Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][N:26]([CH3:33])[CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:30]2[CH2:31][CH2:32][CH:27]([N:26]([CH3:33])[CH3:25])[CH2:28][CH2:29]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(CCCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for step D of example 223 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (100 mg, 0.23 mmol) and N,N-dimethylpiperidin-4-amine (6.0 mg, 0.28 mmol). The title compound was afforded as a solid (30.0 mg, 25% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.02 (2H, s), 8.88 (1H, m), 8.46 (1H, s), 3.23 (2H, m), 2.93 (2H, m), 2.31 (9H, m), 1.91 (2H, m), 1.79 (2H, m), 1.66 (2H, m), 1.41 (2H, m). MS m/z: 518.16, 520.15 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].[C:7]([O:11][C:12]([CH2:14][O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH:24]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:39])[NH:37][OH:38])=[CH:32][CH:31]=1)[C:25]([O:27]C)=[O:26])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1.O>[C:7]([O:11][C:12]([CH2:14][O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH:24]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](=[NH:39])[NH:37][OH:38])=[CH:34][CH:35]=1)[C:25]([OH:27])=[O:26])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)C(Nc1ccc(C(=N)NO)cc1)c1cc(Cl)cc(Cl)c1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(Cl)cc1C(Nc1ccc(C(=N)NO)cc1)C(=O)O
Temperature: 57.5 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
3.7 g of finely powdered lithium carbonate were added to a solution of 1.96 g of methyl (RS)-(2-tert-butoxycarbonylmethoxy-3,5-dichloro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetate (see Example 276.2) in 200 ml of THF and 100 ml of water. The suspension was stirred for 8 hours at 55-60° C. The reaction mixture was then concentrated and the aqueous suspension remaining was neutralized with 100 ml 1N HCl. The precipitate was filtered off, washed with water and dried overnight at 50° C. in a high vacuum. There were obtained 1.59 g of (RS)-(2-tert-butoxycarbonylmethoxy-3,5-dichloro-phenyl)-[4-(N-hydroxycarbamimidoyl)-phenylamino]-acetic acid; MS (ISP) m/z 484.3 (M+H)+, 506.2 (M+Na)+.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][C@H:19]([C:27]([OH:29])=O)[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])[CH:9]=[CH:8]2.C(OCC)C.S(Cl)([Cl:37])=O>>[N:1]#[N:2].[ClH:37].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([S:15]([NH:18][C@H:19]([C:27]([Cl:37])=[O:29])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:26])[NH2:25])(=[O:17])=[O:16])[CH:9]=[CH:8]2
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)ccc2c1
Reactant: O=S(Cl)Cl
Agent: N#N
Solvent: CCOCC
Product: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.5 g of N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride hydrochloride.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([O:14]CC)=O.P(Cl)(Cl)(Cl)=O.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][NH2:30].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[C:12](=[O:14])[C:3]2=[CH:4][NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:30]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (3.8 g, 17 mmol) was dissolved in phosphorus oxychloride (25 mL, 0.26 mol, 15 equiv) and stirred at ambient temperature for 14 hours. The mixture was concentrated in vacuo and the residue was concentrated from toluene (3×25 mL). The resulting residue was dissolved in 1,2-dimethoxyethane (60 mL) and degassed N,N-dimethylformamide (10 mL) and treated with 2-fluorophenylhydrazine (4.4 g, 35 mmol, 2 equiv) and potassium carbonate (12 g, 87 mmol, 5 equiv). The mixture was placed into a preheated oil bath at 80° C. for 14 hours. The mixture was cooled to ambient temperature, diluted with water (100 mL) and ethyl acetate (100 mL) and filtered. The solid was collected and dried in vacuo, providing the titled compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:12]([N:9]([CH2:10][CH3:11])[C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([C:1]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16](=[O:24])[N:2]=2)=[CH:4][CH:5]=1)[CH3:13]
Reactant: CCN(CC)C(=O)c1ccc(C#N)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 30.5 %

Procedure:
