Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:13]2[CH2:16][N:15](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14]2)[C:10]([CH3:12])=[CH2:11])[CH:5]=[C:6]([F:8])[CH:7]=1>CO.Cl.CCOCC.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:13]2[CH2:14][NH:15][CH2:16]2)[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=C(C)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)[C@H](c1cc(F)cc(F)c1)C1CNC1
Reaction time: 8 h

Procedure:
A mixture of 250 mg (0.64 mmole) of 3-[(1R)-1-(3,5-difluorophenyl)-2-methylprop-2-en-1-yl]-1-(diphenylmethyl)azetidine and 50 mg of 10% Pd/C in 10 mL methanol and 2 mL of 1M HCl in ether was shaken under 40 psi H2. After 8 h, the solution was filtered and the filtrate was concentrated. The residue was triturated with hexane to remove diphenylmethane and the residue was collected to afford the title compound as a white solid; Mass Spectrum m/e=226 (M+1)
Reaction SMILES: C([C:4]1[CH:8]=[C:7]([CH3:9])[S:6][C:5]=1[CH3:10])(=O)C.[NH:11]1[CH2:16][CH2:15][O:14]CC1.[S].C([OH:20])C>>[N-:11]1[CH2:9][CH2:7][S:6][CH2:5][CH2:4]1.[CH3:10][C:5]1[S:6][C:7]([CH3:9])=[CH:8][C:4]=1[CH2:16][C:15]([OH:14])=[O:20]
Reactant: C1COCCN1
Reactant: CC(=O)c1cc(C)sc1C
Reactant: CCO
Agent: [S]
Product: C1CSCC[N-]1
Product: Cc1cc(CC(=O)O)c(C)s1

Procedure:
10.0 g (64.8 mmol) of 3-acetyl-2,5-dimethylthiophene, 13.0 ml (13.0 g; 149 mmol) of morpholine and 3.49 g (109 mmol) of sulfur are heated under reflux for 16 hours. The mixture is cooled, poured into 20 ml of ethanol and concentrated, water is added, and the mixture is extracted with dichloromethane. Drying over magnesium sulfate, filtration and concentration gives 16.6 g of an oil which is purified by column chromatography on silica gel with dichloromethane/ethyl acetate 1:1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-valinol (8.80 g, 0.037 mol) and triethylamine (30.00 g, 41.3 mL, 0.30 mol) in 100 mL dimethylsulfoxide under a nitrogen atmosphere was added a solution of sulfur trioxide pyridine complex (20.62 g, 0.130 mol) in dimethylsulfoxide (100 mL) dropwise via an addition funnel. An ice water bath was used to maintain the temperature of the reaction mixture below room temperature during the addition. After 30 min the cooling bath was removed and the reaction was allowed to warm to room temperature over 2 h. The brown solution was acidified with cold 2 N HCl to approximately pH 2 and extracted with ether (3×150 mL). The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and evaporated to give 7.40 g of N-benzyloxycarbonyl-L-valinal (84.8%) as a yellow oil. The resulting material can be used without purification or further purified using column chromatography (silica gel, 9:1 hexanes:ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)c1ccncc1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)c3ccncc3)c2c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b, 1.0 g, 3.15 mmol) in dry DMF (20 mL) was added isonicotinic acid (504 mg, 4.10 mmol), followed by EDCI (783 mg, 4.10 mmol), HOBt (554 mg, 4.10 mmol), and triethylamine (414 mg, 4.10 mmol) at room temperature under nitrogen. After it was stirred at room temperature for 12 hrs, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and extracted with EtOAc (3×). The aqueous layer was basified with 2N NaOH to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by chromatography on silica gel eluting with 10% MeOH in dichloromethane to give the title compound as a yellow solid (1.1 g, 83%). 1H NR (400 MHz, DMSO-d6) δ 1.29 (t, J=4 Hz, 3H), 1.51 (s, 6H), 2.94 (s, 3H), 4.28 (q, J=4 Hz, 2H), 4.42 (s, 2H), 6.93 (dd, J=1, 8 Hz, 1H), 7.24 (dd, J=1, 8 Hz, 2H), 7.52 (t, J=8 Hz, 1H), 7.69 (dd, J=2, 4 Hz, 2H), 8.14 (s, 2H), 8.37 (s, 1H), 8.67 (dd, J=2, 4 Hz, 2H). MS 423 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.Cl[Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][Si:24](Cl)([CH3:26])[CH3:25].[Na+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si:24]([CH3:26])([CH3:25])[CH2:23][CH2:22][Si:21]2([CH3:29])[CH3:28])=[N:6][CH:7]=1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: Nc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
In a 500 mL three-necked flask, 5-bromopyridin-2-amine (5 g, 28.9 mmol) was combined with THF (80 ml) to give a light yellow solution. Cooled to −78° C. and n-butyllithium in hexane (18.2 ml, 29.2 mmol) was added via syringe. The reaction was stirred at −78° C. for 1 hr, then 1,2-bis(chlorodimethylsilyl)ethane (6.22 g, 28.9 mmol) was added dropwise over 15 min. After stirring for 90 min at −78° C., n-butyllithium in hexane (18.2 ml, 29.2 mmol) was added. The reaction was allowed to warm to 25° C. and stirred for 2 hr. The reaction mixture was diluted with 50 mL sat NaCl and extracted with diethyl ether (2×200 mL). The organic layers were combined, washed with H2O (1×25 mL), sat NaCl (1×25 mL), dried over MgSO4 and concentrated in vacuo. The crude brown oil was purified by vacuum distillation (1 mm Hg, 170° C.). The product solidified upon cooling to give 4.89 g (54%) of the title compound as a white crystalline solid. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.15 (d, J=2.6 Hz, 1H), 7.47 (dd, J=8.9, 2.5 Hz, 1H), 6.47 (d, J=8.7 Hz, 1H), 0.83 (s, 4H), 0.24-0.38 (m, 12H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:14]([Br:17])[CH:15]=[CH2:16]>C1(C)C=CC=CC=1>[Br-:17].[OH:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N+:4]([CH2:16][CH:15]=[CH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: Oc1cccnc1-c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC[n+]1cccc(O)c1-c1ccccc1
Product: [Br-]
Temperature: 0 °C

