Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[C:8]([Cl:23])=[C:7]([CH3:24])[C:6]=1[C:25](=[O:27])[CH3:26].[NH:28]1[CH2:33][CH2:32][S:31][CH2:30][CH2:29]1>>[Cl:23][C:8]1[C:7]([CH3:24])=[C:6]([C:25](=[O:27])[CH3:26])[C:5]([O:4][CH2:3][CH2:2][N:28]2[CH2:33][CH2:32][S:31][CH2:30][CH2:29]2)=[C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]=1[O:21][CH3:22]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCCc1ccccc1
Reactant: C1CSCCN1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCSCC2)c1OCCCc1ccccc1
Temperature: 65 °C
Yield: 79 %

Procedure:
Example 34b (201 mg, 0.44 mmol) and thiomorpholine were reacted as described under the General Procedure B (except heated to 65° C.) and the crude was purified by flash chromatography (silica-gel, EtOAc/hexane 1:4) yielding the title compound (166 mg, 79%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.02 (m, 5H), 4.13-4.06 (m, 4H); 3.88 (s, 3H); 2.82 (dd, J=9.3, 7.5 Hz, 2H); 2.76-2.73 (m, 4H); 2.68-2.64 (m, 6H); 2.52 (s, 3H); 2.20 (s, 3H), 2.13-2.03 (m, 2H). MS (ES+) m/z 478 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[C:12](I)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([SiH](CC)CC)C.CN(C)[CH:45]=[O:46]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[C:12]([CH:45]=[O:46])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCc2ccccc2)c1=O
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1ncc2c(c(C=O)cn2COCc2ccccc2)c1=O
Yield: 40 %

Procedure:
In 500 ml of an autoclave made of stainless were charged 45.3 g (86.8 mmol) of 1-benzyloxymethyl-3-iodo-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 33-(c), 390 mg (1.74 mmol) of palladium acetate, 1.92 g (3.47 mmol) of 1,1′-bis(diphenylphosphino)ferrocene, 30.2 ml (220 mmol) of triethylamine, 27.7 ml (170 mmol) of triethylsilane and 300 ml of N,N-dimethylformamide, and the mixture was stirred at 80° C. for 8 hours under carbon monoxide atmosphere of 15 atm. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 14.2 g of the title compound as a brownish solid. (Yield: 40%)
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH:26]=O.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](=[O:40])[CH3:39])=[CH:30]1.[OH-].[K+]>C(O)C.O>[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](=[O:40])/[CH:39]=[CH:26]/[C:3]2[N:4]=[CH:5][N:6]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:2]=2[CH3:1])=[CH:30]1
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1cn(C)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(/C=C/C(=O)c2cn(C)c3ccccc23)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 133.1 %

Procedure:
A mixture of 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (2.5 g), 1-(1-methyl-1H-indol-3-yl)-1-ethanone (1.0 g) and potassium hydroxide (3.1 g) in absolute ethanol (50 ml) and water (25 ml) was stirred at room temperature for 72 h, then at 50° for 18 h. The mixture was partitioned between 2N sodium carbonate (200 ml) and ethyl acetate (2×200 ml) and the combined organic layers were washed with brine (150 ml), dried and evaporated in vacuo to leave a foam (3.9 g) which was purified by FCC eluting with ethyl acetate:hexane (1:1) to give the title compound (1.76 g) as a solid, m.p. 216°-219°.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:13]1([CH2:1][C:3]2[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1csc(C=O)n1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1csc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-formyl-1,3-thiazole-4-carboxylate (315 mg) in anhydrous DCM (25 ml) was added morpholine (0.164 ml) and the mixture stirred under nitrogen for 3 h at RT. Sodium triacetoxyborohydride (759 mg) was added and the mixture stirred at RT for 16 h. Sodium bicarbonate (50 ml) and DCM (50 ml) were added and the aqueous layer was extracted with DCM (2×25 ml) using a hydrophobic frit. The solvent was removed in vacuo, the residue was dissolved in DCM (5 ml) and purified by chromatography on silica gel eluting with a gradient of 0-100% ethyl acetate in cyclohexane over 30 min. The solvent was removed in vacuo to give a white solid. The solid was dissolved in methanol (15 ml) and loaded onto an SCX SPE cartridge (50 g), which was preconditioned with methanol and allowed to stand for 15 min. The column was washed with methanol (50 ml) and elution with 2M ammonia in ethanol gave the title compound.