Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=[O:22])=CC=1.[C:25]1([CH3:31])C=CC=CC=1>>[Br:1][C:2]1[C:7]([CH:8]2[O:22][CH2:25][CH2:31][O:9]2)=[C:6]([F:10])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Br)c(C=O)c1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Product: CCOc1ccc(Br)c(C2OCCO2)c1F
Yield: 98.8 %

Procedure:
A Dean-Stark condenser was attached, and a mixture of compound (53) (17.0 g, 68.81 mmol), EG (12.8 g, 200.2 mmol) and PTSA (0.17 g, 1 wt %) was refluxed in a toluene (200 mL) solvent for 3 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and dried over magnesium sulfate. Toluene was distilled off by evaporator, and thus 2-(6-bromo-3-ethoxy-2-fluorophenyl)-1,3-dioxolane (54) (19.8 g, yield 98.8%) was obtained.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[CH:14][NH:13][CH:12]=1)=[O:10])[CH3:7].[OH-].[Na+].CN([CH:22]=[O:23])C>O>[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:22]=[O:23])[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c[nH]cc1C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c[nH]c(C=O)c1C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
POCl3 (4 mL, 1.1 eq) added to 9 mL (3 eq) of DMF cooled in an ice bath. After 15 mins, a solution of the 4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (6 g, 39.2 mmol) in DMF (2M, 20 mL) was added to the reaction and stirring continued at rt. After 2 hr, the reaction mixture was diluted with water (100 mL) and basified to pH=11 with 1N NaOH. The aqueous layer was extracted into DCM (2×250 mL), washing the combined organic layers with water (2×400 mL), dried (MgSO4), filtered through a plug of silica and concentrated to afford a pinkish solid. Trituration with hexanes afforded 3.3 g (46%) of 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester as a tan solid
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][CH2:16][CH:17](O)[CH3:18].O1CCC[CH2:21]1>>[CH3:18][C:17]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[CH3:21])[CH2:12][C:11]=2[NH:15][CH:16]=1
Reactant: CC(O)CN
Reactant: C1CCOC1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Product: Cc1ccccc1C1CC(=O)c2c(C)c[nH]c2C1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 5-phenylcyclohexane-1,3-dione (2.0 g), 3-aminopropan-2-ol (0.97 g), molecular sieves 4A (12 g) and tetrahydrofuran (30 ml) was refluxed for 12 hours and cooled, and insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dimethylformamide (40 ml). To the mixture were added 2-bromomesitylene (2.0 g), tetrakistriphenylphosphine palladium (0.29 g) and potassium carbonate (2.7 g), and the mixture was stirred at 150° C. for 5 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (1.1 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[OH:13][C:14]1[C:23]([CH2:24][CH:25]=[CH2:26])=[C:22]([CH3:27])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>O>[C:1]([O:13][C:14]1[C:23]([CH2:24][CH:25]=[CH2:26])=[C:22]([CH3:27])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: C=CCc1c(C)ccc(C(=O)OC)c1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCc1c(C)ccc(C(=O)OC)c1OC(C)=O

