Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]([CH3:27])=[CH:23][NH:22][C:21]2=[O:28])[CH2:13][CH2:12]1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Cl>>[ClH:31].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][N:22]1[CH:23]=[C:24]([CH3:27])[C:25](=[O:26])[N:20]([CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][C:2]([F:29])([F:1])[F:30])[CH2:16][CH2:15]2)[C:21]1=[O:28]
Reactant: ClCc1cccc(Cl)c1
Reactant: Cc1c[nH]c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cc1cn(Cc2cccc(Cl)c2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 3-{3-[4-(2-(2,2,2-trifluoroethoxy)phenyl)piperazin-1-yl]propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione and 3-chlorobenzyl chloride gave 1-(3-chlorobenzyl)-3-{3-[4-(2-(2,2,2-trifluoroethoxy)phenyl)piperazin-1-yl]-propyl}-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 142°-144° C.; Anal.: Calcd. for C27H30ClF3N4O3.HCl: C, 55.03; H, 5.33; N, 9.50%; Found: C, 54.80; H, 5.27; N, 9.46%;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 19.4 %

Procedure:
A mixture of 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (1.0 g, 5.0 mmol), 2-methoxyphenyl boronic acid (1.1 g, 7.2 mmol), [RhCl(cod)]2 (110 mg, 0.25 mmol) and TEA (5 mmol) in H2O (14 ml) and 1,4-dioxane (1 ml) was stirred at 90° C. in a sealed vial for 6 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/acetone) to provide 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-propionic acid methyl ester XXXVII (300 mg, 20% yield) as a yellow film.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1C=CC=CC=1>[N+:17]([C:13]1[CH:12]=[C:11]([C:10]2[S:32][C:6]([C:5]3[CH:21]=[CH:22][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(C(=O)NNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(-c2nnc(-c3cccc([N+](=O)[O-])c3)s2)cc1
Temperature: 60 °C

Procedure:
A mixture of 1-[(4-methyl)benzoyl]-2-(3-nitrobenzoyl)hydrazine (1.40 g, 4.68 mmol) and Lawesson's Reagent (0.95 g, 2.34 mmol) in benzene (25 ml) is slowly heated to 60° C. After 3 hours the solution is concentrated, quenched with 35 ml of water and heated to reflux for 12 hours. The mixture is then cooled to room temperature and the precpitate is collected by filtration. The precipitate is then taken up in chloroform (100 ml) and the insoluble portion is removed by filtration. The filtrate is then dried over MgSO4 and concentrated to yield 2-(3′-nitrophenyl)-5-(p-tolyl)-1,3,4-thiadiazole as a pale yellow solid. (0.67 g, 48%).
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]=1[C:15]([CH3:23])([CH3:22])[CH2:16][O:17]C(OC)=O.[O:26]=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=[C:28]1[C:37](O)=[O:38].N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)[O:50]1)CC.C[O-].[Na+]>CC1OCCC1.O>[C:11]([C:7]1[CH:6]=[C:5]([C:15]([CH3:22])([CH3:23])[CH2:16][OH:17])[C:4]([OH:50])=[CH:9][C:8]=1[NH:10][C:37]([C:28]1[C:27](=[O:26])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=[O:38])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Reactant: COC(=O)OCC(C)(C)c1cc(C(C)(C)C)c(N)cc1COC(=O)[O-]
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC1CCCO1
Product: CC(C)(C)c1cc(C(C)(C)CO)c(O)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a mixture of [5-amino-4-tert-butyl-2-(2-methoxycarbonyloxy-1,1-dimethyl-ethyl)phenyl]methyl carbonate (103 mg, 0.29 mmol), 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (50 mg, 0.26 mmol), and pyridine (42 mg, 0.53 mmol) in 2-MeTHF (3.0 mL) was charged T3P as a 50 wt % solution in 2-MeTHF (286 mg, 0.45 mmol). The mixture was heated to 50° C. for 18 h. After cooling to ambient temperature, the mixture was diluted with water. The organic phase was separated and again washed with water. Sodium methoxide (39 mg, 0.72 mmol) was charged to the organic phase and the solution stirred for 2 hours. The reaction was quenched with 1N HCl, and after separating the phases, the organic phase was washed with 0.1N HCl. The organic phase was than dried in vacuo to yield Compound 27 as a solid. The 1H-NMR spectrum was consistent with that reported above.
Reaction SMILES: Cl[S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)s2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)s2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 1. Reaction of 5-chlorosulfonyl-2-(4-methoxyphenyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide in 50% yield, m.p. 128°-130° C.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[C:9]([Cl:20])[CH:10]=[C:11]([C:15]([O:17]CC)=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2].[OH-].[K+].C(O)C>O>[CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[C:9]([Cl:20])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(SCC)CCS2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSC1CCSc2c(Cl)cc(C(=O)O)c(C)c21
Temperature: 60 °C
Yield: 143.6 %