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45].[OH-].[Na+]>ClCCl.Cl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][N:7]([CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C:10]2[CH:25]=[CH:26][CH:27]=[CH:28][C:9]1=2)[C:44](=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(NCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (+/−) (3,5-Bis-trifluoromethyl-benzyl)-[1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-amine (149 mg, 0.27 mmol) and pyridine (0.33 ml, 4 mmol) in dichloromethane (1.5 ml) at room temperature is added acetic anhydride (0.38 ml, 4.1 mmol) via dropwise addition over 2 minutes. The mixture is stirred at room temperature for 20 hours. The mixture is treated with 1N aqueous NaOH (4 ml) and stirred for 10 minutes, then diluted with 1N HCl (15 ml) and dichloromethane (15 ml). The organic layer is washed with water, dried (Na2SO4), and concentrated to a solid. Purification by silica gel column chromatography (eluent, 35% ethyl acetate in hexanes) gives the title compound as a solid. Mass spectrum (ES+): 585 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+]>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][CH:10]=[CH:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc3c(c2)CCN3)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cn(-c2ccc3[nH]ccc3c2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
5-(1H-Imidazol-1-yl)indoline (3.0 g) was dissolved in DMF (30 ml), and sodium hydride (1.3 g) was added thereto. The mixture was stirred at room temperature for 24 hours. After extraction with ethyl acetate, the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 1.6 g of the title compound 5-(1H-imidazol-1-yl)-1H-indole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([O:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17]2)(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(tert-butoxycarbonylamino)-5-hydroxyindan (100 mg, 0.40 mmol) synthesized in Reference Production Example 1 was dissolved in dry methylene chloride (2 ml), to which pyridine (0.19 ml, 2.3 mmol) and acetic anhydride (0.11 ml, 1.2 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture then was concentrated under reduced pressure, to which diethylether was added. The organic layer was washed with, in the order of, an aqueous solution of saturated potassium hydrogen sulfate, brine, an aqueous solution of saturated sodium hydrogen carbonate, and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5-acetoxy-2-(tert-butoxycarbonylamino)indan (120 mg, 0.40 mmol) having the following physical properties:
Reaction SMILES: [CH:1]([N:3]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N+:15]([O-:17])=[O:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])[CH3:4])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O.C(OCC)(=O)C>[CH3:18][O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([CH2:5][N:3]([CH:1]=[O:2])[CH3:4])[CH:7]=[CH:8][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CN(C=O)Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(CN(C)C=O)ccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 124.2 %

Procedure:
There was dissolved, in 6.8 mL of N,N-dimethylformamide, 3.40 g of 5-(N-formyl-N-methylamino-methyl)-2-nitrobenzoic acid, thereafter 3.94 g of potassium carbonate and 1.77 mL of methyl iodide were added to the solution and then the solution was stirred at a temperature ranging from 20 to 30° C. for 4 hours. After the confirmation of the disappearance of the starting material by HPLC, 20.5 mL of water and 34 mL of ethyl acetate were added to the reaction solution. The organic phase was separated from the aqueous phase, followed by the concentration thereof to give 4.47 g of the intended compound as a crude product (oily state).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.S1C2C(=[N:16]C=CC=2)C=C1CN>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][NH2:16]
Reactant: BrCc1nc2cccnc2s1
Reactant: NCc1cc2ncccc2s1
Product: NCc1nc2cccnc2s1

Procedure:
