 %

Procedure:
6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (400 mg) was dissolved in tetrahydrofuran (16 ml) under a nitrogen atmosphere, and then triethylamine (0.669 ml) and phenyl chloroformate (0.602 ml) were added dropwise thereto while cooling in an ice bath, followed by warming the reaction mixture to room temperature and stirring for 10 min. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then suspended in diethyl ether (4 ml)-hexane (4 ml). The solid was filtered and dried under aeration to provide the titled compound (396 mg, 66.8%) as pale yellow powder.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:41][C:24]4=[N:25][CH:26]=[C:27]([Cl:40])[C:28]([NH:29][C@H:30]5[C@@H:35]([C:36](=[O:38])[NH2:37])[C@H:34]6[CH2:39][C@@H:31]5[CH:32]=[CH:33]6)=[C:23]4[N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:42](Cl)Cl.FC(F)(F)C(O)=O.C(OC(=O)C)(=O)C.C(N(CC)CC)C.C(N(CC)CC)C>C(Cl)Cl.C1COCC1>[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:41][C:24]4=[N:25][CH:26]=[C:27]([Cl:40])[C:28]([NH:29][C@@H:30]5[C@@H:31]6[CH2:39][C@@H:34]([CH:33]=[CH:32]6)[C@@H:35]5[C:36]([NH2:37])=[O:38])=[C:23]4[N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(=[O:5])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cc2)CC1
Reactant: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(Cc2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cc2)CC1
Temperature: 40 °C
Yield: 10 %