Procedure:
0.75 Gram (2.3 mmol) of 4-ethylthio-5-methyl-6-ethoxycarbonyl-8-chlorothiochroman, 0.47 g (7.1 mmol) of potassium hydroxide, 5 ml of ethanol and 2 ml of water were mixed, and the mixture was stirred under heat at 60° C. for 2 hours. After the completion of the reaction, the solvent was distilled off, 5 ml of water was added, and then 2N hydrochloric acid was added to adjust a pH of 1. Then, the mixture was extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 1.0 g (yield 100%) of 4-ethylthio-5-methyl-6-carboxy-8-chlorothiochroman.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH3:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][O:4][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][CH:10]=1
Reactant: CC[C@H](C)CO
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC[C@H](C)COC(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
28.51 g (0.23 moles) of a commercially available (S)-2-methylbutanol was dissolved in 100 ml of pyridine. The mixture was cooled and 50 g (0.23 moles) of a commercially available 4-methylbenzoic chloride was added thereto while cooling. The mixture was then allowed to react with stirring at 50° to 60° C. for 2 hours. On completion of the reaction, 300 ml of water and 300 ml of toluene were added, and after vigorous stirring, the toluene layer was separated out and washed with 6N HCl. Washing was continued until this layer was neutral. This toluene layer was dried with anhydrous magnesium sulfate, after which the toluene was distilled away. The residue was further subjected to evaporation under reduced pressure at 118° to 120° C. (5 mm Hg) and the distillate recovered, whereby 59.61 g of the objective 4-methylbenzoic((S)-2-methylbutyl) ester was obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[CH2:11]([C:14]1[N:19]2[N:20]=[CH:21][C:22]([C:23](OCC)=[O:24])=[C:18]2[CH:17]=[CH:16][CH:15]=1)[CH2:12][CH3:13]>C1C=CC=CC=1>[CH2:11]([C:14]1[N:19]2[N:20]=[CH:21][C:22]([C:23]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:24])=[C:18]2[CH:17]=[CH:16][CH:15]=1)[CH2:12][CH3:13]
Reactant: CCCc1cccc2c(C(=O)OCC)cnn12
Reactant: OC1CN2CCC1CC2
Agent: [Na]
Solvent: c1ccccc1
Product: CCCc1cccc2c(C(=O)OC3CN4CCC3CC4)cnn12
Reaction time: 2 h
Yield: 84.9 %