Intermediate S was prepared from 2-(bromomethyl)thiazolo[5,4-b]pyridine (S-4) following similar procedured for synthesizing intermediate C from C-5, as described above. MS (m/z): 166 (M+1)+.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=O)C.CO.O>C1(C)C=CC=CC=1>[CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:13]
Reactant: CCOC(=O)CCCCCn1ccnc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=CCCCCCn1ccnc1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Under an atmosphere of nitrogen, 8.8 ml of a 25%(W/V) solution of diisobutylaluminium hydride in toluene was added dropwise to a solution of 2.50 g of 1-(5-ethoxycarbonylpentyl)imidazole in 120 ml of toluene at -70° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added one ml of methanol at -70° C., and one ml of water at 0° C., then the mixture was stirred at 30° C. for one hour. The reaction mixture was filtered, the filtrate was dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (25:1) as eluent to give 1.15 g of the title compound having the following physical characteristics:
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=2)=[CH:9][C:8]=1[CH3:34])C.[OH-].[Na+].Cl>C(O)C>[CH2:30]([O:29][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:35])=[O:3])=[C:8]([CH3:34])[CH:9]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CCOC(=O)COc1ccc(Oc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Oc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid ethyl ester (260 mg; 0.56 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 180 mg; 72%. HPLC-MS: m/z: 454.6 (M+H)+; Rt: 1.77 min. δH(400 MHz; CDCl3) 1.01 (d, 6H), 2.02-2.10 (m, 1H), 2.28 (s, 3H), 3.10-3.55 (m, 4H), 3.68 (d, 2H), 3.93-4.07 (m, 4H), 4.10 (s, 2H), 4.67 (s, 2H), 6.47 (m, 1H), 6.57-6.59 (m, 1H), 6.66-6.69 (m, 1H), 6.71 (d, 1H), 6.79 (dd, 1H), 6.86 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:23][C:22]#[CH:21])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: Cc1cc(Cl)c(N2C(=O)C3=CCCCN3C2=O)cc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1C
Yield: 65.4 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2-chloro-4-methyl-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, 1.11 mmol), propargylbromide (0.11 mL, 1.22 mmol) and potassium carbonate (0.15 g, 1.11 mmol) was stirred for 30 minutes under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/4-1/2) to obtain a white solid of 2-(2-chloro-4-methyl-5-propargyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.24 g, yield:63.2%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:20]1([C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3ccccc32)nc(N2CCOCC2)cc1=O
Temperature: 80 °C
Yield: 20.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 174 mg of 2,3-dihydro-1 H-indole, and 185 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 3 ml of N,N-dimethylformamide. After silica column purification, eluent: 93/07 CH2Cl2/MeOH, the solid is taken up with 4 ml of methanol and a few drops of acetone. The suspension is heated at a temperature of 80° C., filtered while hot, and then recrystallized at a temperature of 20° C. and then of 0° C. The solid is filtered off, rinsed with diethyl ether, and then dried under a vacuum bell jar. 52 mg of 2-[2-(2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of white crystals, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1.S(Cl)(Cl)=O.[CH:32]1([CH2:35]O)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:35][CH:32]2[CH2:34][CH2:33]2)=[O:26])=[CH:23][CH:24]=1
Reactant: OCC1CC1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(C(=O)OCC2CC2)cc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
2.0 g of (+/−)-cis-8,9-dimethoxy-6-(4-carboxyphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine are suspended in 12.0 ml of cyclopropylmethanol, admixed with 1.0 ml of thionyl chloride and stirred at 50° C. for 4 days. The solution is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and dilute sodium bicarbonate solution. The organic phase is dried with sodium sulfate and concentrated. The residue is recrystallized from ethyl acetate. This gives 1.33 g (63.7% of Th.) of the title compound of m.p.: 147-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[N:18]2[N:19]=[C:20]([C:22]3([CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[CH:39]=[CH:38][C:25]4[CH2:26][CH2:27][N:28](CCS(=O)(=O)NC)[CH2:29][CH2:30][C:24]=4[CH2:23]3)[N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1.ClCC(N(C)C)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:12])[F:10])=[CH:5][C:4]=1[C:13]1[N:18]2[N:19]=[C:20]([C:22]3([CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[CH:39]=[CH:38][C:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=4[CH2:23]3)[N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1
