Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]([Cl:18])([Cl:17])[CH2:12][C:13](Cl)([CH3:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-].O>ClCCl>[Cl:10][C:11]([Cl:18])([Cl:17])[CH2:12][C:13]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH2:8][CH3:9])=[CH:2][CH:3]=1)([CH3:15])[CH3:14]
Reactant: CCOc1ccccc1
Reactant: CC(C)(Cl)CC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(C(C)(C)CC(Cl)(Cl)Cl)cc1
Reaction time: 4 h
Yield: 20.3 %

Procedure:
A mixture of 61 g (0.5 mol) of phenetole and 105 g (0.5 mol) of 1,1,1,3-tetrachloro-3-methyl-butane is added slowly with stirring at 0° C. to a suspension of 66.5 g (0.5 mol) of AlCl3 in 100 ml of dichloromethane. After stirring for 4 hours, 1,000 ml of water are added to the reaction mixture with ice-cooling. The mixture is extracted several times with dichloromethane and, after drying, the combined extracts are worked up by distillation. 30 g (=20% of theory) of 1,1,1-trichloro-3-p-ethoxyphenyl-3methyl-butane (b.p.: 145°-150° C./0.1 mbar) are obtained in addition to unreacted starting material.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][CH:5]([CH:7]([OH:11])/[CH:8]=[CH:9]/[I:10])[CH2:4]1)[CH3:2].[CH2:12]([O:14][CH:15]=[CH2:16])[CH3:13]>P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>[I:10]/[CH:9]=[CH:8]/[CH:7]([O:11][CH:12]([O:14][CH2:15][CH3:16])[CH3:13])[CH:5]1[CH2:6][CH:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: C=COCC
Reactant: CCC1CC(C(O)/C=C/I)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(C)OC(/C=C/I)C1CC(CC)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
A mixture containing 4.8 g (0.018 mole) of 1-(3-ethylcyclobutyl)-trans-3-iodoprop-2-en-1-ol (prepared in 1I) and 38.2 g (50 ml, 0.51 mole) of ethylvinyl ether (Aldrich Chemical Company; Beilstein 1:433) was prepared. One drop of phosphorus oxychloride was added thereto and the mixture was allowed to stir for about 15 hr at room temperature. The mixture was poured into 50 ml of saturated aqueous sodium bicarbonate and the products were extracted with 150 ml (3×50 ml) of ether. The combined ether extract was washed with 50 ml of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed in vacuo. The residue was chromatographed on silica gel 60 (0.063-0.2 mm, 70-230 mesh, ASTM) using chloroform as the eluant to yield 4.2 g of the title compound having the following physical characteristics:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([NH:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12]2)[CH:5]=1.Br[CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([N:10]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH3:20])=[CH:12]2)[CH2:22][CH2:23][CH3:24])[CH:5]=1
Reactant: Cc1cn(Nc2cc(Cl)ncn2)c2ccccc12
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(c1cc(Cl)ncn1)n1cc(C)c2ccccc21
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60% in oil, 1.52 g) in 40 ml dimethylformamide (hereafter DMF) at ice bath temperature was added 9.0 g of 6-chloro-N-(3-methyl-1H-indol-1-yl)-4-pyrimidinamine dropwise, in 50 ml DMF. After addition was complete, the reaction was stirred for 5 minutes and then 3.45 ml of 1-bromopropane was added dropwise to the cool mixture. Reaction was allowed to proceed for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([N+:16]([O-])=O)[CH:7]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=1)[NH2:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Cc1cc(N)cc(C(F)(F)F)c1