Procedure:
After a suspension of 330 mg (2.60 mmol) of 3-quinuclidinol in 30 ml of benzene was refluxed for 0.5 hour by using a Dean-Stark apparatus, 0.1 g of metal sodium was added and the resultant mixture was refluxed under stirring for further 2 hours. Unreacted sodium was removed and 200 mg (0.86 mmol) of ethyl 7-propylpyrazolo[1,5-a]pyridine-3-carboxylate were added, followed by heating under reflux for 20 hours. The solvent of the reaction mixture was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (chloroform: methanol=10:1), whereby 230 mg (0.73 mmol) of the title compound were obtained as an oily substance (yield: 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[C:13]([NH:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[C:13]([NH:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(NC(=O)c1cccc(-c2ccncc2[N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2N)c1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution containing 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (2.0 g, 5.5 mmol) and methanol (18.5 mL) was added 10% Pd/C (1.6 g, 0.76 mmol, wet, 50% water) in one portion under a nitrogen atmosphere. The reaction mixture was stirred for 2 h under an atmosphere of hydrogen gas (balloon), filtered and concentrated to afford 3-(3-aminopyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a pale yellow oil which was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.47 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.85 (d, J=4.77 Hz, 1H), 7.81 (ddd, J=7.65, 1.63, 1.51 Hz, 1H), 7.52-7.61 (m, 2H), 7.36-7.41 (m, 2H), 7.24-7.30 (m, 2H), 7.15 (t, J=7.28 Hz, 1H), 7.04 (d, J=5.02 Hz, 1H), 5.15 (s, 2H), 1.64-1.70 (m, 6H). LCMS: retention time: 1.240 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 332 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([C@H:24]1[CH2:29][CH2:28][C@@H:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:30][C@H:27]1[CH2:26][CH2:25][C@@H:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:29][CH2:28]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@H]1CC[C@@H](C(=O)OCC)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with cis-4-amino-cyclohexanecarboxylic acid ethyl ester following general procedure B to afford 8-methoxy-4-(cis-4-ethoxycarbonyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (198 mg). Thus obtained amino-ester (175 mg, 0.44 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish cis-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-cyclohexane-carboxylic acid ethyl ester (138 mg). LCMS: m/z 508 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[CH:3]=1.OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Cl)cc(-c2ccccc2C(F)(F)F)n1
Agent: O=S(=O)(O)O
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (617.5 mg, 2.27 mmol, prepared as described in STEP A above) was cooled to 0° C. and treated slowly with H2SO4 (10 mL). The mixture was stirred at 0° C. for 1 h. Nitric acid (133 μL, 2.94 mmol) was added slowly, and the mixture continued to stir at 0° C. for an additional 1.5 h. Ice (50 mL) was added. A precipitate formed and was filtered, dissolved in DCM (70 mL), and washed with saturated aqueous NaHCO3 (70 mL). The aqueous layer was extracted with DCM (30 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 35 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, then 1:19 to 1:3 over 40 min) to yield 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as a yellow solid. The basic mother liquor and acidic filtrate were carefully combined, made basic with 1 N aqueous NaOH, and extracted twice with DCM (100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to yield additional product. 1H-NMR (400 MHz, CDCl3) δ: 7.76-7.90 (m, 1H), 7.55-7.71 (m, 2H), 7.46 (d, J=7.3 Hz, 1H), 6.93 (s, 1H), 6.11 (br. s., 2H). Mass Spectrum (LCMS, APCI pos.): Calculated for C12H7N3O2ClF3: 318.0 (M+H); Measured: 318.0.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15].[Cl-].[NH4+].C(Cl)Cl>CCO.O.[Fe]>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:15]
Reactant: CN1C(=O)COc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)COc2cc(N)ccc21
Temperature: 80 °C

Procedure:
To a stirred suspension of 4-methyl-7-nitro-2H-1,4-benzoxazin-3-one (DE 19802239, 2.43 g, 11.67 mmol) in EtOH (20 mL) and water (10 mL) is added ammonium chloride (6.25 g, 116.70 mmol). To this mixture is added iron (1.95 g, 35.00 mmol) in 3 equal portions. The resulting mixture is heated to 80° C. for 2 h at which time the reaction is cooled to room temperature followed by addition of CH2Cl2 (100 mL). The resulting mixture is filtered through celite and the filtrate is further diluted with water (100 mL). The organic layer is separated followed by further extraction of the aqueous phase with CH2Cl2 (3×50 mL). The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure, and the product is purified by silica gel column chromatography (EtOAc) to give the title compound in quantitative yield, MS m/z 179.1 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:18]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[S:26]>>[BrH:1].[C:5]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]2([OH:17])[N:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:18]=[C:19]3[S:26][CH2:2]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)C(c1ccccc1)c1ccccc1
Reactant: S=C1NCCCCCN1
Product: Br
Product: OC1(C(c2ccccc2)c2ccccc2)CSC2=NCCCCCN21

Procedure:
1-Bromo-3,3-diphenyl-2-propanone is reacted with hexahydro-1,3-diazocin-2(1H)-thione by the procedure of Example 22, giving the desired product, m.p. 211°-213° C. (dec.).
Reaction SMILES: C([N:3](CC)CC)C.[Al+3].[Cl-].[Cl-].[Cl-].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].CCOC(C)=O>ClCCCl>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH2:3])=[O:13]
Reactant: O=C1OCc2ccccc21
Reactant: CCN(CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1CO
Temperature: 17.5 °C
Yield: 97.5 %