Reactant: CNS(=O)(=O)CCN1CCC2=C(CC1)CC(CC(=O)N(C)C)(c1nc3cccc(-c4cc(C(F)(F)F)ccc4OC)n3n1)C=C2
Agent: CN(C)C(=O)CCl
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(C3(CC(=O)N(C)C)C=CC4=C(CCNCC4)C3)nn12
Yield: 29 %

Procedure:
2-(7-[5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(2-methylsulfamyl-ethy)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-N,N-dimethyl-acetamide was prepared from [5-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepin-7-yl)-amine (0.118 g, 0.26 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.047 g, 0.387 mmol) in a manner analogous to Example 235. Product was isolated as a foam (0.041 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.91 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.57-7.52 (m, 2H), 7.39 (s, 1H), 7.33-7.29 (m, 1H), 7. 21 (d, J=8.8 Hz, 1H), 7.06-6.98 (m, 2H), 6.91 (s, 1H), 4.67-4.56 (m, 4H), 3.89 (s, 3H), 3.21 (s, 2H), 3.17-3.09 (m, 4H), 2.99 (s, 6H). MS=539 (MH)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[O:23][C:24]3[CH:25]=[CH:26][C:27]4[C:31]([C:32](O)=[O:33])=[C:30]([CH3:35])[S:29][C:28]=4[CH:36]=3)[CH:15]=2)=[O:13])[CH2:8]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClC(Cl)C.C(Cl)Cl>[CH:37]1([NH:40][C:32]([C:31]2[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:20]4[CH:19]=[CH:18][N:17]=[C:16]5[CH:15]=[C:14]([C:12]([N:9]6[CH2:10][CH2:11][C@@H:7]([O:6][CH3:5])[CH2:8]6)=[O:13])[S:22][C:21]=45)=[CH:36][C:28]=3[S:29][C:30]=2[CH3:35])=[O:33])[CH2:39][CH2:38]1
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Reactant: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NC6CC6)c(C)sc5c4)c3s2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
Thionyl chloride (31 μl, 0.427 mmole) was added to a suspension of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 11c (40 mg, 0.085 mmole) in dichloroethane (1 ml). The reaction mixture was heated to reflux for 90 minutes, cooled to room temperature, and concentrated in vacuo. The yellow residue was dissolved in CH2Cl2 (1 ml) and cyclopropylamine (30 μl, 0.427 mmole) was added. The resulting mixture was stirred at ambient temperature for 16 hours, diluted with CH2Cl2 (10 ml), and washed with H2O (5 ml). The aqueous layer was extracted with CH2Cl2 (2×5 ml) and the combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (5% MeOH/EtOAc) to afford 20 mg (46%) of a pale yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.3 Hz), 8.46 (1H, d, J=4.5 Hz), 8.06 (1H, s) 7.96 (1H, d, J=2.3 Hz), 7.81 (1H, J=8.7 Hz), 7.32 (1H, dd, J=2.3, 8.7 Hz), 6.75 (1H, d, J=5.3 Hz), 4.10-3.82 (4H, m), 3.61 (2H, m), 3.27, 3.24 (3H, s), 2.91 (1H, m), 2.72 (1H, m), 2.57 (3H, s), 0.76-0.70 (2H, m), 0.50-0.55 (2H, m). Anal. Calcd. for C26H25N3O4S2: C, 61.52; H, 4.96; N, 8.28; S, 12.63. Found: C, 59.30; H, 4.78; N, 7.95; S, 12.23.
Reaction SMILES: O[C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OCC)(=O)C>CN(C)C=O>[N+:17]([C:14]1[CH:15]=[CH:16][C:8]2[C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[O:11][C:10](=[O:12])[C:9]=2[CH:13]=1)([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-c1cccnc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=c1oc2ncccc2c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2-(2-Hydroxypyridin-3-yl)-5-nitrobenzoic acid (Reference Compound No. 1-3-(3), 50 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (5 mL), then N,N-diisopropylethylamine (141 μL, 0.81 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (154 mg, 0.41 mmol) were added thereto, and then the reaction mixture was stirred at room temperature overnight. Ethyl acetate (30 mL) was added to the reaction mixture, the whole was washed with water (30 mL) and saturated brine (30 mL) successively. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Chloroform was added to the obtained residue, and then filtered to give the titled reference compound (35 mg) as a pale yellow solid. (Yield 71%)