Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:9])[CH3:18]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-methylacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]2)=[CH:16][C:15]=1[O:30][CH3:31].IC>C1COCC1.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23]([CH3:1])([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]2)=[CH:16][C:15]=1[O:30][CH3:31]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(c2ccc(Cl)c(OC)c2)CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A 50-mL 2-neck round bottom flask was fitted with a nitrogen inlet and rubber septum and charged with N,N-diisopropylamine (0.598 mL, 4.26 mmol) in anhydrous THF (15 mL). The solution was cooled to −70° C., treated with n-butyllithium (3.05 mL, 4.26 mmol) and stirred for 30 min. A solution of methyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate (1.10 g, 3.88 mmol) in THF (3 mL) was added dropwise to the reaction and the resulting mixture was stirred at −70° C. for 1 h. After this time, the mixture was treated with iodomethane (0.253 mL, 4.07 mmol) and slowly warmed to RT. TLC and LC-MS (m/z=298.21) indicated the reaction was complete. The mixture was treated with water (25 mL) and extracted with EtOAc (3×30 mL). The extract was dried (Na2SO4) and concentrated on a rotary evaporator to give methyl 1-(4-chloro-3-methoxyphenyl)-4-methylpiperidine-4-carboxylate (1.06 g, 3.56 mmol, 92% yield) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.17 (1 H, d, J=8.56 Hz), 6.48 (1 H, s), 6.44 (1 H, dd, J=8.69, 2.14 Hz), 3.86 (3 H, s), 3.70 (3 H, s), 3.38 (2 H, ddd, J=12.72, 4.03, 3.90 Hz), 2.82-2.91 (2 H, m), 2.19-2.26 (2 H, m), 1.52-1.64 (2 H, m), 1.24 (3 H, s).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][NH:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[C:20]([O:24][C:25](=[O:38])[NH:26][C:27]([CH3:37])([CH3:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)C1C=CC=CC=1)C>ClCCl>[C:20]([O:24][C:25](=[O:38])[NH:26][C:27]([CH3:37])([CH3:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:2]2[C:7]([CH2:8][NH:9][C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=2)[CH:30]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Cl)n1
Reactant: CC(C)(Cc1cccc(N)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)c1ccccc1
Product: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2cccc(CC(C)(C)NC(=O)OC(C)(C)C)c2)n1
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
A solution of 520 mg (1.6 mmol) of 4-chloro-5-(2,6-dichloroanilinomethyl)-2-methylthiopyrimidine, 420 mg (1.6 mmol) of (2-(3-aminophenyl)-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester and 250 mg (1.7 mmol) of N,N-diethylaniline in 5 ml of dichloromethane was heated at 80° C. until the solvent had evaporated and then to 120° C. for 30 minutes and then cooled. The product was purified by flash chromatography on silica gel eluting with diethyl ether/isohexane in a ratio 1:1 to give 350 mg (39%) of (2-(3-[5-[(2,6-dichlorophenylamino)-methyl]-2-methylthiopyrimidin-4-yl-amino]-phenyl)-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester as a white solid. [Mass spectrum (ESI) MH+ =562].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2([C:13]#N)CCC2)[CH:5]=[CH:6][C:7]=1Cl.C([Mg]Cl)C1C=CC=CC=1.C(Cl)C1C=CC=CC=1.[Mg].[CH3:33][CH2:34][O:35]CC>C1(C)C=CC=CC=1>[CH:34](=[O:35])[CH3:33].[C:4]1([CH2:9][CH:13]=[O:35])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl[Mg]Cc1ccccc1
Agent: [Mg]
Solvent: ClCc1ccccc1
Solvent: Cc1ccccc1
Product: CC=O
