Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C([Li])CCC.C1(NC2CCCCC2)CCCCC1.[C:21]([O:24][CH2:25][CH3:26])(=[O:23])[CH3:22].Cl[C:28]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29].C(O)(=O)C>O1CCCC1>[O:29]=[C:28]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:22][C:21]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCCC(=O)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)CCCC(=O)OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55.1 %

Procedure:
A five liter round bottom flask was fitted with a mechanical stirrer, thermometer and a one liter additional funnel. The addition funnel was in turn fitted with a septum into which was introduced a N2 line, an equalizing line and a liquid reagent inlet line. The equalizing line was further connected with tubing to a straight vacuum adapter and this adapter was fitted between the addition funnel and the flask. The flask was charged with N2 and then with 976 ml. (2.05 moles=2.25 equiv.) n-butyllithium in 800 ml. of anhydrous tetrahydrofuran (THF), and the mixture cooled to -78° C. in a dry ice/acetone bath. To this was added 408 ml. (2.05 moles) of dicyclohexylamine in 375 ml. THF dropwise over 45 minutes (temperature kept below -67° C.). After equilibrating to -78° C., 201 ml. (2.05 moles) of ethyl acetate in 100 ml. THF was added dropwise over 45 minutes (temperture kept below -67° C.). The mixture was allowed to stir at -78° C. for 15 minutes and then 150 g. (0.91 mole) of methyl 4-(chloroformyl)butyrate in 200 ml. THF was added dropwise over 30 minutes (temperature kept below -70° C.). After stirring for 1 hour at -78° C., 231 ml. (2.05 moles) of glacial acetic acid was added dropwise over 25 minutes, after which the dry ice/acetone bath was removed, and the reaction allowed to warm to 0° C., diluted with one liter Et2O, and the white inorganics filtered. The solids were washed well with ether. The combined filtrate and washes were evaporated in vacuo and the residue was partitioned between one liter ether and one liter water. The ether was separated, washed in sequence 2x with 500 ml. 0.5N HCl, 1x with 500 ml. H2O, 1x with 500 ml. saturated NaHCO3, 1x with 500 ml. H2O and 1x with 500 ml. brine, dried over MgSO4, filtered and evaporated in vacuo to yield 108.5 g. (55.1%) of title product as a gold colored mobile liquid. Nmr (CDCl3): 4.1 (q, 2H), 3.6 (s, 3H), 3.4 (s, 2H), 1.7-2.7 (m, 6H), 1.25 (t, 3H). M/e: 216 (m+).
Reaction SMILES: [NH2:1][C@H:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@@H:3]([OH:7])[C:4]([OH:6])=[O:5].[Cl:15][Si](C)(C)[CH3:17]>CO>[ClH:15].[CH3:17][O:5][C:4](=[O:6])[C@H:3]([OH:7])[C@H:2]([NH2:1])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: N[C@H](Cc1ccccc1)[C@@H](O)C(=O)O
Solvent: CO
Product: COC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Product: Cl

Procedure:
A mixture of (2R,3R)-3-amino-2-hydroxy-4-phenylbutyric acid (200 mg, 1.0 mmol, Sigma Chemical Co. (St. Louis, Mo.), chlorotrimethylsilane (500 mg, 4.6 mmol) and methanol (2 mL) was heated at reflux for 5.5 hours and concentrated to a foam: Yield 244 mg, 100%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>ClCCl.O>[CH3:25][N:17]([CH2:16][CH2:15][NH:14][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
2-Nitrobenzenesulfonyl chloride (4.9 g, 22 mmol) was added to a dichloromethane solution (100 ml) of tert-butyl (2-aminoethyl)methylcarbamate (3.5 g, 20 mmol) and triethylamine (3.3 ml, 24 mmol) at 0° C., and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2→2:3). The purified product was concentrated under reduced pressure to thereby obtain 5.06 g (yield: 70%) of tert-butyl methyl-[2-(2-nitrobenzenesulfonylamino)ethyl]carbamate as a yellow oil.
Reaction SMILES: [CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Na].Cl.[CH2:13](O)C>>[C:1]1([C:7]([O:9][CH2:10][CH3:13])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCO
Reactant: COC(=O)C1C=CCCC1
Agent: Cl
Agent: [Na]
Product: CCOC(=O)C1=CCCCC1
Yield: 90 %