Procedure:
351 g of acetic anhydride followed by 2.5 ml of sulphuric acid (d=1.84) in small amounts, and finally, 355 g of methyl 2-hydroxy-3-allyl-4-methylbenzoate were introduced into a 2-liter round-bottomed flask. The temperature rose up to 35° C. The contents were heated under reflux for 3 hours and the solution obtained was then poured into 2 liters of iced water. The oily layer formed was decanted and extracted with ether and the solution containing ether was dried over sodium sulphate.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]([CH:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5].[CH2:15]([SH:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:15]([S:27][CH:2]([CH3:1])[CH2:3][C:4]([CH:6]1[C:11]([CH3:12])([CH3:13])[CH2:10][CH:9]=[CH:8][CH:7]1[CH3:14])=[O:5])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C/C=C/C(=O)C1C(C)C=CCC1(C)C
Reactant: CCCCCCCCCCCCS
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCSC(C)CC(=O)C1C(C)C=CCC1(C)C
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A solution of 8-damascone (10.0 g; 52.1 mmol) and 1-dodecanthiol (8.42 g, 41.7 mmol) in THF (150 ml) was treated with DBU (7.92 g; 52.1 mmol) and stirred at 45° C. for 90 min. The reaction solution was treated with 5% aqueous HCl, extracted twice with ether, washed with H2O, saturated aqueous NaHCO3, then brine, dried over Na2SO4, and concentrated at 70° C./0.01 mbar. Yield of crude product: 16.2 g (99%).
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26][C:27](=O)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[O:20])[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:35](O)=[O:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:39][O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH2:45][S:46][CH3:47])[NH2:43].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([N:9]1[C:13]2([CH2:14][CH2:15][CH:16]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[O:20])[CH2:17][CH2:18]2)[S:12][CH2:11][C@H:10]1[C:35]([NH:43][C@@H:42]([CH2:44][CH2:45][S:46][CH3:47])[C:41]([O:40][CH3:39])=[O:48])=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCNC(=O)C1CCC2(CC1)SC[C@@H](C(=O)O)N2C(=O)c1ccccc1)OC(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@@H]1CSC2(CCC(C(=O)NCCC(=O)OCc3ccccc3)CC2)N1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
In 9 ml of anhydrous tetrahydrofuran was dissolved 0.60 g of (3R)-4-benzoyl-8-({[3-(benzoyloxy)-3-oxopropyl]-amino}carbonyl)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid. At 0-5° C., 0.26 g of L-methionine methyl ester hydrochloride, 0.19 g of 1-hydroxybenzotriazole monohydrate and 0.14 ml of N-methylmorpholine were successively added. After stirring the mixture at the same temperature as above for 30 minutes, 0.27 g of dicyclohexyl carbodiimide was added and the resulting mixture was stirred at the same temperature as above for 30 minutes and then at ambient temperature for 6 hours. The insoluble matter was filtered off, the filtrate was added to a mixture of water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=1:2] gave 0.62 g of methyl (2S)-2-({[(3R)-4-benzoyl-8-({[3-(benzyloxy)-3-oxopropyl]amino}carbonyl)-1-thia-4-azaspiro[4.5]decan-3-yl]carbonyl}amino)-4-(methylthio)butyrate as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[NH:12][N:13]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1.O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:30])([F:29])[F:31])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[NH:12][N:13]=2)[CH:6]=[CH:5][C:4]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: CCOC(=O)CCC(c1nc(-c2ccc(-n3cnc(C)c3)c(OC)n2)n[nH]1)c1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(-c2n[nH]c(C(CCC(=O)O)c3ccccc3C(F)(F)F)n2)ccc1-n1cnc(C)c1
Reaction time: 3 h
Yield: 59.5 %

Procedure:
Ethyl 4-[5-[6-methoxy-5-(4-methyl-imidazol-1-yl)-pyridin-2-yl]-2H-[1,2,4]-triazol-3-yl]-4-(2-trifluoromethylphenyl)-butyrate (370 mg) was dissolved in tetrahydrofuran (1 ml). Water (1 ml) and 5 N sodium hydroxide (1 ml) were added and the reaction was initiated. After three hours, the reaction solution was partitioned with diethyl ether and water. The resulting aqueous layer was neutralized with 5 N hydrochloric acid and extracted with methylene chloride twice. Concentration under reduced pressure gave an orange oil (208 mg) which was used for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1
Reactant: COC(=O)[C@H](CC#Cc1cnc(N)cn1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCCc1cnc(N)cn1)NC(=O)OC(C)(C)C
Yield: 78.1 %

Procedure:
A mixture of methyl (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-pent-4-ynoate (10.0 g; 31.2 mmol), ammonium formate (29.7 g; 468.0 mmol) and active 10% palladium-on-charcoal (1.2 g) in methanol (100 ml) is refluxed for 3 hours. The reaction mixture is filtered and concentrated under reduced pressure. The residue obtained is taken up in ethyl acetate (300 ml), washed with brine (2×200 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue obtained is purified on a column of silica eluted under pressure with a dichloromethane/methanol mixture (96/4). 7.9 g of methyl (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoate are isolated in the form of a viscous oil.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].O>CN(C)C=O>[NH:31]([C:29]([CH2:28][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1)=[O:30])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C(CCl)Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CNC1CCN(CCc2c[nH]c3ccccc23)CC1)Nc1ccccc1
Reaction time: 24 h
Yield: 109.2 %

Procedure:
3-[2-(4-Amino-1-piperidyl) ethyl]indole hydrate (1.31g.) was dissolved in dimethylformamide (15 ml) containing triethylamine (2 ml) and chloroacetanilide (0.85g) added. The mixture was stirred for 24 hours, poured into water (100 ml) and extracted with chloroform (2 × 50 ml). The combined chloroform layers were washed with water, dried (MgSO4), filtered and evaporated to give the title compound as an amber oil (2.06 g). This was converted to the hydrochloride (1.29 g), m.p. 240.7°, on addition of EtOH-HC1 and Et2O.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:8])[S:6][CH:7]=1)[CH3:2].[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[Cl:9][C:10]1[C:11]([CH3:20])=[C:12]([S:16]([NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=2)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCc1csc(N)n1
Product: CCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Yield: 17 %