Procedure:
A suspension of 1-methylsulfonylmethyl-3-nitro-5-trifluoromethyl-benzene (520 mg; 2.170 mmol) and 50 mg of Pd/C 10% in methanol (50 ml) was hydrogenated (1 bar) overnight. The reaction mixture was filtered on a celite pad and the obtained solution concentrated in vacuo. The crude was washed with dichloromethane in order to filter salts, coming from the previous reaction. 100 mg (0.395 mmol; 18% yield) were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.ClC(OCC(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[Na+]>CN(C)C=O.C(OCC)C.C(N(CC)CC)C>[CH2:23]([N:30]1[CH2:35][CH2:34][N:33]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:32][CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
To a solution of 50 ml of dimethylformamide with 5.0 g of 6-carboxy-3,4-dihydrocarbostyril and 4 ml of triethylamine, 3.87 g of isobutyl chloroformate in 2 ml of dimethylformamide solution was added dropwise. After stirring at a room temperature for 30 minutes, 5.5 g of benzylpiperazine in 3 ml of dimethylformamide solution was added to the former solution and stirred at a room temperature for 30 minutes, then stirred continuously at 50°-60° C. for 1 hour. The reaction mixture was poured into a voluminous amount of a saturated sodium chloride aqueous solution and extracted with chloroform and the chloroform extract was washed with water and dried. After removal of the solvent, to the residue thus obtained was added diethyl ether to crystallize the residue and recrystallized from ethanol to obtain 3.4 g of 6-(4-benzyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 198°-200° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][C:17]([OH:23])=[CH:18][C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:24])[CH2:8]1)=[O:5])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:23][C:17]1[CH:16]=[C:15]2[C:22]3[C:12]([CH2:11][C@@H:10]4[C@@H:20]([C:19]=3[CH:18]=1)[CH2:21][C@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:25][CH3:26])[CH2:8][N:9]4[CH3:24])=[CH:13][NH:14]2)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(O)cc4[nH]cc(c34)C[C@H]2N(C)C1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(OC(C)=O)cc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 1 h

Procedure:
At room temperature, 100 mg of 1,1-diethyl-3-(13-hydroxy-6-methyl-8α-ergolinyl)urea is dissolved in 1 ml of pyridine and 1 ml of acetic anhydride. After one hour, the mixture is poured on ice, extracted, after 15 minutes of stirring, with methylene-chloride, the organic phase is dried with sodium sulfate, and evaporated. The residue is crystallized from ethyl acetate.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH:9]([C:26](=[O:28])[NH2:27])[NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[C:26]([CH:9]([NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:7][C:6]([OH:29])=[O:5])(=[O:28])[NH2:27]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(Nc2ncccn2)cc1)C(N)=O
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C(CCC(=O)O)NC(=O)c1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Carbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino]-butyric acid tert-butyl ester was dissolved in dichloroethane (10 mL), followed by the addition of TFA (5 mL). The mixture was stirred at room temperature for 4 hrs. TLC indicated the reaction was complete. Solvents were then removed by rotavap and the residue was washed with EtOAc. A solid was collected by filtration and dried in vacuum oven overnight. 4-Carbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino]-butyric acid was obtained in quantitative yield (285 mg). MS (ESI) m/z 344.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].[N:9]1([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1>[OH:8][C:4]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:20][CH:21]=1)([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1]
Reactant: Br[Mg]c1ccc(OCCCN2CCCCC2)cc1
Reactant: CCCC(=O)CCC
Solvent: C1CCOC1
Product: CCCC(O)(CCC)c1ccc(OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-heptanone (471 mg) in tetrahydrofuran (4 mL) is added a solution of 4-(3-piperidinopropoxy)phenylmagnesium bromide in tetrahydrofuran (11 mL, 3.3 mmol). The mixture is stirred overnight at room temperature and quenched at 0° C. with a saturated aqueous solution of ammonium chloride (20 mL). The solution is extracted with ethyl acetate (20 mL) and the organic layer is washed with a saturated aqueous solution of ammonium chloride (20 mL), dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel with a gradient dichloromethane/methanol from 98/2 to 95/5 as eluent. Fractions containing the expected product are pooled and concentrated under reduced pressure to give 1-{3-[4-(1-hydroxy-1-propylbutyl)-phenoxy]propyl}piperidine as a yellow oil. Salt formation with oxalic acid in ethanol and precipitation with diethyl oxide affords 1-{3-[4-(1-hydroxy-1-propylbutyl)-phenoxy]propyl}piperidine, oxalate as a white solid melting at 118° C.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:31].[CH2:32](O)[CH3:33]>>[N:1]#[N:2].[ClH:31].[ClH:31].[CH2:32]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:33]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: CCO
Agent: Cl
Agent: N#N
Product: CCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 1 h
Yield: 95 %