A mixture of 4-cyano-N,N-diethylbenzamide (0.60 g, 3.0 mmol), methyl thiosalicylate (0.75 g, 4.5 mmol), triethylamine (0.54 g, 5.3 mmol) and toluene (5 ml) was heated and refluxed under a nitrogen flow for 70 hours. To the reaction solution, ethyl acetate was added and the solid precipitated was removed by filtration. After the filtrate was ice-cooled, the crystals precipitated were taken by filtration and recrystallized from ethyl acetate to give the title compound (0.31 g, 30%) as crystals.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C@H:7]([OH:10])[CH2:8][OH:9])=[O:4].CC(C)([O-])C.[K+].CO.O>C(O)(CC)(C)C>[OH:9][CH2:8][C@@H:7]1[CH2:6][NH:5][C:3](=[O:4])[CH2:2][O:10]1
Reactant: O=C(CCl)NC[C@H](O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCC(C)(C)O
Solvent: O
Product: O=C1CO[C@H](CO)CN1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
(S)-2-Chloro-N-(2,3-dihydroxypropyl)acetamide (4.77 g, 28.45 mmol) in tert-amyl alcohol (75 mL) was added over 2 h to a stirred solution of potassium tert-butoxide (3.59 g, 21.4 mmol) in tert-amyl alcohol (25 mL) at room temperature under nitrogen. After 1 hr, methanol (12 mL) and water (0.7 mL) were added and the reaction mixture was stirred for an additional 20 min. The mixture was concentrated under vacuum and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (2/8), to give the title compound as a white solid (1.26 g, 45%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.O[CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]>ClCCl>[CH2:13]([Cl:1])/[CH:14]=[C:15](\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])/[CH3:22]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C\CCl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of N-chlorosuccinimide (10.0 g) and dimethylsulfide (6.56 ml) in dichloromethane (200 ml) was added nerol (7.71 g) while being cooled with ice. The mixture was stirred at 0° C. for 4 hours. The reaction solution was washed with brine and dried over sodium sulfate anhydride. Then, the solvent was evaporated, thereby yielding a raw product of neryl chloride. In a manner similar to Reference Example 1, this raw product was reacted with methyl 4- hydroxybenzoate (7.61 g) and then hydrolyzed to yield 7.47 g (55%) of 4- neryloxybenzoic acid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[NH:30][CH2:29][C@:28]2([C:31](=[O:34])[CH2:32][OH:33])[C@H:7]1[CH2:8][C@H:9]1[C@H:22]3[C@@:13]([F:26])([C@:14]4([CH3:25])[C:19]([C@@H:20]([F:23])[CH2:21]3)=[CH:18][C:17](=[O:24])[CH:16]=[CH:15]4)[C@@H:12]([OH:27])[CH2:11][C@@:10]12[CH3:35])=[O:5])C.Cl>C1COCC1.O.[Cl-].[Na+].O>[CH2:8]([N:30]1[CH2:29][C:28]2([C:31](=[O:34])[CH2:32][OH:33])[CH:7]([CH2:8][CH:9]3[CH:22]4[C:13]([F:26])([C:14]5([CH3:25])[C:19]([CH:20]([F:23])[CH2:21]4)=[CH:18][C:17](=[O:24])[CH:16]=[CH:15]5)[CH:12]([OH:27])[CH2:11][C:10]32[CH3:35])[CH:6]1[C:4]([OH:3])=[O:5])[C:9]1[CH:22]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1NC[C@]2(C(=O)CO)[C@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC12C=CC(=O)C=C1C(F)CC1C3CC4C(C(=O)O)N(Cc5ccccc5)CC4(C(=O)CO)C3(C)CC(O)C12F
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
To a solution of compound 119 (66 mg; 0.113 mmol) in dry THF (3 ml) and water (1 ml) 1 N NaOH (400 μl) is added and the reaction mixture is stirred at RT overnight. The reaction mixture is poured into 1 N HCl (10 ml) and brine (10 ml), and the aqueous phase is extracted with AcOEt (3×40 ml). The combined organic extracts are dried and concentrated. Crude is purified by preparative HPLC, to afford title compound (15% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:22])[N:19]=[CH:20][CH:21]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:25]N1C(=O)CCC1=O>ClCCl>[F:24][C:2]([F:1])([F:23])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:17]3[N:18]([CH3:22])[N:19]=[CH:20][C:21]=3[Br:25])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3ccnn3C)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3c(Br)cnn3C)ccc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a solution of N-trifluoroacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (30 mg, 0.082 mmol) in dichloromethane (1 mL) was treated with N-bromosuccinimide (15.3 mg, 0.086 mmol) and stirred overnight at 20° C. The product mixture was absorbed on silica and purified by flash chromatography (2-5% MeOH in CH2Cl2, silica) resulting in 37 mg of a white crystalline solid. MS calculated for C17H17BrF3N3O+H: 416, observed: 416.
