Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[C:13]([NH:23][C:24]([CH3:29])([C:26](O)=[O:27])[CH3:25])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:26](=[O:27])[C:24]([NH:23][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])([CH3:29])[CH3:25])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCN1C(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of proline-tert-butyl ester (47) (2.00 g, 12 mmol, in CH2Cl2 (15 ml) was added N-carbobenzyloxy-2-methylalanine (3.05 g, 13 mmol), HOBT (2.36 g, 17 mmol) and EDC (3.43 g, 18 mmol) and the solution was stirred at room temperature under N2 for 48 hours. The solvent was evaporated, the crude material dissolved in EtOAc and washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine and was dried over anhydrous Na2SO4, filtered and evaporated to give a white solid (4.68 g, 100%). 1H-NMR (500 MHz, CDCl3) δ 1.20-2.15 (m, 4H), 1.43 (s, 9H), 1.59 (d, 6H), 3.21-3.79 (m, 2H), 4.35 (br s, 1H), 4.82-5.19 (m, 3H), 5.74 (br s, 1H), 7.17-7.49 (m, 5H). Analytical HPLC (C18 column) 10.66 min. LC-MS (ES+) m/e=391.3 (M+H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][NH:6][C:7]2[CH:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH:31]=[CH:30][C:8]=2[C:9]([NH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=4)[CH:19]=3)[NH:14][N:13]=2)=[O:10])[CH2:2]1.C=O.O.[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([F:29])[CH:25]=1)[CH2:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:11][C:9](=[O:10])[C:8]1[CH:30]=[CH:31][C:32]([N:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)=[CH:33][C:7]=1[NH:6][CH2:5][CH:3]1[CH2:2][N:1]([CH3:44])[CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CNC3)c2)CC1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NCC3CN(C)C3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.4 %

Procedure:
To a solution of 2-[(azetidin-3-ylmethyl)amino]-N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide (100 mg, 0.14 mmol) in dichloromethane (2 mL) were added formaldehyde 37 wt. % in water (0.014 mL, 0.168 mmol), TEA (0.4 mmol) and sodium triacetoxyborohydride (45 mg, 0.21 mmol). The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with aqueous NaHCO3 sat. sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH3 5N in MeOH 100:10:1 as the eluant, affording 5 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21](N)=[O:22]>O>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:12]([CH3:18])([CH3:19])[C:13](=[O:15])[NH:20][C:21]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C)(C)NCCOCc1ccccc1
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1CCOCc1ccccc1
Temperature: 180 °C

Procedure:
A mixture of ethyl 2-(2-benzyloxyethylamino)-2-methylpropionate (29 g) and urea (8.5 g) was heated at 180° C. for 1 h. After cooling to room temperature water (250 ml) was added and the resulting mixture was extracted with diethyl ether (500 ml). The organic phase was washed with brine (400 ml) and dried (Na2SO4). Evaporation of the solvents in vacuo afforded 9a as an oil: 28 g.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[H][H]>CCOC(C)=O.CCO.O=[Pt]=O>[Br:1][C:2]1[C:3](=[O:25])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:5]([CH3:16])=[CH:6][C:7]=1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [H][H]
Reactant: Cc1cc(C#Cc2ccccc2)c(Br)c(=O)n1Cc1cccc(F)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(CCc2ccccc2)c(Br)c(=O)n1Cc1cccc(F)c1

