Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with ethanesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give ethanesulfonic acid isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amide as a light yellow oil. MS: 433.4 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:21][CH2:20][C:13]3[N:14]=[CH:15][N:16]=[C:17](OC)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].CN(C)C1C=CC=CC=1.CN(C)C=O.P(Cl)(Cl)([Cl:38])=O.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:21][CH2:20][C:13]3[N:14]=[CH:15][N:16]=[C:17]([Cl:38])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncnc2c1CN(c1ccc(Cl)cc1C#N)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Temperature: 110 °C

Procedure:
A mixture of 5-chloro-2-(4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (4.15 g, 13.1 mmol), N,N-dimethylaniline (0.18 mL, 1.4 mmol), N,N-dimethylformamide (0.21 mL, 2.7 mmol) and acetonitrile (35 mL) was heated to dissolve at 105° C. Phosphoryl chloride (5.3 mL, 56 mmol) was added dropwise over 3 mins and the mixture was heated to reflux at 110° C. After another 20 hours refluxing, the reaction mixture was allowed to cool and poured over ice (200 g), and then 45% NaOH (75 mL) was added. The mixture was extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc/hexane) to afford a yellow oil which became a solid in the freezer.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH3:15][O:16][C:17](=[O:40])[C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:27][CH:26]=2)=[C:20](N)[CH:19]=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.O>[CH3:15][O:16][C:17](=[O:40])[C:18]1[CH:19]=[CH:20][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])=[CH:27][CH:26]=2)=[C:22]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:23]=1
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Temperature: 120 °C
Yield: 62 %

Procedure:
A suspension of N′-(3-cyano-6-methyl-pyridin-2-yl)-N,N-dimethyl-formamidine (1.00 g, 5.3 mmol) and 3-amino-4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-benzoic acid methyl ester (prepared in Example 385C) (1.99 g, 5.3 mmol) in AcOH (20 mL) was heated at 120° C. for 30 minutes under N2. After cooling to room temperature, the reaction mixture was portioned between AcOEt (250 mL) and H2O (200 mL), and then made basic to pH 9 with K2CO3 under stirring. The organic layer was separated, washed with 10% NaHCO3, H2O and brine, dried over MgSO4, and evaporated to give pale brown oil. The oily residue was separated by silica gel column chromatography (AcOEt) to yellow amorphous, which was solidified by the treatment of i-Pr2O. The resulting solid was collected by filtration, washed with i-Pr2O, and dried at 40° C. overnight under reduced pressure to give the title compound as pale yellow crystal (1.70 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a solution of 2-methyl-benzoic acid methyl ester (4.58 g, 30.5 mmol) in CCl4 (75 mL) was added N-bromosuccinimide (5.79 g, 32.5 mmol) followed by 1,1′-azobis(cyclohexanecarbonitrile) (1.42 g, 5.80 mmol). The resultant mixture was refluxed for 6 hours then cooled to room temperature, filtered through filter paper, and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:hexanes-EtOAc) provided 5.44 g (78%) of 2-bromomethyl-benzoic acid methyl ester as a colorles oil. 1H NMR (CDCl3) δ 3.95 (s, 3H), 4.96 (s, 2H), 7.36-7.50 (m, 3H), 7.97 (d, 1H, J=7.8 Hz).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:24](=[CH:25][C:26]([N:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[N:23]([C:43]3[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=3)[CH:22]=2)=[CH:17][CH:16]=1.O>CN(C=O)C>[CH3:6][N:5]([CH3:7])[CH2:4][CH2:3][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:29]3[C:24](=[CH:25][C:26]([N:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)=[CH:27][CH:28]=3)[N:23]([C:43]3[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=3)[CH:22]=2)=[CH:19][CH:20]=1
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Chloro-N,N-dimethylethylamine hydrochloride (7.3 mg, 0.051 mmol) and cesium carbonate (33 mg, 0.101 mmol) were added to a mixture solution of tert-butyl 4-(3-(4-hydroxyphenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (12 mg, 0.025 mmol) in DMF (1 mL). After room temperature stirring at room temperature for 16 hours, followed by addition of water, the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound was obtained as white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:27](=O)[C:26]3[CH:29]=[CH:30][CH:31]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19]2=O)[CH2:12][CH2:11]1>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]2[CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[CH2:19]2)[CH2:14][CH2:15]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCN1CCN(c2ccccc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccccc1N1CCN(CCN2Cc3cccc4cccc(c34)C2)CC1