Product: O=CCc1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (6.56 g) in toluene (100 ml) was added dropwise under nitrogen to a stirred solution of benzylmagnesium chloride [prepared in the usual manner from benzyl chloride (5 ml) and magnesium (1.08 g)] in ether (100 ml). When the addition was complete, ether was distilled from the mixture until the internal temperature rose to 95° C., then the mixture was stirred at this temperature for 19 h, cooled to ambient temperature, and quenched by the dropwise addition of water (30 ml) followed by concentrated hydrochloric acid (10 ml). The mixture was stirred at 95° C. for 2.5 hours, then it was cooled to ambient temperature. The organic phase was separated, washed with water (2×100 ml) and saturated brine (100 ml), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified via flash chromatography over silica using a 5:95 mixture of ethyl acetate and toluene as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenyl)ethanone]-2-phenylethanone as a colourless oil (5.08 g) which solidified slowly at ambient temperature to give a colourless solid, m.p. 53-55° C.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][CH2:13][CH2:14][OH:15])[CH:9]=[C:8]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O.C(N(CC)C(C)C)(C)C>C(#N)C>[OH:15][CH2:14][CH2:13][N:12]1[C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=2[C:9]2[C:8]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[N:7][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:11][C:10]1=2
Reactant: OCCNc1cc(N2CCCC2)nc(N2CCCC2)n1
Reactant: O=C1CCCCC1Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OCCn1c2c(c3c(N4CCCC4)nc(N4CCCC4)nc31)CCCC2

Procedure:
A mixture of 2-[(2,6-di-(1-pyrrolidinyl)pyrimidin-4-yl)amino]ethanol (VI, Example1, 5.55 g), 2-bromocyclohexanone (3.54 g), N,N-diisopropylethylamine (2.65 g) and acetonitrile (60 mL) is heated at reflux for 44 hr. The reaction mixture is cooled to 20°-25° and concentrated under reduced pressure. The residue is partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered, and concentrated. Chromatography (silica gel, 2.5% acetone/chloroform) gives the title compound, NMR (CDCl3) 7.64, 4.05, 3.91, 3.67, 3.55, 2.72, 2.56, 2.0-1.7 δ; MS (m/z) calc'd=355.2372, found=355.2368.
Reaction SMILES: [S:1]([CH2:5][CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([OH:4])(=[O:3])=[O:2].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[C:20](#N)[CH3:21].[CH:23](O)([CH3:25])[CH3:24]>>[S:1]([CH2:5][CH2:6][N:7]1[C:11]([SH:12])=[N:10][N:9]=[N:8]1)([OH:4])(=[O:3])=[O:2].[CH:13]1([NH:19][CH:21]2[CH2:20][CH2:5][CH2:25][CH2:23][CH2:24]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC#N
Reactant: CC(C)O
Reactant: NC1CCCCC1
Agent: O=S(=O)(O)CCn1nnnc1S
Product: C1CCC(NC2CCCCC2)CC1

Procedure:
A mixture of 21.5 g. (0.087 mol.) of methyl 2-sulfoethyldithiocarbamate potassium salt (0.5 hydrate) and 7.16 g. (0.11 mol.) of sodium azide in 200 ml. of water was refluxed for two hours. The solution was cooled to 25° and extracted with ethyl acetate. The aqueous phase was treated with Amberlite IR-120H resin, washed with ether and evaporated to give an oil. The oil was dissolved in acetone, the solution as filtered and the filtrate was evaporated to dryness to give 1-(2-sulfoethyl)-tetrazole-5-thiol. The thiol was dissolved in isopropanol, cyclohexylamine was added until pH 8-9 and acetonitrile was added to give 1-(2-sulfoethyl)tetrazole-5-thiol as the di-cyclohexylamine salt.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([S:17](Cl)(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16]>C(Cl)Cl>[CH2:13]([S:17]([NH:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16]
Reactant: COCCN