Procedure:
[4-{4-[7-((1R,2R,3S,4S)-3-Carbamoyl-bicyclo[2.2.1]hept-5-en-2-ylamino)-6-chloro-3H-imidazo[4,5-b]pyridin-2-yl]-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (159.0 mg, 0.2750 mmol) was taken up into Methylene chloride (8.4 mL, 130 mmol) and treated with Trifluoroacetic Acid (3 mL, 40 mmol) and stirred @ 40° C., O/N. The solution was then concentrated. The residue was taken up into methanol and treated with 900 mg mp carbonate for ½ hour. The resin was removed by filtration and filtrate concentrated. The residue was taken up into DCM/THF (˜30 mL) and Acetic anhydride (0.56 mL, 5.9 mmol) was added followed by triethylamine Triethylamine (0.56 mL, 4.0 mmol). Solution was stirred at RT for 1 hr and then concentrated. The residue was purified via reverse phase chromotography using a gradient of MeCN with 0.1% TFA in Water with 0.1% TFA on a Phenomenex Gemini-NX C18 AXIA column. Fractions containing desired product were poured into sat'd sodium bicarbonate and extracted with 3 portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to yield a yellow solid, 15.00 mg, 10% yield. (300 MHz, DMSO-d6) 13.26 (s, 1H), 8.10 (d, J=8 Hz, 2H), 7.95 (s, 1H), 7.78 (m, 1H), 7.48 (d, J=8 Hz, 2H), 7.22 (m, 2H), 6.44-6.33 (m, 2H), 5.17 (t, J=17 Hz, 9 Hz, 1H), 3.56 (s, 2H), 3.43 (m, 4H), 2.89 (s, 1H), 2.80 (s, 1H), 2.62 (d, J=9 Hz, 1H), 2.40 (m, 2H), 2.33 (m, 2H), 2.25 (d, J=8 Hz, 1H), 1.98 (s, 3H), 1.38 (d, J=8 Hz, 1H). MS=521 (M+H), HPLC: 1.47 min. (G Method)
Reaction SMILES: [NH2:1][CH:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([N:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=3[C:15]3=[N:23][O:24][C:25]([CH3:26])=[C:14]3[C:13]2=[O:27])[CH2:7]1)=[O:4].Cl.[CH3:35][N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1.Cl.CN(C)CCCN=C=NCC.CC1C=C(C)C=C(C)N=1.ON1C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.O.C([O-])(O)=O.[Na+]>[Cl:22][C:17]1[C:16]2[C:15]3[C:14](=[C:25]([CH3:26])[O:24][N:23]=3)[C:13](=[O:27])[N:12]([CH:8]3[CH2:9][CH2:10][CH2:11][CH:6]([NH:5][C:3]([CH:2]([NH:1][C:42]([CH:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[O:43])[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:4])[CH2:7]3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(N)c3ccccc3)C1)c1cccc(Cl)c21
Reactant: CN1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(NC(=O)C3CCN(C)CC3)c3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A product from Example 638 (50 mg; 0.108 mmol) was dissolved in anhydrous dimethylformamide (10 mL) under a nitrogen atmosphere, mixed with 1-methyl-piperidine-4-carboxylic acid hydrochloride (58.0 mg; 0.323 mmol; 3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (61.8 mg; 0.323 mmol; 3 equiv), 2,4,6-trimethylpyridine (86 μL; 0.645 mmol; 6 equiv), and 1-hydroxy-7-azabenzotriazole (43.9 mg; 0.323 mmol; 3 equiv), and stirred overnight at room temperature. The reaction solution was diluted with 2 volumes ethyl acetate, 10 volumes water, and 1 volume saturated NaHCO3(aq). The organic layer was separated and then washed with saturated NaCl(aq), dried over Na2SO4(S), filtered, and concentrated in vacuo. The resulting material was purified by radial chromatography on a 2 mm thick silica gel rotor with a 2% then 4% methanol/dichloromethane (v/v) mobile phase and finally a 2% methanol/0.5% triethylamine/dichloromethane (v/v/v) mobile phase. The desired product was isolated as a white solid in 74% yield (47 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:29])[CH2:16][NH:17][CH2:18][C:19]23[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]4)[CH2:20]2)[CH2:26]3)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:19]12([CH2:18][NH:17][CH2:16][CH:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[OH:29])[CH2:28][CH:23]3[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]3)[CH2:26]1)[CH2:20]2
Reactant: OC(CNCC12CC3CC(CC(C3)C1)C2)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(C(O)CNCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of 1-(4-(benzyloxy)phenyl)-2-((1-adamantylmethyl)amino)ethanol (0.8 g, 2.05 mmol) in MeOH (10 mL) was added Pd(OH)2 (80 mg). The mixture was stirred at rt under H2 for 30 min. The mixture was filtered and concentrated to give 4-(2-((1-adamantylmethyl)amino)-1-hydroxyethyl)phenol (0.5 g, yield: 81%). 1H NMR: (CDCl3, 400 MHz) δ=1.53 (m, 6H), 1.65 (m, 6H), 1.97 (m, 3H), 2.26 & 2.36 (dd, 2H), 2.62&2.83 (dd, 2H), 4.60 (m, 1H), 6.78 (m, 2H), 7.22 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[NH:6]1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7](=[O:20])[NH:6]1
Reactant: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NC[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Reaction time: 1 h

Procedure:
A suspension of 0.499 g (1.81 mmole) of cis-2-azidomethyl-4-oxo-3-phenoxyacetylaminoazetidine and 0.189 g of 10% palladium on carbon in 25 ml of absolute ethanol was hydrogenated at atmospheric pressure and at 40° for 1 hour. The solution was filtered through celite and the solvent was removed in vacuo to afford the title compound as a colorless gum.
Reaction SMILES: COC(N[C@@H](C(C)C)C([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17]CC)=[O:16])=O)=O.[Li+].[OH-]>CO>[CH3:14][CH:13]1[NH:9][CH:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12]1
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1CCC(C(=O)O)N1
Yield: 56 %

Procedure:
(2S,5S)-Ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate (39.3 mmol, assuming complete conversion from the previous transformation) was suspended in MeOH (200 mL) and aqueous LiOH (1.0 M, 100 mL, 100 mmol) was added. The reaction mixture was stirred o/n, then concentrated under reduced pressure to remove most of the MeOH. The aqueous solution was washed 2× with DCM before being acidified to pH˜1-2 with 10% HCl. The acidic aqueous phase was then extracted 5× with EtOAc. The combined EtOAc extracts were dried over MgSO4 filtered and concentrated under reduced pressure to afford (2S,5S)-1-(S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylic acid (6.89 g, 56% over 2 steps).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[S:12][C:13]([CH3:19])=[C:14]([N+:16]([O-])=O)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Ni]>[CH2:1]([O:8][C:9]([C:11]1[S:12][C:13]([CH3:19])=[C:14]([NH2:16])[CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1sc(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)OCc2ccccc2)cc1N
Yield: 107 %