Procedure:
To a solution of 3-bromo-1-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(1H)-one (0.55 g, 0.0014 mol) in EtOAc (10.0 mL) and EtOH (10.0 mL) was added PtO2 (0.05 g) and stirred in an atmosphere of hydrogen gas at 15 psi for 30 min. The catalyst was removed by filtration, the filtrate was concentrated and the residue was purified by silica gel flash chromatography using 25% EtOAc in hexane as the eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[NH:11]1[C:19]2[C:14](=[CH:15][C:16](B(O)O)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C([O-])(=O)C.N1C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][CH:12]=[CH:13]3)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
1H-pyrazole-4-carboxylic acid ethyl ester (1.00 g, 7.14 mmol) and 1H-indol-5-ylboronic acid (1.15 g, 7.14 mmol) were dissolved in N,N-dimethylformamide (70 mL). Cupper (II) acetate (0.972 g, 5.35 mmol) and pyridine (1.2 mL, 14.8 mmol) were added, and the mixture was stirred for 3 days at room temperature. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to give the title compound (1.40 g, 5.47 mmol, 77% Yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.532 g (4.5 mmol) 4-aminobenzonitrile is heated for 1.5 h at 90° C. The reaction mixture is then distributed between dichloromethane and 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 and). 25:1). Title compound is obtained after crystallization of the product-containing fractions from dichloromethane and drying under HV (8 h, 90° C.); m.p. 228-230° C.; ESI-MS: (M+H)+=338.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.[C:22](=O)=[O:23]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:5]2[C:4]=1[C:22](=[O:23])[O:13][CH:6]2[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=O
Reactant: COc1cccc(C(O)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc2c1C(=O)OC2c1ccccc1

Procedure:
To 3-methoxybenzhydrol (42.8 g.) in dry ether (800 ml.) is added 2.3 M. n-butyl lithium in hexane (250 ml.), dropwise with stirring under nitrogen. The deep red solution is stirred and heated under reflux for 2 hours and then poured into a stirred slurry of a large excess of solid carbon dioxide in ether and stirred until no carbon dioxide remains. The resulting suspension is extracted with water, the extract is acidified with concentrated hydrochloric acid, the precipitate is filtered off, washed with water, dried, and recrystallised from isopropanol to give 7-methoxy-3-phenylphthalide, m.p. 135°-138°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([CH2:19][O:20][CH3:21])=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:24][NH2:25]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][O:20][CH3:21])=[CH:15][CH:14]=3)=[N:24][NH:25][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COCc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1
Solvent: O
Product: COCc1ccc(-c2n[nH]c(=O)c3cc(OC)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 5-methoxy-2-(4-methoxymethylbenzoyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([OH:27])[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:31]([F:33])[F:32].O>CN(C)C=O>[F:32][CH:31]([F:33])[O:27][C:12]1[CH:13]=[CH:14][C:15]2[N:10]([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[N:11]=1
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(O)ccc23)cc1
Reactant: FC(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(OC(F)F)ccc23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-6-ol (0.2 9) in anhydrous dimethyl formamide (5 ml) was treated with sodium hydride (0.046 g, 60% dispersion in mineral oil), after effervescence ceased a stream of bromodifluoromethane gas was passed through the mixture at ambient temperature for 30 minutes. The reaction mixture was then poured into water (50 ml) and extracted with ethyl acetate (50 ml), the organic extract was washed with water (3×50 ml), dried and concentrated in vacuo. The residue was purified by chromatography to give the title compound as a white solid (0.17 g).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>CCOC(C)=O>[Br:1][C:2]1[C:3]([O:16][C:13]2[N:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: Nc1ccc(O)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncccc2Br)nc1
Reaction time: 18 h

Procedure:
3-Bromo-2-chloropyridine (7.27 g, 37.8 mmol), 5-aminopyridin-2-ol (4.99 g, 45.3 mmol), freshly ground cesium carbonate (36.9 g, 113 mmol), and DMSO (37.8 ml, 37.8 mmol) were added into a glass round bottom pressure vessel equipped with a stir bar. The vessel was sealed and placed in a preheated oil bath at 130° C. After 18 h, the reaction was diluted with EtOAc (4×250 mL) and the whole solution was sonicated. After the solid was settled, the top solution was decanted through a pad of celite and silica gel (each layer was 1 cm). This procedure was repeated for the salt residue which left in the flask to remove the product and DMSO from the salt. The filtrate was concentrated to give an oil which included the product and DMSO. The product was extracted with EtOAc (3×300 mL) and DCM (1×100 mL). The EtOAc and DCM layers were washed separately with a minimum amount of brine. The organic phases were dried separately over a minimum amount of MgSO4. The MgSO4 was filtered off and the filtrates were combined and concentrated. A wet, light green solid was obtained. The solid was triturated with hexanes. The solid was filtered off, collected, and dried under vacuum. The product, 6-(3-bromopyridin-2-yloxy)pyridin-3-amine was collected as tan solids. A second batch was obtained from the filtrate. The filtrate was concentrated to give an oil. The oil was purified by ISCO column chromatography using 90:10 DCM:(90:10:1 DCM:MeOH:NH4OH). A light yellow solid, was obtained, dried under vacuum, and given a sample ID: A wet, green solid was obtained, dried under vacuum. MS Calcd for C10H8BrN3O: [M]+=265. Found [M+1]+=266.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=2)=[C:4]([CH3:36])[CH:3]=1.Cl.[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH2:42]>>[CH3:38][O:39][C:40](=[O:43])[CH2:41][NH:42][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:36])[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]3[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=3)=[CH:22][CH:23]=2)=[CH:28][CH:29]=1)=[O:34]
Reactant: COC(=O)CN
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(-c2ccc(C(C/C(=N\O)c3ccc(=O)n(C)c3)c3ccc(F)cc3C)cc2)cc1