Reaction SMILES: [CH2:1]([O:8]C(N1CCC2C(CO)(C2)C1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O.O>[CH2:2]([C:1]([OH:8])=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: O=C(OCc1ccccc1)N1CCC2CC2(CO)C1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of the compound of Step 3 (580 mg, 2.22 mmol) in acetone (10 ml) was added Jones reagent (2.8 ml) at 0° C. The mixture was stirred at this temperature for 1 hour. After addition of methanol (5 ml), the reaction mixture was warmed to room temperature and diluted with water. The product was extracted into methylene chloride, and the combined organic layers were washed with brine and dried over magnesium sulfate. Removal of solvent in vacuo provided the title compound as a white solid, (570 mg, 2.1 mmol, 93% yield).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:5][CH2:4]1.Br[CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>CN(C=O)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH:3]1([NH:6][C:7](=[O:25])[C:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:18]=[CH:17]4)[C:11]([CH3:23])=[C:10]([F:24])[CH:9]=2)[CH2:4][CH2:5]1
Reactant: BrCC1CCCCO1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 12 mg) was added to N-cyclopropyl-3-fluoro-5-(1H-indazol-5-yl)-4-methylbenzamide (Intermediate 3, 45 mg) in DMF (5 ml) and the mixture was stirred at room temperature for 1 h. 2-(Bromomethyl)tetrahydro-2H-pyran (20.5 μl) was added and stirring continued for 18 h. The mixture was diluted with chloroform/ethyl acetate (1:1, 5 ml) and washed with water (2×5 ml). The organic phase was concentrated under vacuum and the residue was purified by preparative HPLC to give the title compound as a colourless glass (23 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][OH:12])[CH2:5]2.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[OH:12][CH2:11][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:13]#[N:14])[CH:3]=2)[CH2:7]1
Reactant: CN(C)C=O
Reactant: OCC1Cc2ccc(Br)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CC(CO)C2
Temperature: 110 °C

Procedure:
A mixture of (5-Bromo-2,3-dihydro-1H-inden-2-yl)methanol (10 g, 44 mmol), Zn(CN)2 (10.3 g, 88 mmol) and Pd(PPh3)4 (1 g, 0.88 mmol) in 100 mL of DMF was heated at 100-120° C. under N2 atmosphere overnight. Most of the solvent was concentrated and the residue was partitioned between water (100 mL) and EtOAc (100 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified with column chromatography (EtOAc/PE=1:20) to give the title compound. 1H-NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 3.64 (d, J=6.6 Hz, 2H), 3.05-3.13 (m, 2H), 2.70-2.84 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Yield: 39.6 %

Procedure:
2-Chloroquinoline (0.04 moles, 6.54 g), 4-aminothiophenol (0.04 moles, 5.0 g) and potassium carbonate (0.04 moles, 5.52 g) were stirred at room temperature in 200 ml of ethanol for 18 hr. The reaction mixture was concentrated, ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with ethyl acetate/hexane to yield 2-(4-aminophenylthio)quinoline 4.0 g, 40%. Mass Spec (FD) 252. Calculated for C15H12N2S: C, 71.40; H, 4.79, N, 11.10. Found: C, 71.11; H, 4.98N, 11.20.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O[O:20][C:21]([CH3:24])(C)C)(C)(C)C.[C]=O.[CH2:27]([OH:29])C>>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:27]([O:20][CH2:21][CH3:24])=[O:29])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C)cc1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: CCO
Agent: [C]=O
Product: CCCCCCOc1ccc(CC(=O)OCC)cc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
4-(n-hexyloxy)toluene (2.88 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 116 mg ethyl 2-(4-(n-hexyloxy)phenyl)acetate was obtained by column chromatography, in a yield of 88%. 1HNMR (400 MHz, CDCl3) δ 0.88 (t, J=7.2 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 1.31-1.36 (m, 4H), 1.41-1.46 (m, 2H), 1.73-1.79 (m, 2H), 3.54 (s, 2H), 3.91 (t, J=6.8 Hz, 2H), 4.11 (q, J=7.2 Hz, 2H), 6.83-6.87 (m, 2H), 7.17-7.19 (m, 2H); 13CNMR (100 MHz, CDCl3) δ 14.0, 14.2, 22.6, 25.7, 29.3, 25.7, 29.3, 31.6, 40.6, 60.8, 68.0, 114.6, 126.0, 130.2, 158.2, 171.9; HRMS (ESI) calcd. for C16H24NaO3 [M+Na]: 287.1618. found: 287.1622. The ethyl 2-(4-(n-hexyloxy)phenyl)acetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 97 mg product 2-(4-(n-hexyloxy)phenyl)acetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 94%.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:10])[O:7][CH2:8][CH3:9])C.[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][C:17]2=[O:23].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH:16]([C:6]([O:7][CH2:8][CH3:9])=[O:10])[C:17]2=[O:23]