Reactant: CCCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NCCOC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.4 ml of 2-methoxyethylamine (5.5 g, 73.7 mmol) and 10.2 ml of triethylamine (7.4 g, 73.7 mmol) were dissolved at room temperature in 72 ml of methylene chloride. Likewise at room temperature 9.6 ml of n-butanesulfonyl chloride (11.5 g, 73.7 mmol) were added dropwise to this solution over the course of one hour. After 1 h of stirring at room temperature the reaction mixture was washed twice with 100 ml of water. The organic phase was dried over magnesium sulphate, the methylene chloride was distilled off and the oily residue which remained was dried in vacuo. This gave 12.4 g of the target compound, whose constitution was verified by NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[C:7]3[CH2:15][CH:14](O)[CH:13]=[C:12]([S:17][CH3:18])[C:8]=3[CH:9]=[CH:10][S:11][C:5]=2[CH:4]=1.[Cl-:21].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:21][CH:15]1[C:14]2[CH:13]=[C:12]([S:17][CH3:18])[CH:8]=[CH:9][C:10]=2[S:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=2[CH2:7]1
Reactant: [Cl-]
Reactant: COc1ccc2c(c1)SC=CC1=C2CC(O)C=C1SC
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(Cl)C2
Reaction time: 3 h

Procedure:
15.7 G. of 10,11-dihydro-3-methoxy-8-(methylthio)-dibenzo thiepin-10-ol, 250 ml. of benzene and 6 g. of finely pulverized calcium chloride are saturated with hydrochloric acid gas over a period of 21/2 hours at 15° and subsequently stirred for an additional 3 hours. After the addition of 0.8 g. of activated charcoal, the mixture is filtered and washed with benzene. The benzene phase is evaporated under reduced pressure, whereby there is obtained 10-chloro-10,11-dihydro-3-methoxy-8-(methylthio)-dibenzo [b,f]thiepin, having a melting point of 120°-123°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]([CH2:23][C:24]3[CH:36]=[CH:35][C:34]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][C:26]=4[CH:25]=3)[C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:60][O:61][C:62](=[O:66])[CH2:63][CH2:64][NH2:65].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:60][O:61][C:62](=[O:66])[CH2:63][CH2:64][NH:65][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([N:13]([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH2:23][C:24]2[CH:36]=[CH:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][C:26]=3[CH:25]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(N(Cc2ccc3c(c2)Cc2ccccc2-3)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(N(Cc2ccc3c(c2)Cc2ccccc2-3)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
4-[[4-(4-Chlorophenyl)thiazol-2-yl]-(9H-fluoren-2-ylmethyl)amino]benzoic acid (300 mg; 0.59 mmol) was suspended in a mixture of DCM (4 mL) and DMF (4 mL). HOBt (88 mg; 0.64 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (128 mg; 0.64 mmol) were added. The mixture was stirred for 1 hour to give a clear solution. Then, β-alanine methyl ester hydrochloride (67 mg, 0.64 mmol) and DIPEA (350 μL) were added. The mixture was stirred at room temperature for 16 hours, then diluted with DCM (20 mL) and washed twice with water and once with brine. The organic phase was dried with anhydrous sodium sulphate and concentrated in vacuo to afford 310 mg (88%) of 3-{4-[[4-(4-chlorophenyl)thiazol-2-yl]-(9H-fluoren-2-ylmethyl)amino]benzoylamino}propionic acid methyl ester as a foam.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].N1C2[C:25](=[CH:26]C=CC=2)[C:24]2(CO[C:32]3C=C4C(=C[C:31]2=3)CCO4)C1=O.BrCCCCC.ClCC1C=NC(OC)=NC=1>>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21])[CH2:25][CH2:24][CH2:31][CH3:32]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Solvent: CCCCCBr