Procedure:
Following the procedure of example 88(a) but substituting 5.2 g. (0.026 mole) of 1-(o-chlorophenyl)piperazine for the N-phenylpiperazine, one obtains the hydrochloride salt of 2-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-1H-benz[de]-isoquinoline-1,3(2H)-dione. This salt is neutralized with aqueous sodium hydroxide and extracted with chloroform. The chloroform solution is dried (Na2SO4), concentrated to 200 ml. and allowed to stand open to the air. The product slowly crystallizes and is removed by filtration. Drying at 50° (60 mm.) overnight yields 4 g. of 2-[2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl]-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 213°-214°.
Reaction SMILES: [C:1]([O:4][CH:5]1[C@@H:22]2[CH2:23][C@@H:21]2[C@@:20]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:25])[CH2:6]1)(=[O:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[C:1]([O:4][CH:5]1[C@@H:22]2[CH2:23][C@@H:21]2[C@@:20]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:25])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2C[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)[C@H]2C[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A solution of 6.8 g of 3-acetoxy-1α,2α-methylene-5α-androstan-17β-ol in 68 ml of dichloromethane is combined with 10.2 g of pyridinium chlorochromate and stirred for one hour at room temperature, then diluted with diethyl ether, washed with water, and dried. Evaporation yields 7.0 g of 3-acetoxy-1α,2α-methylene-5α-androstan-17-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: NCCO
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NCCO)s1
Yield: 46 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (43 mg, 46%) which was obtained as an off white solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) and trituration from methanol. MS: m/e=375.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]([O:36][C:37](=[O:47])[NH:38][C:39]1[C:44]([CH:45]=[O:46])=[CH:43][CH:42]=[CH:41][N:40]=1)([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[C:32]([O:36][C:37](=[O:47])[NH:38][C:39]1[C:44]([CH:45]([C:2]2[C:7]([N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=3)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=2)[OH:46])=[CH:43][CH:42]=[CH:41][N:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1ncccc1C=O
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1cccnc1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (3.27 g, 6.64 mmol) in THF (20 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 6.62 mL, 13.25 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of (3-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (590 mg, 2.65 mmol) in THF (3 mL) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (10 mL) and extracted with EtOAc (2×50 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (50 mL), brine (50 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain [3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzene sulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (750 mg) in 44% yield as yellow solid. ESMS m/z (relative intensity): 637 (M+H)+ (100).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:15]([C:16]([C:18](=[CH:24]N(C)C)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])=[CH:14][C:13]2[C:8](=[C:9]([F:30])[C:10]([F:29])=[C:11]([F:28])[CH:12]=2)[N:7]=1.C(O)C.C1CCN2C(=NCCC2)CC1>ClC(Cl)Cl>[CH:1]1([N:4]2[C:6]3[N:7]=[C:8]4[C:9]([F:30])=[C:10]([F:29])[C:11]([F:28])=[CH:12][C:13]4=[CH:14][C:15]=3[C:16](=[O:17])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24]2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Cyclopropylamine (4.12 g) is added in the course of 5 minutes to a solution, maintained at a temperature in the region of 20° C., of ethyl 2-(2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (7 g) in trichloromethane (100 cc), and the mixture is stirred for a further 4 hours at the same temperature. The reaction mixture is concentrated under reduced pressure (20 kPa) at approximately 50° C. The oily residue obtained is taken up with ethanol (100 cc) and DBU (3 g). The mixture is heated to 80° C. and kept stirring at the same temperature for 1 hour and a half. After cooling to approximately 20° C., the insoluble matter is drained and washed with ethanol (2×30 cc) and isopropyl ether (2×30 cc). 1-Cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (4.5 g) is obtained in the form of a colorless solid, m.p. 260° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=2[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27]1(=O)[O:32][C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C(O)CO.C(Cl)Cl>O>[OH:32][C:27]1[C:28]2[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[N:1]([C:3]2[CH:8]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[CH:12]=[C:11]([CH2:23][OH:24])[C:10]=3[CH2:25][OH:26])[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(NN)c3)c2cc1OC
Solvent: ClCCl
Solvent: OCCO
Solvent: O
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4nc(O)c5ccccc5c4=O)c3)c2cc1OC
Temperature: 130 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A mixture of 1-(2-hydrazino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (2.0 g), phthalic anhydride (0.92 g) and ethylene glycol (10 ml) is heated with stirring at 130° C. for two hours. The mixture is cooled to room temperature, and thereto are added methylene chloride and water. The methylene chloride layer is separated, washed, dried, concentrated under reduced pressure to remove the solvent, and the residue is crystallized from ethanol to give 1-[2-{4-(hydroxy)-1(2H)-phthalazinon-2-yl}-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (1.68 g, yield; 61%), which is listed in Table 10.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([N:10]1[C:15](=[O:16])[C:14](Cl)=[C:13]([N:18]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH2:21][OH:22])[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7]>C(O)C.O>[C:6]([N:10]1[C:15](=[O:16])[C:14]2[O:22][CH2:21][CH2:20][CH2:19][N:18]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:38])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[C:13]=2[CH:12]=[N:11]1)([CH3:7])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1ncc(N(CCCO)Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)n1ncc2c(c1=O)OCCCN2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 142.5 %