Procedure:
A solution of triethylamine (TEA, 0.824 g, 1.13 ml, 8.14 mmol, 1.5 equiv.) in 1,2-dichloroethane (3 ml) was added dropwise under stirring and cooling with ice to a suspension of AlCl3 (0.796 g, 5.97 mmol, 1.1 equiv.) in 1,2-dichloroethane (7 ml). The temperature was maintained at 15-20° C. during the addition and the mixture was then allowed to warm up at room temperature. A solution of 1-dimethoxytrityl-6-amino-hexan-1-ol (16) (2.505 g, 5.97 mmol, 1.1 equiv., prepared as described by Woo and Fung (1996), International Pat. App. Pub. No. WO 96/05215, which is incorporated herein by reference in its entirety) and phthalide (17) (0.728 g, 5.43 mmol, 1.0 equiv.) in 1,2-dichloroethane (3 ml) was added over a period of 20 min and the mixture was stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis (EtOAc containing 1% TEA). The reaction mixture was then quenched with an ice-water mixture (30 ml) and stirred for further 30 min. The resulting suspension was filtered through a bed of Celite® and the filter cake was washed with 1,2-dichloroethane (10 ml). The organic phase of the combined filtrates was separated, washed with water (30 ml) and brine (20 ml), dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (15-70% EtOAc in hexanes containing 1% of TEA, gradient elution) yielding 0.80 g (27%) of compound (19) as a pale yellow oil. Rf=0.68 (EtOAc containing 1% TEA). 1H NMR (400 MHz, CD3CN) δ 7.61-7.19 (m, 14H), 6.85 (d, J=8.9 Hz, 4H), 5.33 (s, 1H), 4.50 (s, 2H), 3.75 (s, 6H), 3.32 (q, J=6.6 Hz, 2H), 3.01 (t, J=6.6 Hz, 2H), 1.63-1.53 (m, 4H), 1.44-1.28 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]([F:14])([F:13])[C:7]1[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=1.CN1CCOCC1.[OH-].[Na+].Cl>C(Cl)Cl>[F:5][C:6]([F:14])([F:13])[C:7]1[CH:11]=[C:10]([NH:12][C:1](=[O:3])[CH3:2])[NH:9][N:8]=1
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
Acetyl chloride (7.7 ml, 108 mmol) was added over a period of 45 minutes to a solution of 3-(trifluoromethyl)-1H-pyrazol-5-amine (6.5 g, 43 mmol) and N-methylmorpholine (12.3 ml, 112 mmol) in CH2Cl2 (160 ml) with cooling in an ice bath. The reaction was allowed to warm to room temperature and stirred for 16 h, the solvent was removed in vacuo and the residue dissolved in methanol (150 ml). The solution was cooled in an ice bath and 25% aqueous NaOH (7.3 ml, 65 mmol) was added. After 3.25 h, 25% aqueous NaOH (0.5 ml, 4.4 mmol) was added and the reaction stirred for an additional 1.5 h. 2N HCl (20 ml) was added and the organic solvents were removed in vacuo at below 35° C. Water was added and the crude then extracted EtOAc (×2) and the extracts dried (MgSO4) and concentrated in vacuo. The resultant residue was suspended in CH2Cl2 (20 ml) with stirring. The solid was filtered and washed with CH2Cl2 (2×3 ml) and dried in vacuo to provide the title compound as a white solid (7.3 g) which was used in the subsequent step.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[C:16]1([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[OH:1][CH:2]([CH2:15][N:25]1[CH2:26][CH2:27][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(O)CN1CCC(c2ccccc2)CC1

Procedure:
A solution of 1.980 g (9.744 mM) of N-(2,3-epoxy-propan-1-yl)phthalimide and 1.73 g (10.7 mM) of 4-phenylpiperidine in 50 ml of ethanol was refluxed for one hour, at the end of which time the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) and crystallized from diethyl ether-hexane to provide the title compound.
Reaction SMILES: C(O[C:4](Cl)([CH2:6][CH3:7])C)=O.[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:22]([OH:24])=O)[CH3:21])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25]([N:27]1CCCCC1)C>C(Cl)Cl>[CH2:25]([NH:27][C:22](=[O:24])[C@H:20]([CH3:21])[NH:19][C:17]([O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:18])[CH:6]([CH3:4])[CH3:7]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN1CCCCC1
Reactant: CCC(C)(Cl)OC=O
Solvent: ClCCl
Product: CC(C)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
14 ml of chloro-sec. butyl formate added at -10 degrees C. to a solution of 23 grams of benzyloxycarbonyl alanine in 200 ml of methylene chloride and 14 ml of N-ethyl piperidine, 20.7 g of a product having a melting point of 109 to 111 degrees C. was obtained by the procedure described in Example 1 by crystallization from 60 ml of ethyl acetate and 200 ml of petroleum ether [α]D20 8.7 degrees (c 0.3; dimethylformamide).