Product: CCCCCN1C(=O)[C@]2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-bromopentane to replace 5-(chloromethyl)-2-methoxypyrimidine, (3R)-1′-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp 128-129° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.33-7.26 (m, 1H), 7.17 (d, J=7.1 Hz, 1H), 7.07-7.02 (m, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.41 (s, 1H), 4.92 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 8.64 (t, J=4.5 Hz, 2H), 3.87-3.63 (m, 2H), 2.99 (t, J=4.5 Hz, 2H), 1.79-1.69 (m, 2H), 1.40-1.35 (m, 4H), 0.94-0.89 (m, 3H); 13C NMR (75 MHz, CDCl3) δ177.5, 161.6, 161.2, 142.4, 133.0, 128.6, 123.8, 123.0, 120.3, 119.7, 118.7, 108.4, 93.1, 80.5, 72.3, 57.6, 40.3, 29.0, 27.1, 22.3, 13.9; MS (ES+) m/z 349.9 (M+1).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][Cl:29].P(=O)(O)(O)O>C1(C)C=CC=CC=1>[Cl-:29].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][P+:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=1)([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Reactant: COc1cccc(CCl)c1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: COc1cccc(C[P+](c2ccc(C)cc2)(c2ccc(C)cc2)c2ccc(C)cc2)c1
Product: [Cl-]
Temperature: 25 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 5 gms (0.0164 mole) of tri-p-tolyl phosphine and 25 gms of toluene. The slurry is maintained at 25° C. then 3 gms (0.0191 mole) of 3-methoxybenzyl chloride is added. This reaction mass is maintained at 25° C. for 15 hours, then heated to 70° C. and maintained for 2 hours, then cooled to 90° C. and maintained for 2 hours, then cooled to 70° C. and the resulting phosphonium salt collected by filtration. The salt is washed with 5 gms of toluene then vacuum dried. There is obtained 1.2 gms of catalyst which has a melting point of >250° C. and a chemical shift of 22.1 ppm (phosphoric acid reference).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1>>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[NH:7][C:8]3[C:3]([C:4]=2[CH:16]=1)=[C:2]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc(NC(=O)c2ccccc2)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2cc(C(F)(F)F)ccc12
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccc(C(F)(F)F)cc4c23)cc1)c1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 378, method 2 using 1-chloro-9-trifluoromethyl-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-amino-phenyl)-benzamide to provide 403. LC-MS (M+H=475, obsd.=475). 1H NMR (400 MHz, DMSO-d6): δ 6.96 (d, 1H), 7.18 (d, 2H), 7.54 (m, 3H), 7.76 (m, 2H), 7.78 (d, 1H), 7.97 (d, 1H), 8.10 (d, 1H), 8.27 (s, 1H), 8.85 (d, 1H), 8.99 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7](Cl)[N:6]=1.[CH2:36]([NH2:46])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[OH:1][CH:2]([CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]1)[CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH:13]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[OH:14])[N:8]=[C:7]([NH:46][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[N:6]=1
Reactant: CC1(C)CC(C(O)CNc2nc(Cl)nc(NCC(O)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Reactant: CCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCCCCCCNc1nc(NCC(O)C2CC(C)(C)NC(C)(C)C2)nc(NCC(O)C2CC(C)(C)NC(C)(C)C2)n1

Procedure:
2,4-Bis{2-hydroxy-N-(2,2,6,6-tetramethyl-4-piperidyl)ethylamino}-6-chloro-1,3,5-triazine (3.0 g) and n-decylamine (1.5 g) were dissolved in dioxane (70 ml), followed by addition of potassium carbonate (1.0 g). The mixture was refluxed for 5 hours with stirring. After completion of the reaction, dioxane was distilled off and the resulting residue was recrystallized from ligroin to give the desired product as white crystals melting at 106°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19]([OH:21])=O)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:30][CH2:31][O:32][CH3:33])[CH:23]=1>>[ClH:1].[CH3:33][O:32][CH2:31][CH2:30][N:29]([CH2:28][C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1)[C:19](=[O:21])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)cc3)nc2c1
Reactant: COCCNCc1cccnc1
Product: COCCN(Cc1cccnc1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2cc(C)ccn12
Product: Cl
Yield: 69.4 %

Procedure:
