Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(I)cc1
Reactant: Sc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Sc2ccccc2)cc1

Procedure:
A mixture of 6.04 g of methyl α-(p-chlorophenoxy)(p-iodophenyl)acetate, 3.36 g of cuprous phenylmercaptide, and 800 mg of thiophenol in 150 ml of pyridine is heated under Argon overnight. The mixture is poured into 300 ml of water and extracted with two 100 ml portions of chloroform. The combined organic layers are washed with two 50 ml portions of 5% NaOH, two 50 ml portions of water, 50 ml of saturated brine and dried over MgSO4. Evaporation of the solvent at reduced pressure yields an oil. After column chromatography (benzene) and bulb-to-bulb distillation (173° C. @ 0.01 mm) there is obtained the product as a yellow oil.
Reaction SMILES: Br[CH:2]1[CH:10]([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[C:3]1=[O:13].[C:14]([NH2:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:13])[N:22]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:21][CH:2]3[CH:10]([OH:11])[C:9]=2[CH:8]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C1c2ccc(Cl)cc2C(O)C1Br
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: OC1c2cc(Cl)ccc2C2(O)N=C(c3ccccc3)SC12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.6 g (2.3 mmol) of 2-bromo-5-chloro-3-hydroxyindan-1-one and 0.473 g (3.45 mmol) of thiobenzamide were dissolved in 5 ml of isopropanol. 0.478 ml (3.45 mmol) of triethylamine was added, and the mixture was then stirred at room temperature for 12 h and subsequently at 50° C. for 8 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel by initially using n-heptane/ethyl acetate 3/1 and then toluene/acetone 5/1. This gave 6-chloro-2-phenyl-8,8a-dihydroindeno[1,2-d]thiazole-3a,8-diol having a melting point of 151-153° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.[N:14]1[C:27]2[C:18](=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:17]=[CH:16][CH:15]=1>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[C:27]4[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][CH:15]=[N:14]4)[N:25]=2)=[CH:4][CH:3]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: Brc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Brc1ccc(-c2ccc3ccc4cccnc4c3n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A solution of 6.79 g (24 mmol) of 4-bromoiodobenzene in 100 mL of diethyl ether was cooled to −70° C., added with 14 mL (23.4 mmol) of n-butyllithium dropwise, and stirred for 30 min and further for 30 min after elevating the temperature to 0° C. The resulting solution was added dropwise to 100 mL of a diethyl ether solution of 3.60 g (20 mmol) of 1,10-phenanthroline at 0° C., and the mixture was stirred for 3 h. Ice water was added, an organic layer was separated, and an aqueous layer was extracted with dichloromethane (100 mL×2). The obtained organic layers were combined and dried over anhydrous sodium sulfate, followed by filtration. To a filtrate, 20 g of manganese dioxide was added, and the mixture was stirred for 30 min. Thereafter, 20 g of manganese dioxide was further added, and the mixture was stirred for one hour and allowed to stand at room temperature overnight. The reaction solution was filtered, and a filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain 2.50 g (yield: 37%) of 2-(4′-bromophenyl)-1,10-phenanthroline as a yellow solid.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].[CH:17]1([Mg]Br)[CH2:19][CH2:18]1>C1COCC1>[CH:17]1([CH:1]([OH:2])[C@H:3]2[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C(O)C2CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of (R)-tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (Aldrich, 12.44 g, 54.26 mmol) in THF (150 mL) at −78° C. was added cyclopropylmagnesium bromide (217 mL, 108.52 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight. The reaction was quenched with water and diluted with ethyl acetate and brine. The resulting emulsion was filtered through celite and the layers separated. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound as a light yellow oil (12.47 g, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([CH3:13])[CH:3]=1.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:24])[OH:20])=[CH:3][C:4]=1[CH3:13])[CH3:10]
Reactant: CCN(CC)c1ccc(Br)cc1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCN(CC)c1ccc(B(O)O)cc1C
Yield: 111.2 %