Procedure:
A suspension of 3-hydroxy-2-phenylpyridine (15 g, 116 mmol) in toluene (250 ml) was heated at reflux for 30 minutes. Allyl bromide (30 ml) was added and the reaction mixture was heated at reflux for 20 hours and cooled using the ice bath. Solid was filtered off and washed twice with ether to afford crude 3-hydroxy-2-phenyl-N-(prop-2-enyl)-pyridinium bromide, which was used treated with acrylonitrile (100 ml), triethylamine (15 ml) and 1,4-dioxane (200 ml) was heated at reflux for 28 hours and cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated to give a crude mixture of regio and stereoisomers in ratio (6R*):(6S*):(7R*):(7S*)=7:8:1:5. Isomers were separated by chromatography on silica gel (iso-hexane:ethyl acetate).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.[N+]([O-])(O)=O.[C:19]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1)(=[NH:21])N.[C:32](=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[CH:4]=[CH:3][N:21]=[C:19]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH2:29])=[O:28])=[CH:30][CH:31]=3)[CH:32]=2)=[CH:8][CH:9]=1
Reactant: N=C(N)Nc1ccc(C(N)=O)cc1
Reactant: O=C([O-])[O-]
Reactant: CN(C)/C=C/C(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: NC(=O)c1ccc(Nc2cc(-c3ccc(Cl)cc3)ccn2)cc1
Temperature: 25 °C

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-(4-chlorophenyl)prop-2-en-1-one (0.10 g, 0.48 mmol), 4-(amidinoamino)benzamide nitrate (0.116 g, 0.48 mmol), and potassium carbonate (0.132 g, 0.96 mmol) in ethanol (10 ml) with was heated to 120° C. overnight in a sealed vessel. The reaction mixture was cooled to room temperature and the resulting solid was collected then washed with ethanol, water, and diethyl ether to provide the title compound as a beige solid, identical in all respects with the compound prepared in Example 1.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: NNC(N)=S
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(C(CCCCl)=NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Thiosemicarbazide (6.84 g, 75 mmol) was added under nitrogen to a solution of 4-chloro-4'-methylbutyrophenone (10.0 g, 50 mmol) in 175 mL of methanol plus 13.5 mL of 1 N HCl plus 12.5 mL of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration and dissolved in methylene chloride. The organic solution was washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 10.15 g of an off-white solid. Recrystallization of the solid from isopropyl alcohol gave 8.65 g (64%) of the tide compound as an off-white solid, mp133-135° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17]([OH:19])=[O:18])(=[O:13])=[O:12]>>[N+:6]([C:21]1[CH:20]=[C:16]([CH:15]=[C:14]([S:11]([Cl:10])(=[O:13])=[O:12])[C:22]=1[Cl:23])[C:17]([OH:19])=[O:18])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a mixture of concentrated sulfuric acid (87 ml.) and concentrated nitric acid (16 ml., density = 1.42) is added 3-chlorosulfonyl-4-chlorobenzoic acid (11.5 g.; 0.045 mole). The reaction mixture is heated at 85°-90° C. with stirring for 20 hours then poured into ice water. The 3-nitro-4-chloro-5-chlorosulfonylbenzoic acid which separates is filtered, washed with water and dried, m.p. = 189°-90° C. (corr.); yield, 6.6 g. (50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)=[N:6][CH:7]=1.[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:15])[C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: Cn1nnnc1Nc1ccc(Br)cn1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1ccc(Br)cn1)c1nnnn1C
Temperature: 70 °C
Yield: 31.4 %