Procedure:
Sponge nickel (0.6 g water wet) was added to a solution of 5-methyl-4-nitro-thiophene-2-carboxylic acid benzyl ester (0.93 g, 3.4 mmol), prepared as described in Step 1 above, in tetrahydrofuran (50 mL), and the mixture was hydrogenated at room temperature under hydrogen atmosphere at a starting pressure of 50 psi. After a reaction time of 2.4 hours, the pressure was released and the mixture filtered. The slurry was rinsed with tetrahydrofuran, and the filtrate was stripped of solvent under reduced pressure, leaving 0.9 g of 5-methyl-4-amino-thiophene-2-carboxylic acid benzyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)[S:5][C:6]=1[C:7]#[N:8].[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)[S:5][C:6]=1[C:7]#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2nc(N)c(C#N)s2)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1sc(NC2CCCNC2)nc1N

Procedure:
Analogously to the preparation of Example 38A, 240 mg (0.7 mmol) of tert-butyl 3-[(4-amino-5-cyano-1,3-thiazol-2-yl)-amino]piperidine-1-carboxylate (Example 46A) and 25 ml of hydrochloric acid in dioxane (4M) gave 265 mg (57% of theory) of the product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Yield: 86 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (2 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (2.5 g) described in Preparation Example 49, the title compound (3.4 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CN(C)CCCl
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(C)CCOc1ccc(C=O)c(O)c1

Procedure:
A mixture containing 0.8 mole of 2,4-dihydoxy-benzaldehyde, 0.8 mole of 2-chloro-1-dimethylaminoethane and 1.6 mole of potassium carbonate in 1200 ml of anhydrous methyl ethyl ketone is refluxed for 1 hour 30 minutes with stirring. After cooling, the precipitate formed is filtered and washed with methyl ethyl ketone. The filtrate is then evaporated and leads to a brown oil which is purified by chromatography of a silica column using a dichloromethane-methanol mixture (90/10) as eluting solvent. The expected product is then obtained after recrystallization from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(O)(=O)C>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[CH:10]([CH3:23])[N:9]=1
Reactant: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 100 ml of acetone and treated with 6.3 g of potassium carbonate and 3.5 ml of dimethyl sulphate. After stirring for 2 hours at room temperature, a further 1 g of potassium carbonate and 1 ml of dimethyl sulphate are added, after which the mixture is stirred for a further hour at room temperature. The mixture is treated with 3 ml of glacial acetic acid and the acetone is distilled off. The residue is treated with 10% sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulphate, filtered and concentrated. The residue is purified on a column of silica gel (eluant: methylene chloride and methylene chloride/ethyl acetate 10:1) and crystallized from ether/ petroleum ether. There is obtained (+)-5-(o-chlorophenyl)--1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 156°-158° C. and exhibits a rotation of [α]25 D =+376.2° (in methylene chloride, 1%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:13])[S:5][C:6]=1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.[CH3:36][C:37]1([CH3:45])[C:39]([CH3:41])([CH3:40])[CH:38]1[C:42](O)=[O:43]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:13][C:42]([CH:38]2[C:39]([CH3:41])([CH3:40])[C:37]2([CH3:45])[CH3:36])=[O:43])[S:5][C:6]=1[N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Cc1nc(N)sc1N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1nc(NC(=O)C2C(C)(C)C2(C)C)sc1N1CCOCC1