Procedure:
A suspension of 1.0 gram of N2 -dansyl-L-arginine in 15 ml of anhydrous ethanol was saturated with dry hydrogen chloride for 1 hour. The reaction mixture was reflexed for an additional 1 hour. After cooling, the reaction mixture was concentrated in vacuo. The residue was triturated with cold ethyl ether to give a crystalline product. After crystallization from ethanol-ethyl ether, N2 -dansyl-L-arginine ethyl ester dihydrochloride was obtained in 95% yield; mp. 140°-144°C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:19]([N:26]1[CH2:34][C:33]2([C:35]([O:37][CH3:38])=[O:36])[CH:28]([C:29](I)=[CH:30][CH2:31][CH:32]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.COCCOC.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>[CH2:19]([N:26]1[CH2:34][C:33]2([C:35]([O:37][CH3:38])=[O:36])[CH:28]([C:29]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[CH:3]=3)=[CH:30][CH2:31][CH:32]2[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1cc3ccccc3s1)=CCC2c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 9.3 g (17.3 mmol) of benzothiophene-2-boronic acid trimeric anhydride in 100 cm3 of methanol and 400 cm3 of a 2N aqueous sodium carbonate solution are successively added to a solution of 22.36 g (47 mmol) of the levorotatory enantiomer of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-1,2,3,4,5,7a-hexahydroisoindole-3a-carboxylate and of 6.03 g (5.2 mmol) of tetrakis(triphenylphosphine)palladium in 250 cm3 of 1,2-dimethoxyethane, the reaction mixture is then brought to reflux for two hours and stirring is maintained overnight at room temperature. After returning to a temperature in the region of 20° C., the reaction mixture is extracted with 800 cm3 of ethyl acetate and then the organic phase is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The brown residue obtained is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture. 11.04 g (50%) of the levorotatory enantiomer of methyl (3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(2-benzothienyl)-1,2,3,4,5,7a-hexahydroisoindole-3a-carboxylate are thus obtained in the form of a yellow foam, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[CH3:34][NH:35][CH3:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[N:35]([CH3:36])[CH3:34])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)N(C)C
Yield: 77 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (50a) (65 mg, 0.13 mmol), dimethylamine hydrochloride (29 mg, 0.36 mmol), WSC hydrochloride (78 mg, 0.41 mmol) and HOBT (20 mg, 0.15 mmol), to obtain 52.9 mg of the title compound (77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH:38]3[CH2:40][CH2:39]3)(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 66.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.095 g, 0.19 mmol) obtained in step 4 and cyclopropanesulfonamide (0.12 g, 0.95 mmol), the title compound (0.076 g, 66%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[CH2:22]([NH:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH2:22]([N:29]([CH3:30])[C:10](=[O:12])[C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH:14]=[CH2:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CNCc1ccccc1
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CC[C@H](C(=O)N(C)Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h