Procedure:
The title compound was prepared from 4-ethyl-1,3-thiazol-2-ylamine (METHOD H) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellowish solid, 53 mg (17% yield): HRMS Calcd (found) for C12H13ClN2O2S2 m/z 316.0107 (316.0120).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[N:14]2)=[CH:9][C:8]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])[CH:13]=[N:14]2)=[CH:9][C:8]=1[O:26][CH3:27]
Reactant: ClCCCBr
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
1-Bromo-3-chloropropane (0.97 ml, 9.8 mmol) was added to a solution of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.5 g, 8.17 mmol), (prepared as described for the starting material in Example 7), in DMF (40 ml) containing potassium carbonate (2.8 g, 20 mmol). The mixture was stirred overnight at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated to give 7-(3-chloropropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (3.10 g, 100%).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1B(O)O.BrC1C=CC(OC)=CC=1[N+]([O-])=O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[C:30]([N+:44]([O-])=O)[CH:29]=1>>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[C:30]([NH2:44])[CH:29]=1
Reactant: COc1ccc(-c2ccc3ccccc3c2)c([N+](=O)[O-])c1
Agent: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: OB(O)c1ccc2ccccc2c1
Product: COc1ccc(-c2ccc3ccccc3c2)c(N)c1
Yield: 68.2 %

Procedure:
Synthesized from 2-naphthylboronic acid and 4-bromo-3-nitroanisole according to an analogous synthetic method to Preparation Example 79, 2-(4-methoxy-2-nitrophenyl)naphthalene (2.3 g) was used according to an analogous synthetic method to Example 22 to provide the title compound (1.4 g).
Reaction SMILES: [NH2:1]C1SC2C=C([N+]([O-])=O)C=CC=2N=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[C:14]([NH2:1])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a suspension of 2-amino-6-nitrobenzothiazole (Sigma Aldrich, 2.93 g, 15 mmol) in pyridine (20 mL), benzoyl chloride (1.74 mL, 15 mmol) was added. After stirring over-night at r.t., additional benzoyl chloride (1.74 mL, 15 mmol) was added and the mixture was stirred at 60° C. After completion of the reaction, the mixture was poured into water (250 mL) and stirred overnight at r.t. Separation of the resulting precipitate yielded N-6-nitrobenzotihiazol-2-yl)benzamide (3.87 g, 12.9 mmol, 86%) as a yellow solid. LC/ESI-MS: m/z=300 [M+H]+; m/z=298 [M−H]−; Rt=3.93 min.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:12]([C:11]1[C:2]([OH:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(O)c1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(Oc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 11.5 %

Procedure:
To a mixture of methyl 2,3-dihydroxybenzoate (1.50 g, 8.9 mmol), phenylboronic acid (1.08 g, 8.9 mmol) and copper acetate (1.62 g, 8.9 mmol) suspended in dichloromethane (100 ml) was added triethylamine (6.15 ml, 44.5 mmol) and the mixture was stirred at room temperature for 96 h. The solvent was removed and the product chromatographed through a silica column using a gradient of 0-10% methanol in dichloromethane. The product was obtained as a pale yellow oil (0.25 g).
Reaction SMILES: [CH3:1][CH2:2]O.CN1CCC(=N[N:12]([CH2:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)CC1>Cl.O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:20][N:12]1[CH2:2][CH2:1][C:15]2[N:12]([CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:14]=2[CH2:13]1
Reactant: CCO
Reactant: Cc1ccc(N(CCc2ccc(C)nc2)N=C2CCN(C)CC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Temperature: 100 °C
Yield: 63 %

Procedure:
Concentrated HCl (6 cm3) was added to EtOH (4 cm3). The crude N′-(1-methyl-piperidin-4-ylidene)-N-[2-(6-methyl-pyridin-3-yl)-ethyl]-N-p-tolyl-hydrazine was dissolved in this ethanolic HCl and heated to 100° C. for 30 minutes. The reaction was then cooled, and diluted with H2O (10 cm3), saturated with Na2CO3, and extracted with CHCl3 (3×50 cm3). The combined extracts were dried (MgSO4) and solvent removed. The residual brown oil was purified by flash column chromatography over SiO2 (10×2 cm) eluting with 1:1 EtOAc/MeOH to provide the desired product as a pale brown powder (612 mg, 63% yield over 3 steps based on last pure starting material (2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine)).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=2[CH:15]=1)(=O)C.[C:16](Cl)(=[O:20])C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:26][NH2:27]>>[CH3:26][NH:27][C:16]([C:12]1[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:15][C:9]=2[S:10][C:11]=1[CH2:13][CH3:14])=[O:20]
Reactant: CN
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc2ccc(OC(C)=O)cc2s1
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1sc2cc(O)ccc2c1C(=O)NC
Yield: 82 %