Procedure:
In a manner similar to that of Example 1c, by reacting 8 g of (4-bromo-2-methylphenyl)diethylamine (33 mmol) with 16 mL of a 2.5 M solution of n-butyllithium and 11.5 mL (50 mmol) of triisopropyl borate, 7.6 g of 4-diethylamino-3-methylphenylboronic acid (yield=100%) are obtained in the form of a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.[CH3:25][C:26]([CH3:28])=O.C([BH3-])#N.[Na+]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH:26]([CH3:28])[CH3:25])[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N1CCC(CNc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.152 g, 0.4 mmol) in methanolacetic acid (95:5) (5 mL) was treated with acetone (5 mL) and sodium cyanoborohydride (0.111 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 24 h, then it was diluted with 1 N NaOH until pH 13 and extracted with dichloromethane. The organic extracts were combined, dried with MgSO4, filtered and concentrated in vacuo to provide the title compound (0.158 g, 92%). The crude material was triturated in dichloromethane-hexanes, giving a white powder which was filtered and dried under vacuum at 60° C.
Reaction SMILES: [C:1]1(B(O)O)C=CC=CC=1.C([O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]1[CH:33]=[C:32]3[O:34][CH2:35][O:36][C:31]3=[CH:30][C:29]=1[Cl:37])[C:22]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:21]2[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)C1C=CC=CC=1>>[Cl:37][C:29]1[CH:30]=[C:31]2[O:36][CH2:35][O:34][C:32]2=[CH:33][C:28]=1[CH2:27][N:23]1[C:24]2[C:20](=[CH:19][C:18]([OH:17])=[CH:26][CH:25]=2)[C:21]([C:43]2[CH:44]=[CH:45][C:46]([CH3:1])=[CH:47][CH:48]=2)=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2n1Cc1cc2c(cc1Cl)OCO2
Product: CCOC(=O)c1c(-c2ccc(C)cc2)c2cc(O)ccc2n1Cc1cc2c(cc1Cl)OCO2

