Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:3][N:1]=[C:4]3[CH:5]=[CH:6][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:8][C:9]=23)=[CH:25][CH:24]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Product: Cc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, light green solid (107 mg, 78%), MS (ISP) m/z=386.2 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[C:21]4[CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=5)[C:18](=[O:31])[NH:17][C:16]=4[N:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[N:4]([CH3:32])[N:3]=1)=[O:38]
Reactant: COc1ccc(CN2Cc3c(Oc4ccc5c(N)nn(C)c5c4)ccnc3NC2=O)cc1
Reactant: O=C(O)c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN2Cc3c(Oc4ccc5c(NC(=O)c6cccc(F)c6)nn(C)c5c4)ccnc3NC2=O)cc1
Temperature: 100 °C
Yield: 13.4 %

Procedure:
A solution of 5-[(3-amino-1-methyl-1H-indazol-6-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.23 mmol; 1.00 eq.),3-fluorobenzoic acid (35.80 mg; 0.26 mmol; 1.10 eq.), pybop (157.16 mg; 0.30 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (115.48 μl; 0.70 mmol; 3.00 eq.) was stirred at room temperature for 22 hr. Additional pybop was added and the reaction was heated to 100 degrees C. but the reaction did not go to completion. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 17 mg (26%) of 3-fluoro-N-(6-{[3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]oxy}-1-methyl-1H-indazol-3-yl)benzamide as a yellow solid. LC-MS (M+H=553, obsd.=553).
Reaction SMILES: N[C@@H:2]([C@H:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7])[C:3]([OH:5])=[O:4].N([O-])=[O:17].[Na+].[OH-].[Na+].C(OCC)(=O)C>S(=O)(=O)(O)O.O>[CH2:9]([O:8][C@H:6]([CH3:7])[C@H:2]([OH:17])[C:3]([OH:5])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H](O)C(=O)O
Temperature: -5 °C
Reaction time: 6 h

Procedure:
To a solution of (2S,3R)-2-amino-3-benzyloxy-butyric acid (1.1 g) in 2M sulfuric acid (6.31 mL) was added dropwise over 2 h a solution of sodium nitrite (0.65 g) in water (6 mL), keeping the internal temperature of the reaction below 0° C. The reaction mixture was stirred at −5° C. for 6 h then allowed to warm to room temperature overnight. The mixture was adjusted to pH 4 with 50% aqueous sodium hydroxide then ethyl acetate was added. The mixture was stirred vigorously and acidified to pH 2 with concentrated sulfuric acid. The layers were separated and the aqueous layer extracted with further ethyl acetate (×2). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated to give the subtitle compound as a yellow crystalline solid which was used without further purification. Yield: 0.84 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=1.CC(O)C.C(Cl)[Cl:23]>CO>[ClH:23].[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1
Reactant: COc1ncc(-c2ccncc2F)c(OC)n1
Reactant: ClCCl
Solvent: CC(C)O
Solvent: CO
Product: Cl
Product: O=c1[nH]cc(-c2ccncc2F)c(=O)[nH]1
Yield: 85 %

Procedure:
To a solution of 5-(3-Fluoro-pyridin-4-yl)-2,4-dimethoxy-pyrimidine (Prep 66, 725 mg, 3.1 mmol) in MeOH (50 ml) 2N HClaq (20 ml) was added. After refluxing the mixture for 1 hour, the solvents were evaporated and the crude was tritured with hexane then with iPrOH and finally with DCM to give 550 mg of the title compound (85% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[NH:15][CH2:14][CH:13]2[C:23]([O-:25])=[O:24])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:26](N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:36]=1[C:37]([N:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH2:18][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:14]1)=[O:38]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: CCN(CC)CC
Reactant: COc1ccc(S(=O)(=O)N2Cc3ccccc3NCC2C(=O)[O-])cc1
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2ccc(OC)cc2OC)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a cooled (0° C.) solution of 1.0 g (2.66 mmol) of 4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml (13.3 mmol) of triethylamine in 8 ml of CH2Cl2 was added 1.17 g, (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 and washed with 2N citric acid. The organic layer was washed with H2O, 1N Na2CO3, brine and dried over Na2SO4. The solvent was removed and the residue was chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as an eluent to give 1.0 g of methyl 1-(2,4-dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white foam. Anal. for C27H28H2O8S: Calc'd: C,60.0; H,5.2; N,5.2; Found: C,60.0; H,5.2; N,5.1; Mass Spectrum (ES): 541.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[O-]S(C(F)(F)[F:22])(=O)=O.F[N+]1C=CC=CC=1>C(Cl)Cl>[F:22][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:15]#[N:16])[C:8]=2[C:11]([F:12])([F:14])[F:13])[NH:3][C:2]=1[CH3:1]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: F[n+]1ccccc1
Solvent: ClCCl
Product: Cc1[nH]c2ccc(C#N)c(C(F)(F)F)c2c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.1 %