Procedure:
This material was prepared from 6-acetoxy-2-ethylbenzo[b]thiophene 134c (1.77 g, 8 mmole) by acylation with oxalyl chloride in the presence of AlCl3, followed by treatment with methylamine in a manner as previously described for example 1d to give a pale yellow solid (1.55 g, 82%). 1H NMR (DMSO-d6) δ9.57 (1H, s), 8.15 (1H, q, J=4.5 Hz), 7.48 (1H, d, J=8.6 Hz), 7.19 (1H, d, J=2.3 Hz), 6.84 (1H, dd, J=2.3, 8.6 Hz), 2.90 (2H, q, J=7.5 Hz), 2.78 (3H, d, J=4.5 Hz), 1.22 (3H, t, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5].[CH2:15]([NH2:19])[CH2:16]CC.[C:20]12[C:26](=CC=CC=1)[NH:25]C(=O)OC2=O>>[CH2:7]([NH:6][C:4](=[O:5])[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[NH:1][CH2:20][C:26]1[NH:25][CH2:16][CH2:15][N:19]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCCNC(=O)c1ccccc1N
Reactant: CCCCN
Product: CCCCNC(=O)c1ccccc1NCC1=NCCN1

Procedure:
2-Amino-N-butylbenzamide (prepared from butylamine and isatoic anhydride, using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give N-butyl-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]benzamide, isolated as the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH:13]([F:15])[F:14])[C:8]([N+:16]([O-:18])=[O:17])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:19][C:20]([F:29])([F:30])[O:21][C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([NH:11][CH2:12][CH:13]([F:15])[F:14])=[CH:10][C:2]=2[Cl:1])=[CH:27][CH:28]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl

Procedure:
The sub-title compound is prepared in analogy to 1b from 2-chloro-4-(2,2-difluoro-ethylamino)-5-nitro-benzoic acid (2.00 g, 7.1 mmol), 4-trifluoromethoxyaniline (0.96 mL, 7.1 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (1.13 mL, 8.5 mmol), DIPEA (2.85 mL, 16 mmol) and DCM (40 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[CH:25]([O:26][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CC(O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COC1CC(C)(C)Oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 30 °C
Reaction time: 15 h

Procedure:
To the product of Example 68 (250 mg, 0.575 mmol) was added NaH (73.6 mg, 1.84 mmol, 60%) and ethyl 2-bromoacetate (0.23 mL 2.07 mmol) in DMF (3 mL). The reaction was stirred 3 h at 30° C. and 15 h at rt. The reaction was diluted with EtOAc and washed with 2 M aq HCl and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-33% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 520.1 (M+1), 522.0 (M+3); Rt=4.43 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]12[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]([NH2:26])=[N:17]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1>O.O1CCOCC1.O>[Cl:12][C:10]1[N:9]=[CH:8][C:7]2[O:13][C:14]3[C:4]([C:5]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]([NH2:26])=[N:17]4)[C:6]=2[CH:11]=1)=[CH:3][C:2]([C:41]1[C:36]([F:35])=[N:37][CH:38]=[CH:39][CH:40]=1)=[CH:16][CH:15]=3
Reactant: NC1=NC2(c3ccccc3O1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cccnc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(c3ccccc3O1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 100 °C

Procedure:
A microwave tube was charged with 7′-bromo-3′-chlorospiro[benzo[e][1,3]oxazine-4,5′-chromeno[2,3-c]pyridin]-2-amine (0.135 g, 0.315 mmol), potassium phosphate tribasic (0.078 mL, 0.945 mmol), 2-fluoro-3-pyridineboronic acid (0.049 g, 0.346 mmol) in dioxane water (3 mL, 1:1). The reaction mixture was heated in microwave at 100° C. for 40 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate solution twice, then dried on sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography with gradient of 20-100% EtOAc/Hexane to give 3′-chloro-7′-(2-fluoropyridin-3-yl)spiro[benzo[e][1,3]oxazine-4,5′-chromeno[2,3-c]pyridin]-2-amine. This material (0.049 g, 0.110 mmol) was combined with potassium phosphate tribasic (0.027 mL, 0.330 mmol), 5,6-dihydro-2H-pyran-3-ylboronic acid (0.028 g, 0.220 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.90 mg, 5.51 μmol) in dioxane/water (1 mL, 3:1). The mixture was heated to 100° C. for 1 h. The reaction was completed and it was poured into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography with gradient of 70-100% EtOAc/Hexane to give the desired product. MS m/z=493.1 [M+H]+.