Procedure:
In analogy to example 228, from (E)-4′-(1-(4-fluoro-2-methylphenyl)-3-(hydroxyimino)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)propyl)biphenyl-4-carboxylic acid (example 225) and glycine-methylester hydrochloride was prepared the title compound as a light brown foam, MS (ESI+): m/z=556.22 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].Cl.[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:36][NH2:37]>>[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:36][NH:37][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:13]2[CH2:14][C:9]3[CH2:8][N:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[C:2]([F:29])([F:1])[F:28])[CH2:11][C:10]=3[CH2:12]2)=[N:16][CH:17]=1
Reactant: NCc1nccs1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Agent: Cl
Product: O=C(NCc1nccs1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 28 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (54 mg, 0.134 mmol) was reacted with C-thiazol-2-ylmethylamine, hydrochloride analogously to example 3d. Yield: 28%, M+H+: 500.22.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[CH2:54]4)=[CH:47][CH:46]=2)[CH:39]=[CH:40][CH:41]=1>>[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[S:69])[NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:52]=[C:53]4[C:57](=[CH:58][CH:59]=3)[C:56](=[O:60])[N:55]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[CH2:54]4)=[CH:49][CH:50]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)ccc2C1=O
Yield: 60 %

Procedure:
The compound of example 277 was prepared analogous to compound of example 257 by hydrolysis of compound of example 276.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.O.C([O:16][C:17](=O)[CH2:18][CH3:19])C>>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH2:11][C:17](=[O:16])[CH2:18][CH3:19])=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC(=O)CC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a suspension of NaH (60%, 106 mg, 4.44 mmol) in 2 mL propionic acid ethyl ester was added 1-(4-methylphenyl)ethanone (500 mg, 3.7 mmol) at 0-5° C. The reaction mixture was stirred overnight at rt. Water was added, and the mixture was extracted with EtOAc (3×50 mL). The organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash column chromatography (PE/EtOAc=10/1) to give the title compound (370 mg, 52%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.22 (3H, m), 2.45 (5H, m), 6.17 (2H, s), 7.27 (2H, d, J=10 Hz), 7.81 (2H, d, J=11.2 Hz). [M+H] Calc'd for C12H14O2, 191; Found, 191.
Reaction SMILES: CN1CCN(C[C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15]C3C=CC(C)=C(NC4N=C(C5C=NC=CC=5)C=CN=4)C=3)=[O:14])=[CH:11][CH:10]=2)CC1.OC1C(C(O)=O)=CC2C(C=1)=CC=CC=2.O>C(O)C>[C:13]([NH2:15])(=[O:14])[C:12]1[CH:36]=[CH:37][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Agent: O=C(O)c1cc2ccccc2cc1O
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccccc1