Procedure:
To a solution of sodium ethoxide in ethanol as prepared by dissolving sodium metal (6.5 mg) in ethanol (1 ml) was added a solution of 2-tert-butyl-4-chloro-5-[N-(4-(4-chlorobenzoyl)benzyl)-N-(3-hydroxypropyl)-amino]-3-(2H)-pyridazinone (91 mg) in ethanol (5 ml) and the mixture was refluxed for 46 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous NaCl solution in that order and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1→1:2) to provide the title compound as white powder (120 mg, yield 12%). 1H-NMR (CDC13) 8: 1.62(9H,s), 2.06(2H,q,J=6.2Hz), 3.55(2H,t,J=6.2Hz), 4.42(2H,t,J=6.2Hz), 4.55(2H,m), 7.32(1H,s), 7.41(2H,d,J=8.4Hz), 7.48(2H,d,J=8.4Hz), 7.76(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)[CH2:9]1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(CCCCc2ccccc2OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCCCc2ccccc2OCC2CCCNC2)c1
Reaction time: 2 h
Yield: 85 %

Procedure:
1.79 g of 1-t-butoxycarbonyl-3-{2-[4-(3-methoxyphenyl)butyl]phenoxymethyl}piperidine [prepared as described in step (a) above] were dissolved in 5 ml of dioxane and 5 ml of a 4N solution of hydrogen chloride in dioxane were added to the solution. The mixture was allowed to stand at room temperature for 2 hours, after which the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in 20 ml of ethyl acetate, and the solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 1.31 g (yield 85%) of the title compound as needles, melting at 136°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7].[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)c1c(C)cccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)c1c(C)cccc1Cl
Temperature: 55 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a mixture of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-nitro-L-phenylalanine methyl ester (3.86 mmol, 1.52 g), zinc dust (325 mesh, 39.0 mmol, 2.55 g, 10 equiv.) and ammonium chloride (58.0 mmol, 3.09 g, 15 equiv.) was added methanol (50 mL) and water (25 mL) at room temperature. After addition of water, an exothermic reaction ensued and the temperature rose to between 45 and 50° C. After the suspension was stirred for 2 h at a bath temperature of 50-60° C., TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was filtered through a pad of celite and the filter cake was washed with methanol (50 mL) and water (40 mL). The filtrate was concentrated under vacuum to remove methanol and the product was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give 1.3 g (92%) of 4-amino-N-[(2-chloro-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester as an amorphous yellow solid, which was used directly for next step. HRMS: Obs. mass, 363.0932. Calcd. mass, 363.0934 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1>C(O)C.[Pd]>[NH2:11][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc2c1OCC2
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc2c1OCC2
Yield: 42 %

Procedure:
A solution of 7-methyl-5-nitro-2,3-dihydrobenzofuran (2 g) in ethanol (25 ml) was hydrogenated over palladium on carbon catalyst overnight. The catalyst was filtered off and the solvent removed in vacuo. The residue was partitioned between ether (30 ml) and hydrochloric acid (2M; 30 ml), the acid layer removed and the organic extracted with further acid. The combined acidic extracts were basified with 5M sodium hydroxide and extracted with ether (4×25 ml). The combined, dried (MgSO4), extracts were evaporated in vacuo to give the title compound as a brown solid (0.7 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>ClCCl>[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(Cl)nc2ccccc12
Reactant: NCCCCN
Solvent: ClCCl
Product: COc1cc(NCCCCN)nc2ccccc12
Yield: 46.7 %

Procedure:
2-Chloro-4-methoxyquinoline (prepared as for 2-chloro-4-ethoxyquinoline but using methanol as solvent; 3.873 g, 20 mmol) and 1,4-diaminobutane (12.3 g, 140 mmol) were heated at 60° C. for 50 h. The solution was then reduced in volume in vacuo, and diluted with dichloromethane. The solid was filtered off and washed with dichloromethane. The filtrate was evaporated to dryness and purified by flash chromatography, eluting with 0-10% ‘10% ammonia in methanol’ in dichloromethane, to give 2-(4-aminobut-1-ylamino)-4-methoxyquinoline as a white solid (2.29 g, 47%). This material (2.142 g, 8.73 mmol) in concentrated hydrochloric acid (80 ml) was gently refluxed for 15 h, and then evaporated to dryness to give the title compound as a white foam (2.65 g, 99%); δH (CD3OD) 1.8-1.9 (4H, m), 2.95-3.05 (2H, m), 3.5-3.6 (2H, m), 6.36 (1H, s), 7.46 (1H, t), 7.7-7.9 (2H, m), 8.45(1H, d): MS (ES+) 232 (100%, MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:17][NH:18][CH3:19]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:3]=1[C:4]([N:18]([CH3:19])[CH3:17])=[O:5]
Reactant: O=Cc1ccc(F)c(C(=O)O)c1
Reactant: CNC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(C=O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
The solution of 2-fluoro-5-formylbenzoic acid (3 g, 17.8 mmol) in methylene chloride (10 mL) was added thionyl chloride (2.0 mL, 26.7 mmol) slowly at 0° C. Then the cold reaction mixture was heated to reflux for 3 h. The solution was cooled to 0° C., added dimethylamine (40 wt. % solution in water, 5 mL) slowly, and then stirred at room temperature for 1 h. The solution was washed with water and brine, the organic layer was dried with Na2SO4 and the solvent was removed to get the desired product (2.4 g, yield 76%). LC-MS (ESI) m/z: 196 (M+1)+