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c(C)cc(C)cc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A suspension of 12.2 g (0.53 moles) of sodium hydride in a liter of toluene are maintained under stirring in a 2 liter flask for 2 hours at room temperature, and 85 ml (0.69 moles) of diethylcarbonate are then added. The mixture is heated to 90° C. and 25 g of 5,7-dimethyl-1-tetralone (0.14 moles) dissolved in 150 ml of toluene are added, in about 2 hours. The reaction mixture is kept under stirring for a further 8 hours at 90° C. until the reagent disappears. At the end the reaction mixture is hydrolyzed by pouring it into ice containing 50 ml of glacial acetic acid. The phases are separated and extracted repeatedly with ethyl ether, the overall organic phase is washed with water saturated with NaHCO3, then with water until neutrality and finally dried on anhydrous Na2SO4. Upon removal of the solvents at reduced pressure, 33 g of the desired pure ketoester (XXV) are obtained in the form of a red oil (96% yield). NMR spectra show that the product is present in solution in ketone and enolic form in a ratio of 55% and 45% respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:16][CH2:15][C:14](=O)[CH2:13]1.N1CCCC1.Cl>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:14]1([CH2:15][CH2:16][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCOC1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: C1CCNC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CC2(CCOC2)Oc2ccc(Br)cc21
Yield: 25.8 %

Procedure:
A solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (4.97 g, 23.23 mmol), dihydrofuran-3(2H)-one (3 g, 34.87 mmol) and pyrrolidine (2.48 g, 34.87 mmol) in toluene (60 mL) was refluxed overnight. After cooling, the mixture was treated with water and acidified with concentrated HCl to pH around 1. The resulting solution was extracted with ethyl acetate and washed with brine. The combined organic layers were concentrated and the residue was purified by column to give 6-bromo-4′,5′-dihydro-2′H-spiro[chroman-2,3′-furan]-4-one (1.7 g, 30%). 1H-NMR (CDCl3): 1.9 (m, 1H), 2.3 (m, 1H), 2.8 (m, 2H), 3.65 (m, 1H), 3.9 (m, 1H), 4.0 (m, 2H), 6.8 (m, 1H), 7.5 (m, 1H), 7.9 (m, 1H).
Reaction SMILES: Cl.C([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#N.[OH-].[K+].C1(C)C=CC=CC=1>O>[C:10]1([CH:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C2CCNCC2)cc1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
4-Cyano-4-phenylpiperidine HCl (10.0 g, 45.0 mmol) was combined with KOH pellets and stirred vigorously under Ar at 160° C. for 4 h. The reaction mix was cooled to RT and dissolved into toluene (100 ml) and H2O (100 ml). After separation of the layers, the aqueous layer was back-extracted two times with toluene. The combined organic layer was dried over Na2SO4, concentrated in vacuo, and dried under high vacuum, yielding a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:12])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])=[CH:16][C:15]=1[NH:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.ClCCl>[ClH:12].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[N:33]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[C:15]3[CH:16]=[C:17]([C:18]([N:20]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:19])[CH:31]=[CH:32][C:14]=3[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCN2CCCCC2)c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: ClCCl
Product: COc1ccc(Cc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCN2CCCCC2)cc1
Product: Cl
Temperature: 100 °C

Procedure:
4-methoxyphenylacetylchloride (32 mg, 1.1 eq) is added to a solution of 4-amino-N,N-bis(3-methylbutyl)-3-[(3-piperidin-1-ylpropyl)amino]benzamide (66 mg) in acid acetic (2 ml). The mixture is heated at 100° C. for 18 hours then cooled down and concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogen carbonate is added to the residue obtained dissolved in dichloromethane. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure. Purification of the residue obtained by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of the free base. The corresponding hydrochloride salt is formed by the addition of a 1N solution of hydrochloric acid in diethyl ether. The precipitate obtained is filtered and dried in order to produce the expected monohydrochloride compound (51 mg, 59% yield).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[O:4]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>ClCCCl>[C:24]([C:15]1[CH:16]=[CH:17][C:5]2[O:4][CH:3]([C:2]([F:1])([F:18])[F:19])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=2[CH:14]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1=Cc2ccccc2OC1C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 11.9 %

Procedure:
Ethyl 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 10, Step 1)(1.59 g, 5.8 mmol) was dissolved in 1,2-dichloroethane (3 mL) and added to a 0° C. suspension of aluminum chloride (2.59 g, 19.4 mmol) in 1,2-dichloroethane (3 mL). A solution of benzoyl chloride (1.01 g, 7.2 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction was heated to 80° C. and stirred for 4 hours. The solution was poured onto 3 N HCl and ice and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with 3N HCl, saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo. The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to afford the ester as a white crystalline solid (0.26 g, 12%): mp 114.7–116.1° C. 1H NMR (CDCl3/300 MHz) 7.82 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J=8.7 Hz), 5.79 (q, 1H, J=6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).