According to the method of Example 14, 2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetic acid and N-(3-pyridinylmethyl)-2-methoxyethylamine were used as raw materials for synthesis, white solid powder, yield 69.4%. m.p. 234-235° C., ESI-MS m/z: 450[M+H]+, 1H NMR(DMSO-d6, 400 MHz) δ: 2.39(s, 2.4H), 2.40(s, 0.6H), 3.10(s, 0.6H), 3.11(s, 2.4H), 3.48(t, 2H, J=4.76 Hz), 3.68(t, 2H, J=4.76 Hz), 4.14(s, 0.4H), 4.38(s, 1.6H), 4.63(s, 1.6H), 4.83(s, 0.4H), 7.16-7.22(m, 1H), 7.34-7.47(m, 4H), 7.51(s, 1H), 7.80-7.82(m, 1H), 8.10-8.12(m, 1H), 8.21-8.27(m, 1H), 8.48-8.51(m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)C2CCOCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCOCC1)N1CCCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 258.7 %

Procedure:
To a solution of 13 g (41.7 mmol) of 4-(tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester in DCM (260 mL) were added 32.5 mL of trifluoroacetic acid. The reaction was stirred for 6 h at room temperature. The solvent was removed under reduced pressure. The residual oil was azeotroped with DCM (3×20 mL), chloroform (2×20 mL) and toluene (3×20 mL) to afford 22.9 g of [1,4]diazepan-1-yl-(tetrahydro-pyran-4-yl)-methanone as triple trifluoroacetic acid salt; ES−MS: m/z 213 [M+H+]
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[N:14]1[CH:19]=[C:18]2[C:20]([O:22][C:23](=[O:24])[C:17]2=[CH:16][N:15]=1)=[O:21].[Cl-].[NH4+]>O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:20]([C:18]1[C:17]([C:23]([OH:24])=[O:22])=[CH:16][N:15]=[N:14][CH:19]=1)=[O:21]
Reactant: Fc1ccc(F)cc1
Reactant: O=C1OC(=O)c2cnncc21
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(O)c1cnncc1C(=O)c1cc(F)ccc1F
Temperature: -80 °C
Reaction time: 0.75 h
Yield: 61.3 %

Procedure:
Sec-butyllithium (1.32 M in cyclohexane; 1.25 mL) is added dropwise via syringe over 0.25 h to a stirred solution of 1,4-difluorobenzene (0.162 g) in tetrahydrofuran (THF) (5 mL) at -84° C. under a nitrogen atmosphere. The yellow mixture is stirred for an additional 45 min at -80° C. and then added via a canula over 5 min to a stirred solution of pyridazine 4,5-dicarboxylic acid anhydride (0.22 g; prepared according to J.Het Chem. 14, 1099, (1977)) in THF at -80° C. by nitrogen pressure. The mixture is warmed to room temperature overnight and neutralized with amonium chloride. After removal of THF at reduced pressure the resultant tan solid is treated with an aqueous sodium bicarbonate solution (10 mL) and washed with diethyl ether (10 mL). The aqueous phase is acidified with aqueous hydrochloric acid. The precipitate is collected by filtration, washed with cold water (3×10 mL) and dried to give 4-(2',5'-difluorobenzoyl)pyridazine-5-carboxylic acid (0.23 g) as an off-white solid, m.p. 202°-205° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][C:20]2([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[O:25][C:24](=[O:26])C(=[N+]=[N-])[C:22](=[O:29])[CH2:21]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[C:35]1(C)C=CC=CC=1>C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][C:20]2([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[O:25][C:24](=[O:26])[C:1]([N:2]([CH3:35])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[C:22]([OH:29])[CH2:21]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CNc1ccccc1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(=[N+]=[N-])C(=O)O2)cc1Cl
Reactant: Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(N(C)c3ccccc3)C(=O)O2)cc1Cl
Yield: 29 %

Procedure:
To a refluxing solution of N-methylaniline (0.115 mL, 1.1 mmol) and rhodium (II) acetate (9.4 mg) in toluene (1.6 mL) was added 6-[2-(3-chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-3-diazo-dihydro-pyran-2,4-dione (0.080 g, 0.213 mmol) from Step 1 below over 1 hour. The reaction was stirred at reflux for three more hours. The reaction was concentrated by rotary evaporation, and then purified by preparatory HPLC to give the desired product (28 mg, 29% yield).