Procedure:
Following the procedure of Example 1(a)-1(c) except substituting 4-methylphenylboronic acid for phenylboronic acid in step (b), and the procedure of Example 9(a), except substituting ethyl 5-benzyloxy-1-(2-chloro-4,5-methylenedioxybenzyl)-3-(4-methylphenyl)indole-2-carboxylate for ethyl 5-benzyloxy-1-(2-chloro-4,5-methylenedioxybenzyl)-3-phenylindole-2-carboxylate, the title compound was prepared as a white solid (0.304 g, 81%). 1HNMR (400 MHz, CDCl3) δ 7.37 (m, 2H), 7.24 (s, 1H), 7.15 (d, 1H), 6.97 (m, 3H), 6.00 (s, 1H), 5.89 (s, 2H), 5.71 (s, 2H), 4.56 (s, 1H), 4.13 (q, 2H), 2.43 (s, 3H), 1.03 (t, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:9][C:10]([C:12]1[C:25]2[C:16](=[N:17][C:18]3[C:23]([N:24]=2)=[C:22]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:21]2=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=1)=[O:11])[CH2:5][N:6]([CH3:8])[CH3:7].[BH4-].[Li+]>O1CCCC1.C(O)(C)C>[CH3:7][N:6]([CH3:8])[CH2:5][CH:4]([NH:9][C:10]([C:12]1[C:25]2[C:16](=[N:17][C:18]3[C:23]([N:24]=2)=[C:22]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:21]2=[CH:20][CH:19]=3)[CH:15]=[CH:14][CH:13]=1)=[O:11])[CH2:3][OH:2]
Reactant: COC(=O)C(CN(C)C)NC(=O)c1cccc2nc3ccc4c(OC)cccc4c3nc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1cccc2c1ccc1nc3cccc(C(=O)NC(CO)CN(C)C)c3nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-dimethylamino-2-[(4-methoxy-benzo[a]phenazine-11-carbonyl)-amino]-propionic acid methyl ester (335 mg) and lithium borohydride (72 mg) in tetrahydrofuran (10 mL) and isopropanol (10 mL) was stirred at room temperature for 18 hours. Another 5 equivalents of lithium borohydride were added and the mixture stirred for another 18 hours. The reaction was quenched with ammonium chloride solution and extracted with ethyl acetate, dried (MgSO4) and the solvent removed in vacuo to yield a brown gum. Purification using flash chromatography and trituration with ether yielded the desired title compound as an orange powder.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[CH:6][N:7]=1)[CH3:2].[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>>[CH2:1]([C:3]1[S:4][C:5]([C:15]2([OH:18])[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)=[CH:6][N:7]=1)[CH3:2]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCc1nccs1
Product: CCc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from 2-ethyl-thiazole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=2[Cl:23])=[CH:10][CH:9]=1>>[Cl:19][C:18]1[CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=[C:14]([Cl:23])[C:13]=1[O:12][C:11]1[CH:24]=[CH:25][C:8]([O:7][CH3:6])=[C:9]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To cooled chlorosulfonic acid (2.0 mL) at 0° C. was added 4-(4-methoxy-phenoxy)-3,5-dichloro-nitrobenzene (700 mg, 2.2 mmol) in several portions. The resulting mixture was stirred at 0° C. for 5 min, then at RT for 2.5 h. The solution was added dropwise to ice water (40 mL) and the product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried and concentrated to yield the title compound of Step A (920 mg) as a crude product which was used in the next step without purification. MS (APCl−) Calc.: 410.9, Found: 392.1 (M−1-Cl+OH, sulfonic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]#N)=[CH:6]2.[H-].C([Al+]CC(C)C)C(C)C.C[OH:27].Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([CH:14]=[O:27])=[CH:6]2
Reactant: CO
Reactant: COc1cc2c(cc1OC)CC(C#N)=C2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)CC(C=O)=C2
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
5,6-Dimethoxy-1H-indene-2-carbonitrile (1.8 g) was suspended in dry toluene (40 ml) under an atmosphere of nitrogen. The reaction mixture was cooled to -5° C. and treated dropwise with a solution of diisobutylaluminium hydride in toluene (1.5M, 13 ml). After 30 minutes the solution was treated with methanol (5 ml) then poured into hydrochloric acid (1M, 200 ml) and stirred for 15 minutes. The resultant solution was extracted into dichloromethane (4×100 ml) then the organic extracts were combined, washed with brine, dried over magnesium sulphate and evaporated to dryness. The residue (1.4 g) was crystallised from dichloromethane:ether to give 5,6-dimethoxy-1-H-indene-2-carboxaldehyde as a white solid, m.p. 125°-128° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-:3])=[O:2].[NH3:19]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:19])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: N
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccn1
Solvent: CCO
Product: Nc1ccc(C(=O)c2ccccn2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 63 g. (0.24 mol) of 2-(3-nitro-4-chlorobenzoyl)pyridine in 3 liters of a saturated solution of ammonia in ethanol was autoclaved at 100° C. for 24 hrs. The mixture was concentrated in vacuo and the resulting residue dissolved in 1.5 liters of warm 5N hydrochloric acid. The solution was cooled to room temperature and neutralized with concentrated ammonium hydroxide. The resulting yellow product was collected, washed with water and dried to yield 2-(3-nitro-4-aminobenzoyl)pyridine, mp. 186° -187° C. (acetone-water).
Reaction SMILES: N1C=CC=CC=1.[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.Cl.[CH3:18][NH:19][O:20][CH3:21]>ClCCl>[CH3:18][N:19]([C:12]([C:11]1[CH:15]=[CH:16][C:8]([I:7])=[CH:9][CH:10]=1)=[O:13])[O:20][CH3:21]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A solution of pyridine (104 g, 1.32 mol) in dichloromethane (150 ml) was added dropwise to an ice-cooled, stirred suspension of 4-iodobenzoyl chloride (251 g, 0.94 mol) and N,O-dimethylhydroxylamine hydrochloride (97 g, 0.94 mol) in dichloromethane (850 ml). The mixture was allowed to warm to room temperature and then stirred for a further 18 hours. The resulting solution was evaporated under reduced pressure, the residue dissolved in ethyl acetate (1 l) and this solution then washed sequentially with hydrochloric acid (2M, 3×400 ml) and saturated aqueous sodium bicarbonate solution (300 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by distillation under reduced pressure to give the title compound (241 g) as a yellow oil, b.p. 130° C./13.3 Pa (0.1 mm Hg). δ(CDCl3): 3.32(3H,s), 3.50(3H,s), 7.40(2H,d) 7.72(2H,d).
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].ClC(Cl)(Cl)C(=N)O[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.FC(S(O)(=O)=O)(F)F>C(Cl)Cl>[CH2:15]([O:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](O)CC(C)C
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)OCc1ccccc1
Yield: 74.7 %