Procedure:
A solution of 4.8 g (19.6 mmol) of 2-(S)-(3,4-dichlorophenyl)-4-pentenoic acid in 50 mL of CH2Cl2 and 10 drops of DMF was cooled in an ice bath and 1.8 mL of oxalyl chloride was added. The solution was stirred for 15 min after gas evolution had ceased. The mixture was concentrated in vacuo and the residue was diluted with 50 mL of CH2Cl2. The solution was cooled in ice bath as 2.6 mL (20.4 mmol) of N-benzyl-methyl amine and 1.7 mL (21 mmol) of pyridine were added. After stirring for 1 h at ice bath temperature the solution was diluted with CH2Cl2 and washed with water, 1.2N HCl and brine. The solution was dried over Na2SO4 and concentrated to give N-benzyl-N-methyl-2(S)-(3,4-dichlorophenyl)-4-pentenoamide as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=O)[C:6]([CH3:14])([CH3:13])[O:5][C:4]=2[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:11]=[N:10][C:9]2[NH:8][CH2:7][C:6]([CH3:14])([CH3:13])[O:5][C:4]=2[CH:3]=1
Reactant: CC1(C)Oc2cc(Br)cnc2NC1=O
Solvent: C1CCOC1
Product: CC1(C)CNc2ncc(Br)cc2O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 7-bromo-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (0.360 g, 1.39 mmol) in THF (8.9 mL) at 0° C. was added BH3 (8.43 mL of a 1.0 M solution in THF, 8.43 mmol). The solution was heated to reflux. After 18 h, the solution was cooled to 0° C. and the reaction quenched with MeOH (15 mL). The mixture was concentrated and the resulting off-white solid was dissolved in MeOH (15 mL) and NaOH (10 mL of a 1 N solution). The mixture was heated at reflux to 4 h. The MeOH was removed under reduced pressure. The resulting precipitate was collected by filtration and washed with H2O (10 mL). The white solid was dried to give the title compound (0.260 g, 76%) as white needles: 1H NMR (300 MHz, DMSO-d6) δ 7.62 (d, J=2.1 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 7.03 (br s, 1H), 3.14 (d, J=2.4 Hz, 2H), 1.25 (s, 6H); MS (ESI) m/e 243 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>C1COCC1>[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:21]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Cc1cccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)C(Cl)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 124.4 %

Procedure:
To an ice-cooled solution of 6-methylpyridin-2-amine [CAS 1824-81-3] (5.22 g, 44.08 mmol) in 350 mL anhydrous THF was added diisopropylethylamine (15.36 mL, 88.16 mmol). Chloro(phenyl)acetyl chloride [CAS 2912-62-1] (10.0 g, 52.9 mmol) was added dropwise and the resulting mixture was stirred for 1 h while cooling was maintained. The mixture was partitioned between ethyl acetate and water and the organic phase was washed with brine. The organic phase was filtered through a Whatman filter and the volatile components were removed by the use of a rotary evaporator to give title compound (14.3 g) in ˜80% purity (LC-MS). The crude material was forwarded directly to the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH:10]=[CH:11][O:12][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[Si](C)(C)Cl
Reactant: N#Cc1cccc(CCC=O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC=CCc1cccc(C#N)c1

Procedure:
A stirred solution of 3-(3-cyanophenyl)propanal (3.1 g), trimethylsilyl chloride (3.0 ml) and triethylamine (6.5 ml) in dimethylformamide (45 ml) was heated under reflux on an oil bath at 150°-160° C. for 4 hours. The mixture was cooled and filtered and the filtrate was diluted with hexane (200 ml) and rapidly washed successively with cold sodium bicarbonate solution, cold dilute hydrochloric acid and cold sodium bicarbonate solution again. The hexane solution was dried and evaporated and the residue was distilled under vacuum in a bulb-to-bulb apparatus to give the product as a colourless oil, b.p. 140°-150° C./0.1 mm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1>O>[Cl:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: C1CNCCN1
Solvent: O
Product: Clc1cnc(N2CCNCC2)c(Cl)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Piperazine (24.0 g) was melted by heating at 140° C. and 2,3,5-trichloropyridine (5.00 g) was added thereto. The mixture was stirred at 120° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3,5-dichloro-2-pyridyl)piperazine (6.43 g) as a brown solid.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:16]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH:25](Cl)[CH3:26])[CH2:21][CH2:20]1>C(O)C>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:17][C:16]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[O:9][C:8](=[O:18])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:21][CH2:20]1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Reactant: CC(Cl)N1CCOCC1
Solvent: CCO
Product: O=c1oc2c(c(OCCN3CCOCC3)c1-c1ccccc1)CCCC2
Yield: 71 %

Procedure:
The desired product is prepared according to the method of Example 9 from 14.5 g. (0.06 mol) of 3-phenyl-4-hydroxy-5,6,7,8-tetrahydro-coumarin and 11.7 g. (0.078 mol) of 2-morpholino-2-chlorethane. M.P. 115° C. (ethanol); weight 15.1 g. (yield 71%, theoretical yield 21.3 g.).