Procedure:
5-bromo-N-(1-methyl-1H-tetrazol-5-yl)pyridine-2-amine (1 g, 3.9 mmol) was dissolved in 50 mL THF, potassium tert-butylate (0.88 g, 7.8 mmol) and iodomethane (1.1 g, 7.8 mmol) were added slowly. The reaction was heated to 70° C. and reacted for 12 h. After filtration and concentration, 330 mg of product was obtained by separation on a silica gel column (dichloromethane:methanol=100:1), at a yield of 31%.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([CH:16]=[N:17][OH:18])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.[CH3:27][O:28][CH2:29][C:30]#[CH:31].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([C:16]2[CH:31]=[C:30]([CH2:29][O:28][CH3:27])[O:18][N:17]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCOC
Reactant: O=C(c1ccccc1)N1CCC(Cl)=C(C=NO)C1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(C2=C(Cl)CCN(C(=O)c3ccccc3)C2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzoyl-4-chloro-3-formyl-1,2,5,6-tetrahydropyridine oxime (5.3 g, 20 mmol) in 100 ml dry dimethylformamide was added N-bromosuccinimide (4.5 g, 25 mmol) dissolved in 20 ml dry dimethylformamide. The reaction mixture was stirred at room temperature for 1 h. Now methylpropargylether (1.5 ml, 25 mmol) and 2 ml triethylamine was added and the reaction mixture stirred at room temperature overnight. 200 ml water was added and the aqueous phase extracted with 3×50 ml ether. The combined ether extracts were washed with 2×50 ml water, dried over magnesiumsulfate and concentrated in vacuo. The compound was finally purified by column chromatography with methylenechloride/ethylacetate 4:1 as eluent. Yield: 3.5 g. M.p. 60.5°-62° C.
Reaction SMILES: C(O[C:5](=[O:21])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.[CH3:42][O:43][C:44]1[CH:65]=[CH:64][C:47]([C:48]([NH:50][C:51]([CH3:63])([CH3:62])[C:52]([N:54]2[CH2:58][CH2:57][CH2:56][CH:55]2C(O)=O)=[O:53])=[O:49])=[CH:46][CH:45]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.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>[CH2:14]([O:13][CH:8]1[CH:7]([NH:6][C:5]([CH:55]2[CH2:56][CH2:57][CH2:58][N:54]2[C:52](=[O:53])[C:51]([NH:50][C:48](=[O:49])[C:47]2[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:65][CH:64]=2)([CH3:63])[CH3:62])=[O:21])[CH2:11][C:10](=[O:12])[O:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: COc1ccc(C(=O)NC(C)(C)C(=O)N2CCCC2C(=O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(=O)NC(C)(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
To a solution of (2-benzyloxy-5-oxo-tetrahydrofuran-3-yl)-carbamic acid allyl ester (40) (1.027 g, 3.5 mmol) in CH2Cl2 (20 ml) was added DMBA (543 mg, 3.48 mmol) and Pd(PPh3)4 (280 mg, 0.24 mmol) and the solution was stirred at room temperature under N2 for 20 minutes. A solution of 1-[2-(4-methoxy-benzoylamino)-2-methyl-propionyl]-pyrrolidine-2-carboxylic acid (818 mg, 2.45 mmol) in CH2Cl2 (5 ml) was added, followed by HOBT (0.534 g, 3.95 mmol) and EDC (738 mg, 3.84 mmol). The reaction was stirred at room temperature for 18 hours under N2. 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 yellow solid. Purification by flash column chromatography, eluting with ethyl acetate/hexanes (20/80 to 50/50%), gave the product as pale yellow solid (760 mg, 61% yield). 1H-NMR (500 MHz, CD3OD) δ 1.53 (d, 6H), 1.65-1.93 (m, 3H), 1.96-2.14 (m, 1H), 2.60 (dd, 0.1H), 2.77 (dd, 0.85H), 2.94 (dd, 0.85H), 3.04-3.11 (m, 0.2H), 3.42-3.52 (m, 1H), 3.57-3.67 (m, 1H), 3.84 (s, 3H), 4.38-4.76 (m, 3H), 4.84 (d, 1H), 5.64-5.70 (m, 1H), 6.96-7.03 (m, 2H), 7.23-7.43 (m, 5H), 7.78-7.97 (m, 2H). Analytical HPLC (C18 column) 13.32, 14.37 min. LC-MS (ES+) m/e=524.3 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[F:14][C:15]([F:29])([F:28])[C:16]1[CH:17]=[C:18]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:19]=[CH:20][CH:21]=1>C(O)C>[ClH:1].[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:2][N:25]1[CH2:24][CH:23]=[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:14])([F:28])[F:29])[CH:17]=2)[CH2:27][CH2:26]1
Reactant: ClCCc1ccc2ccccc2c1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Solvent: CCO
Product: Cl
Product: FC(F)(F)c1cccc(C2=CCN(CCc3ccc4ccccc4c3)CC2)c1