Procedure:
To a stirred solution of methyl (2S)-2-hydroxy-4-methylpentanoate (0.5 g, 3.4 mmol) in anhydrous CH2Cl2 (10 mL) at R.T. under Ar was added benzyl 2,2,2-trichloroacetimidate (1.4 mL, 6.8 mmol) and trifluoromethylsulfonic acid (25 μl). After 30 min the reaction mixture was taken up in CH2Cl2 (20 mL). The organic layer was washed with sat. NaCl (2×10 mL), 1N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4). filtered and concentrated. Purification by flash chromatography on silica gel (EA:H; 1:10) afforded methyl (2S)-2-benzoxy-4-methylpentanoate as an oil (0.6 g, 73.5%): 1H NMR (CDCl3, 300 MHz) δ 0.80-0.98 (m, 6H), 1.40-1.58 (m, 1H), 1.69-1.87 (m, 2H), 3.74 (s, 3H), 3.93-4.06 (m, 1H), 4.42 (d, 1H, J=12.0 Hz), 4.68-4.80 (m, 1H), 7.14-7.32 (m, 5H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[I-].[CH3:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:22][CH2:23][CH3:24]
Reactant: COC(=O)C=Cc1ccc(F)cc1O
Reactant: CCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCOc1cc(F)ccc1C=CC(=O)OC
Yield: 100 %

Procedure:
3-(4-Fluoro-2-hydroxy-phenyl)-acrylic acid methyl ester (110.5 mg) was reacted with K2CO3 (111 mg) and propane iodide (0.1 ml) at 80° C. overnight as described above to yield title compound (134 mg, 100%)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[N+:8]([O-])[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(OCC(C)C)c[n+]([O-])c1
Product: COC(=O)c1cnc(Cl)c(OCC(C)C)c1

Procedure:
To 3-isobutoxy-5-(methoxycarbonyl)pyridine 1-oxide (7.04 g) was added phosphoryl chloride (25 mL), and the mixture was heated under reflux for 30 min. The solvent in the reaction mixture was evaporated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added at 0° C. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound (3.18 g) as a white amorphous solid. This compound was used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.[CH:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])OCC>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:13][CH2:14][CH2:15]2)[C:5]([O:10][CH3:11])=[C:6]([CH:16]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[CH:9]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1c(C=O)cc(Br)cc1C1CCC1
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(Br)cc(C2CCC2)c1OC