Procedure:
A mixture of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (4.94 g, 10 mmol) and 4,4′-methylenebis[3-hydroxy-2-naphthoic acid (Fluka, Buchs, Switzerland; 3.88 g, 10 mmol) in ethanol (50 mL) is heated. Water (25 mL) is then added. Upon cooling, the product crystallises and is filtered-off and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, pamoate as a pale-yellow solid, having the following analytical properties: Analysis found: C, 69.12; H, 5.62; N, 10.88%; H2O, 2.50%. Calculated for C52H47N7O7-1.26 H2O: C, 69.04; H, 5.52; N, 10.84%; H2O, 2.51%.
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:16]1[C:24](=O)[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[CH2:18][CH2:17]1)[CH2:14][CH3:15]>>[CH2:13]([CH:16]1[CH2:17][CH2:18][C:19]2[S:23][CH:22]=[CH:21][C:20]=2/[C:24]/1=[N:11]\[OH:12])[CH2:14][CH3:15]
Reactant: O/N=C1\CCOc2ccccc21
Reactant: CCCC1CCc2sccc2C1=O
Product: CCCC1CCc2sccc2/C1=N\O

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.98, 7.28, 7.15, 7.10, 3.55, 2.99–2.81, 2.21–1.83, 1.59–1.31, 0.95–0.90; (MS/CI) calcd for C10H13NOS+H 195.3, found 195.7.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18](F)=[O:19].[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30])[OH:28])[OH:26].C(=O)(O)[O-].[Na+].Cl>CC(C)=O.O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([O:23][C@@H:24]1[O:32][C@H:31]([C:33]([OH:35])=[O:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]1[OH:26])=[O:19]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)F)C(C)(C)CCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O[C@@H]2O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]2O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 61.1 %

Procedure:
Retinoyl fluoride (2.4 g, 7.9 mmol) was dissolved in 200 ml of acetone. D-glucuronic acid (6 g, 31 mmol) dissolved in 50 ml of water and sodium bicarbonate (970 mg) dissolved in 50 ml of water were added to the retinoyl fluoride solution. The mixture was stirred at room temperature for 20-24 hrs. The solution was neutralized with 1N HCl, diluted with water, and the product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and then evaporated to dryness in a rotary evaporator. The residue was dissolved in 2-3 ml of diethyl ether and transferred to a silica gel (for dry column chromatography, wet packed with hexane) column. The column was developed with hexane containing diethyl ether (5-50%) to remove retinoic acid and other products. The major yellow band containing retinoyl glucuronide was next eluted with a mixture of CH2Cl2 /CH3OH (1:1). The solvent was evaporated to dryness to give solid retinoyl β-glucuronide (2.3 g, 60%). This preparation consisted mainly of the all-trans isomer, and can be used as such.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C@H:15]([CH3:16])[N:8]3[CH:7]=[C:6]([C:17](O)=[O:18])[C:5]2=[O:20])[C:11]=1[F:12].[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:17]([C:6]1[C:5](=[O:20])[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C@H:15]([CH3:16])[N:8]3[CH:7]=1)[C:11]([F:12])=[C:2]([F:1])[CH:3]=2)=[O:18]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Product: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn1c23

Procedure:
The compound is prepared in analogy to the instructions of Example 37A, from (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (for preparation: see Journal of Medicinal Chemistry 1987, 30(12), 2283-2286) and 2,4-dichlorobenzylamine.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:4][CH2:5]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17].C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:8][CH:9]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COC(CCCl)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 72 h
Yield: 73.7 %

Procedure:
A mixture of 3-methoxy-3-(p-chlorophenyl)-1-chloropropane (27.4 mg, 0.125 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.125 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. The reaction mixture was concentrated to a small volume and chromatographed using preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave N-(3-{1-[3-(4-chlorophenyl)-3-methoxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (39.5 mg, 73.8% yield) as a thick oil: 1H NMR δ 7.48 (s, 1H), 7.34-7.3 (m, 2H), 7.25 (m, 4H), 6.96 (d, 1H, J=7.4 Hz), 4.20 (apparent dd, 1H, J=5.9, 7.6 Hz), 3.2 (s, 3H), 3.04 (d, 1H, J=10.1 Hz), 2.99 (d, 1H, J=10.1 Hz), 2.49 (h, 4H, J=6.6 Hz), 2.20-2.10 (m, 4H), 1.82 (m, 4H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 429.4 (M+H)+.