Procedure:
A mixture of 4-methyl-5-morpholin-4-yl-thiazol-2-ylamine (prepared using the method described in Christopher et al., Bioorganic and Medicinal Chemistry Letters 2004, 14(22), 5521-5525), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, and 2,2,3,3-tetramethylcyclopropanecarboxylic acid were processed using the method described in Example 58 to afford the title compound. MS (ESI) m/z 324 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([SH:34])=[N:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([S:34][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]3[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]3)[CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:23])=[N:4][CH:3]=2)=[N:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCOCC2)CC1
Reactant: CCOC(=O)c1cnc(S)n1C
Product: CCOC(=O)c1cnc(Sc2cnc(NC(=O)N(C3CCOCC3)C3CCC(C)CC3)s2)n1C

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea (Example 203) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]2[N:16]=CC=C[N:12]2[CH:17]=1.NN.O>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([NH2:16])[NH:12][CH:17]=1
Reactant: COc1ccccc1-c1cn2cccnc2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1c[nH]c(N)n1
Temperature: 75 °C

Procedure:
To a stirred solution of 2-(2-methoxyphenyl)imidazo[1,2-α]pyrimidine (1.24 g, 5.5 mmol) in EtOH (8 mL) was added NH2NH2.H2O (0.3 mL, 6.1 mmol). After heating to 75° C. for 24 h, the reaction was concentrated under reduced pressure. The residue was suspended in Et2O and filtered to collect 4-(2-methoxyphenyl)-1H-imidazol-2-amine (1 g, 96%) as a light yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.Cl.[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1.O>CN(C)C=O>[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:35][CH2:36]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1
Reactant: ClCCCCCOc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2ccccc2)CC1
Reaction time: 7.5 h
Yield: 44.1 %

Procedure:
Potassium carbonate (2.2 g) and 5-phenoxypentyl chloride (1.2 g) were added to a solution of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) in dimethylformamide (40 ml), an the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give crystals. The obtained crystals were recrystallized from ethyl acetate to give 0.82 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-phenoxypentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.C[Sn](C)(C)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>O1CCCC1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC1C(P(C2C([CH2-])=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.CC(O)=O.CC(O)=O.[Pd].[Pd]>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: CC1Cc2cccc(Br)c2C1=O
Agent: [Pd]
Agent: [CH2-]c1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2cccc(-c3ccccn3)c2C1=O
Yield: 90 %

Procedure:
16.9 g (75 mmol) of (2) and 20 g (90 mmol) of 2-trimethylstannylpyridine were placed in 165 ml of tetrahydrofuran in the reaction vessel, the mixture was degassed a number of times and saturated with argon. 350 mg (0.37 mmol) of trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) were added and the reaction mixture was refluxed for 24 hours. After addition of 200 ml of water, the mixture was extracted 4 times with 150 ml each time of diethyl ether, the ether phase was washed with 100 ml of water and 100 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent and drying for 24 hours at 0.1 mbar at 60° C. (removal of the trimethylstannyl bromide) gave 15.07 g of (24) as an oil.
Reaction SMILES: COC1C=C2C(=C(N)C=1)N=CC=C2.[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])([O-:29])=[O:28]>>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:23]([NH:26][S:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N+:27]([O-:29])=[O:28])(=[O:37])=[O:38])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(N)c2ncccc12
Agent: COc1cc(N)c2ncccc2c1
Product: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c2ncccc12
Yield: 64 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-methoxyquinolin-8-amine (Intermediate 67) (350 mg, 2.01 mmol) and 2-nitrobenzenesulfonyl chloride (533 mg, 2.41 mmol) gave the title compound (460 mg, 64%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:4]=1[CH2:19]Cl.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][C:6]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:19][N:28]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:2]2
Reactant: COc1cc(CCl)c(CCl)cc1OCc1ccccc1
Reactant: NCc1ccccc1
Product: COc1cc2c(cc1OCc1ccccc1)CN(Cc1ccccc1)C2

Procedure:
The procedure of Example 26 is repeated using 1.0 g of bis(chloromethyl)-4-methoxy-5-(phenylmethoxy)-benzene and 0.6 mL of benzyl amine. This affords 0.74 g of the desired product as a beige solid.