Procedure:
To a solution of 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.063 g, 0.28 mmol) in CH2Cl2 (4 mL) was added 1-fluoropyridinium triflate (0.104 g, 0.42 mmol) and stirred at rt for 3 days. The mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with 0.1N HCl and sat'd brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography (10-50% EtOAc-hexanes gradient) to afford the title compound as a white solid (0.015 g, 22% yield, 94% purity): MS (ES) m/z 243 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[CH2:22]([O:21][C:12]1[CH:13]=[C:14]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[CH:3]=3)[O:8][C:9]2=[CH:10][CH:11]=1)[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)cnc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)cnc1O2
Temperature: 110 °C

Procedure:
Combined (R)-3-bromo-7-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (9.15 g, 21.88 mmol), tetrakis(triphenylphosphine)palladium (2.53 g, 2.188 mmol) and 3-pyridylboronic acid (6.72 g, 54.7 mmol). Added THF (146 mL, 21.88 mmol) followed by potassium carbonate (1.5 M) (58.3 mL, 88 mmol). Flushed reaction tube with argon, sealed and heated at 110° C. for 2.5 hours. The reaction was allowed to cool to room temperature before being poured into a separatory funnel containing ethyl acetate (500 mL). Water (1000 mL) was added and, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown foam. This foam was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (330 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (R)-7-(neopentyloxy)-3-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a light yellow solid.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][N:9]([CH2:11][CH2:12][CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[CH2:15]1)[CH3:10].[Cl:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>O>[ClH:25].[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([CH2:26][O:24][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([CH2:13][CH2:12][CH2:11][N:9]([CH3:10])[CH3:8])[CH2:23][CH2:22]3)=[CH:32][CH:31]=1
Reactant: CN(C)CCCC1CCc2cc(O)ccc2C1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCC1CCc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Oily sodium hydride (0.258 g) was added to a DMF solution (20 ml) of 2-[3-(N,N-dimethylamino)propyl]-6-hydroxytetralin (1.00 g) at 0° C. The reaction mixture was warmed to room temperature, and stirred for 30 minutes. This was again cooled to 0° C., and 4-(chloromethyl)biphenyl (1.04 g) as added thereto, and then stirred at room temperature for 4 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated. The residue was purified by alumina column chromatography (eluent: toluene alone to toluene/ethyl acetate=1/1), and then processed with 4 N hydrochloric acid-ethyl acetate to form a hydrochloride. The thus-formed salt was recrystallized from methanol-diisopropyl ether to obtain the entitled compound (1.30 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10]>C(Cl)Cl.O.[Ti](Cl)(Cl)(Cl)Cl>[Cl:6][C:7]1[C:8]([C:9]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:12][CH:13]=[C:14]([Cl:16])[N:15]=1.[Cl:6][C:7]1[C:8]([C:9]([C:3]2[CH:4]=[CH:5][NH:1][CH:2]=2)=[O:10])=[CH:12][CH:13]=[C:14]([Cl:16])[N:15]=1
Reactant: c1cc[nH]c1
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc[nH]c1)c1ccc(Cl)nc1Cl
Product: O=C(c1ccc[nH]1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Titanium (IV) chloride in DCM (10 mL) was added dropwise to a mixture of pyrrole (4 g) and 2,6-dichloro-nicotinoyl chloride (6 g) in DCM (150 mL) at 0° C. The mixture was then stirred at room temperature for 30 mins. The reaction was diluted with water, washed with water (200 mL), 2N NaOH (50 mL) and brine, dried and concentrated. The residue was purified on a silica gel column to give 1.8 g of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-2-yl)-methanone and 380 mg of (2,6-dichloro-pyridin-3-yl)-(1H-pyrrol-3-yl)-methanone.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:32][C:33]([O:35][CH2:36][CH:37]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:43]3[C:38]2=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:34])[C:29](O)=[O:30])=[CH:23][CH:22]=1)(=[O:20])[NH2:19].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH:48]1[C:49]2[CH:37]([CH2:36][O:35][C:33](=[O:34])[NH:32][CH:28]([CH2:27][C:24]3[CH:23]=[CH:22][C:21]([C:18](=[O:20])[NH2:19])=[CH:26][CH:25]=3)[C:29](=[O:30])[N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]3[C:9]3[NH:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: NC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 138 mg (0.5 mmol) of 2-(4-Phenyl-1H-imidazol-2-yl)-piperidine, 215 mg (0.5 mmol) of 3-(4-Carbamoyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid, 135 mg (1.0 mmol) of hydroxybenzotriazole hydrate, 115 mg (0.6 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added 2 mL of dimethylformamide. The resulting mixture was allowed to stir at room temperature under argon overnight. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4 and concentrated to a yellow oil which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([Br:32])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Yield: 69.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (93 mg, 0.22 mmol) and N-bromosuccinimide (44 mg, 0.25 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH) to give 76 mg of the title compound as a yellow solid. MS: (+) m/z 495.21, 497.10 (M+1, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[C:18]2[CH2:26][CH2:25][CH2:24][CH2:23][C:19]=2[S:20][C:21]=1[NH2:22])=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[C:18]2[CH2:26][CH2:25][CH2:24][CH2:23][C:19]=2[S:20][C:21]=1[NH:22][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:11])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: CCOC(=O)c1c(NC(=O)c2cc(Cl)ccc2O)sc2c1CCCC2
Yield: 49.6 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>C1(C)C=CC=CC=1>[CH3:36][O:37][CH2:38][CH2:39][NH:40][C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Reactant: COCCN
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COCCNC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
A suspension of 0.15 mg (0.35 mmol) of 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid in 4 ml of toluene was heated at 50° C. for 4 hours with 0.15 ml (2.1 mmol) of thionyl chloride. After removal of all volatile constituents by distillation the residue was suspended in 5 ml of dioxan, treated with 0.06 g (0.76 mmol) of 2-methoxy-ethylamine and stirred at room temperature for 4 hours. After concentration the residue was taken up in dichloromethane, extracted with water and dried with sodium sulphate. Concentration and washing of the residue with ether gave 0.14 g (74%) of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-amide as a yellow solid.
Reaction SMILES: [C:1]1([Mg]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C@@:14]12[C:22](=[O:23])[CH2:21][C@@H:17]([C:18]1([CH3:20])[CH3:19])[CH2:16][CH2:15]2>C1COCC1>[C:1]1([C:22]2([OH:23])[CH2:21][CH:17]3[C:18]([CH3:19])([CH3:20])[C@:14]2([CH3:13])[CH2:15][CH2:16]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1cccc2ccccc12
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2
Solvent: C1CCOC1
Product: CC1(C)C2CC[C@]1(C)C(O)(c1cccc3ccccc13)C2