Procedure:
5-bromo-3-cyclobutyl-2-methoxybenzaldehyde (1.15 g) was dissolved in n-hexane (5 mL) and triethyl orthoformate (0.93 mL), and Amberlyst-15 (115 mg) was added to the solution, and then the mixture was refluxed for 3 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (1.33 g) as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1)(=[O:37])[CH3:36]
Reactant: COc1ccc2c(c1)CCN(c1ccc(N)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
A solution of 2-(4-aminophenyl)-6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.205 g, 0.46 mmol) and TEA (0.060 g, 0.6 mmol) in 1 mL of CH2Cl2 at 0° C. was treated with acetyl chloride (0.043 g, 0.55 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 (0.5 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×2 mL). The combined organic layer was dried over MgSO4 then concentrated. The crude product was purified by column chromatography to provide the title compound (0.195 g, 87% yield). ES-MS, (m/z) 493 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:15][O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c1oc1ccccc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2c1oc1ccccc12
Temperature: 40 °C
Yield: 98 %

Procedure:
4-hydroxy-dibenzofuran (5.19 g, 28.2 mmoles) is dissolved in acetone (175 mL) under nitrogen atmosphere. Solid K2CO3 (5.85 g, 42.3 mmoles) and iodomethane (7.9 mL, 126.9 mmoles) are added and the resulting mixture is vigorously stirred to reflux (40° C.) to complete conversion of the starting material (7h). The reaction mixture is evaporated to dryness, the crude is then dissolved in water and extracted with DCM; the combined organic layers are washed again with water and brine, dried over sodium sulphate and evaporated to dryness to give the desired product as a white solid (5.48 g) which is employed in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:20]([O:21][CH3:22])=[N:19][C:6]2[CH2:7][CH2:8][N:9](C(=O)C(F)(F)F)[CH2:10][CH:11]([CH3:12])[C:5]=2[CH:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].CO>O>[CH2:1]([C:3]1[C:20]([O:21][CH3:22])=[N:19][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([CH3:12])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1cc2c(nc1OC)CCNCC2C
Yield: 40.6 %

Procedure:
A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-3-vinyl-6,7,8,9-tetrahydro -5H-pyrido[2,3-d]azepine (52 mg, 166 μmol), 5% Pd/C (20 mg), and MeOH (20 ml) was stirred under H2 (1 atm) for 15 h. Filtration and concentration of the filtrate in vacuo yielded 36.0 mg (69%) of 3-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 317.3. A mixture of 3-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (36.0 mg, 114 μmol), K2CO3 (100 mg), MeOH (5 ml) and H2O (1 ml) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 10.2 mg (40%) of 3-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (MeOH-d4) δ 7.30 (s, 1H), 3.89 (s, 3H), 3.17 (m, 5H), 3.06 (m, 1H), 2.87 (m, 1H), 2.57 (m, 2H), 1.31 (d, 3H), 1.15 (t, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)([O-])=O.[NH2:16][C:17]1C=CC=CC=1>>[NH:1]1[C:4]2[C:13]3[C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9][C:8]=3[CH:7]=[CH:6][C:5]=2[N:16]=[CH:17]1
Reactant: O=C1Cc2cccc([N+](=O)[O-])c2C(=O)N1
Reactant: Nc1ccccc1
Product: O=C1Cc2ccc3nc[nH]c3c2C(=O)N1

Procedure:
The general synthesis described in Scheme 1 is similar to the one described in U.S. Pat. No. 4,176,184. Briefly, reduction of 8-nitroisoquinoline-1,3(2H,4H)-dione 1(i) (prepared according to the procedure described in DE 3410168) to the corresponding aniline 1(ii) followed by acylation with acyl chloride and cyclization of the resulting amide gave 1H-imidazol[4,5-h]isoquinoline-7,9(6H,8H)-dione 1 (iii). Alkylation of 1(iii) with 1-bromo-3-chloropropane gave 1(iv), which reacted with a primary amine to give 1(v). If necessary, the transformation of R1a and R3a to R1 and R3 by methods known to the skilled in the art (including, but not limited to, removal of protective group, alkylation, oxidation and reduction) gave the compounds of formula (I) or (Ia).