Procedure:
It has also been found that the reaction of 2-(2-chloroethyl)naphthalene with 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine under the conditions described in EP 0 101 381, i.e. in ethanol under reflux for 20-24 hours, gives 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride with very low yields.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:24])[CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.[OH-].[K+]>ClCCl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][N:15]([C@@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[C:3](=[O:4])[CH2:2][O:24]2)=[CH:11][CH:12]=1
Reactant: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 115 %

Procedure:
A solution of chloroacetyl chloride (19.5 ml, 245 mmol) in dichloromethane (100 ml) was added dropwise to a ice-cooled solution of (1S)-1-(4-bromophenyl)-2-((1R)-1-phenylethylamino)ethanol (intermediate 11, 71.0 g, 222 mmol) and triethylamine (34 ml, 245 mmol) in dichloromethane (600 ml). After the mixture was stirred for 2 hours, 1 M hydrochloric acid was added and the mixture was partitioned between water and chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in 2-propanol (600 ml). The solution was added with potassium hydroxide (85%, 18.3 g, 278 mmol). The mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and the residue was added with ethyl acetate. The mixture was partitioned between water and ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give (6S)-6-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholin-3-one (intermediate 12, 92 g) as a brown oil. This crude product was used for next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]([C:34]2[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:37]1[CH:36]=[CH:35][C:34]([N:27]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:42][CH:41]=2)[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:39][CH:38]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: COc1ccc(CN(c2ccc(Br)cc2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccc(OC)cc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 62.8 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (83.3 mg) was reacted with N-(4-methoxybenzyl)-N-(4-bromophenyl)pyrimidin-2-amine (102.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-methoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (102.4 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=3/1→1/3) and thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=1/5) were used for purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[C:12]([F:16])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[C:6](=[O:20])[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1.[C-:27]#[N:28].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[F:16][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:17][O:18][CH3:19])[C:7]3[C:6](=[O:20])[N:5]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:4]=[C:3]([CH2:2][C:27]#[N:28])[C:15]=3[C:14]=2[CH:13]=1
Reactant: [C-]#N
Reactant: COCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Yield: 86.6 %

Procedure:
A two-phase mixture of 2.8 g (6.7 mmol) of 1-(bromomethyl)-8-fluoro-5-(methoxymethyl)-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 1.3 g (26 mmol) of sodium cyanide and of 0.23 g (0.7 mmol) of tetrabutylammonium bromide in 100 ml of dichloromethane and 100 ml of water is stirred vigorously for 12 h. The organic phase is separated, washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. Diethyl ether is added and the precipitate is collected by filtration and dried under reduced pressure. 2.1 g (5.8 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH:20][CH2:21][CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:18]([N:20]([CH2:21][CH:22]([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH3:19]
Reactant: CCNCC(OCC)OCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OCC

Procedure:
4-Chloro-3,5-dinitrobenzotrifluoride (5.4 grams; 0.02 mole) dissolved in toluene (50 ml) and a solution of N-ethyl-N-(2,2-diethoxyethyl)amine (3.2 grams; 0.02 mole) and triethylamine (2.02 grams; 0.02 mole in toluene (50 ml) were charged into a glass reaction vessel equipped with stirrer, thermometer and reflux condenser. The mixture was heated at reflux overnight resulting in the formation of a precipitate. The reaction mixture was then filtered and the filtrate was washed with water, dried and stripped of solvent to yield the desired product N-ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-4-trifluoromethylaniline.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=O>C1C=CC=CC=1>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][C:15]([CH3:17])([CH3:14])[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: OCC(CO)OCc1ccccc1
Solvent: c1ccccc1
Product: CC1(C)OCC(OCc2ccccc2)CO1

Procedure:
Using the procedure of Example 51, 2-benzyloxy-1,3-propanediol and acetone were reacted, using benzene as solvent, to give, after distillation using a short path column, 5-benzyloxy-2,2-dimethyl-1,3-dioxane. The nmr spectrum was consistent with the assigned structure.