Procedure:
The resulting THF solution of 1-naphthylmagnesium bromide was cooled to room temperature. Then, a THF (200 ml) solution of (-)-camphor (50 g, 0.328 mol) was added thereto, and the whole was heated under reflux for 72 hours. The reaction was terminated by cooling with ice-water and adding saturated ammonium chloride aq solution. Then, the organic layer was filtered off, and the solid residue was treated with 10% hydrochloric acid and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate and, after filtration, concentrated to give 121 g of a crude (1S)-2-(1-naphthyl)-1,7,7-trimethylbicyclo [2.2.1]-heptan-2-ol as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)#[N:2].[C:17]([NH:22][N:23]=[C:24](OCC)[CH2:25][CH2:26][CH2:27][CH3:28])(OCC)=[O:18]>C(O)C>[CH2:25]([C:24]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:14][CH:13]=2)[C:17](=[O:18])[NH:22][N:23]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCC(=NNC(=O)OCC)OCC
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Solvent: CCO
Product: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 400 mg (1.923 mmole) of [(2'-cyanobiphenyl-4-yl)methyl]amine, 457 mg (2.12 mmole) of ethyl valerimidate carbethoxyhydrazone (from Example 2, Step A), and 7 mL of ethanol was stirred under N2 in an oil bath at 50° C. for 3 hours and then at 80° C. for 2 days. The mixture was cooled and concentrated. The residue, re-concentrated from toluene, was flash chromatographed over silica gel (gradient elution with 1.5-5% methanol in CH2Cl2) to give the desired product, homogeneous in TLC (90:10 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 333 (M+1)+.
Reaction SMILES: CN1CCCCC1.[CH:8]1([O:14][C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC(C)C)=O.[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]([NH2:43])[CH3:42])=[CH:37][CH:36]=1)#[N:34]>C(Cl)Cl.O>[C:33]([C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][CH:41]([NH:43][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:16])[CH3:42])=[CH:37][CH:36]=1)#[N:34]
Reactant: CC(N)COc1ccc(C#N)cc1
Reactant: CC(C)[C@H](NC(=O)OC1CCCCC1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=O)OC1CCCCC1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
0.8 g of N-methylpiperidine was added to a solution containing 2.0 g of N-cyclohexyloxycarbonyl-L-valine dissolved in 150 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 1.1 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 1.5 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.5 g of the desired product in the form of light brown powder (yield: 16%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.C([Li])(C)(C)C.[O:20]=[C:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22]1>C1COCC1.CCCCC>[C:10]([O:9][C:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:21]1([OH:20])[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnccc1C1(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
To a flame-dried round bottomed flask with thermometer side-arm, equipped with a stir bar, was added tert-butyl pyridin-3-ylcarbamate (1.104 g, 0.005684 mol) in 75 mL THF under inert atmosphere. The solution was cooled to −78° C. and then 1.7 M of tert-butyllithium in pentane (7.4 mL) was added dropwise. The resulting solution was stirred for 2 h at −78° C., followed by the addition of benzyl 3-oxopyrrolidine-1-carboxylate (1.038 g, 0.004736 mol) in 75 mL THF. The reaction was allowed to warm to rt and stirred for 5 hrs. The reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined organic phases were treated with brine and then magnesium sulfate, filtered, and concentrated. The crude product was purified by combiflash using 50-80% ethyl acetate/hexane to recover the starting material (0.9 g) and then 100% ethyl acetate to obtain the product (0.5 g). The product was verified by LCMS and NMR data.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN(C)C(=O)CCl
Product: COc1ccccc1N1CCN(C(=O)c2cn(CC(=O)N(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.