Procedure:
Methyl 2-cyclohexene-1-carboxylate (5.6 g; 40 m. moles) was added to a solution of sodium (1.1 g; 47.8 m. moles) in ethanol (35 ml) and the mixture was allowed to stand at room temperature for a period of 11/2 hours. The mixture was poured into dilute hydrochloric acid extracted with ether (4×25 ml) and the combined extracts washed with dilute aqueous sodium carbonate. The dried (MgSO4) extract was evaporated and the residue distilled to give ethyl 1-cyclohexene-1-carboxylate (5.5 g; yield 90%), b.p. 92° C./15 mm (N.M.R.: 6.7-7.0 (m,1,CH=C), 3.9-4.25 (q,2,CH2CH3), 1.95-2.42 (m,4,allylic CH2), 1.13-1.42 (t,3,CH2CH3) 1.45-1.92 (m,4,CH2 --CH2)).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd]>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccc(C2=NCCN2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ncc[nH]2)cc1

Procedure:
500 mg (2.3 mmol) of ethyl 4-(2-imidazoline-2-yl)benzoate and 500 mg of 10% palladium/carbon were heated in 20 ml of toluene under reflux in argon atmosphere for 9 hours. The reaction liquid was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated to obtain the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH3:37])[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:20]2[C:15](=[CH:16][C:17]([O:33][CH2:34][CH2:35][OH:36])=[CH:18][CH:19]=2)[O:14]1>N1C=CC=CC=1>[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)([OH:14])(=[O:9])=[O:8].[CH3:12][C:13]1([CH3:37])[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=2)[C:20]2[C:15](=[CH:16][C:17]([O:33][CH2:34][CH2:35][OH:36])=[CH:18][CH:19]=2)[O:14]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC1(C)CC(c2ccc(C(F)(F)F)cc2)c2ccc(OCCO)cc2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 2 h

Procedure:
p-Toluene-sulphonyl chloride (0.42 g) was added portionwise to a solution of 2,2-dimethyl-7-(2-hydroxyethyloxy)-4-(4-trifluoromethylphenyl)chroman (0.7 g) in pyridine (20 ml.) and the solution left at room temperature for 2 hours and then at 0° C. for 12 hours. The reaction mixture was poured onto ice, extracted with ether (2×100 ml.) and the ether extract dried (sodium sulphate). Removal of the solvent under reduced pressure gave an oil (0.65 g.) which had spectroscopic properties consistent within the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][CH2:16][C:17]([N:19]1[CH2:24][C:23]([CH3:25])=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:21]2[N:33]=[CH:34][C:35]([C:36]#[N:37])=[C:20]12)=[O:18]>>[ClH:1].[ClH:15].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[N:21]3[N:33]=[CH:34][C:35]([C:36]#[N:37])=[C:20]3[N:19]([C:17](=[O:18])[CH2:16][N:12]3[CH2:11][CH2:10][N:9]([CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:14][CH2:13]3)[CH2:24][C:23]=2[CH3:25])=[CH:27][CH:28]=1
Reactant: Clc1cccc(CN2CCNCC2)c1
Reactant: CC1=C(c2ccc(Cl)cc2)n2ncc(C#N)c2N(C(=O)CCl)C1
Product: CC1=C(c2ccc(Cl)cc2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3cccc(Cl)c3)CC2)C1
Product: Cl

Procedure:
The above compound was prepared by the reaction of 4-(3-chlorophenyl)methylpiperazine with the compound of Example 14 by the methods of Examples 16 then 77, mp 250° C. (with sintering).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[C:9]1[CH3:29])(C)(C)C.Cl[CH2:32][C:33]1[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][O:36][C:37]=1[CH3:38]>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[CH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20](=[O:27])(=[O:28])[N:19]1[CH2:32][C:33]1[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][O:36][C:37]=1[CH3:38]
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: Cc1onc(-c2ccccc2)c1CCl
Product: Cc1onc(-c2ccccc2)c1CN1C(c2c(C)n(CC(=O)O)c3ccc(Cl)cc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 6, step c) and 4-chloromethyl-5-methyl-3-phenyl-isoxazole. 1H NMR (DMSO-d6) 7.99-7.91 (m, 1H), 7.69-7.60 (m, 2H), 7.43 (d, J=8.7 Hz, 1H), 7.36 (d, J=7.2 Hz, 2H), 7.23-6.75 (m, 6H), 5.94 (s, 1H), 4.96 (s, 2H), 4.33 (d, J=14.1 Hz, 1H), 4.07 (d, J=14.1 Hz, 1H), 3.30 (s, 3H), 2.41 (s, 3H); MS: ESI (negative): 560, 562 (M−H).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:12]=1[C:13]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[CH:14][NH:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26]I>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:12]=1[C:13]([CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[CH:14][N:15]2[CH3:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CN(C)CCc1c[nH]c2c(F)ccc(OCc3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCc1cn(C)c2c(F)ccc(OCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
At 0° C., NaH (2 eq) was added to a solution of 1 eq of compound 1-7c in DMF. After 30 min, a solution of 0.1 M methyl iodide in DMF was added slowly over 30 min, and then the reaction mixture was allowed to warm to 25° C. and stirred at that temperature for 1 h. After standard workup, the brown oil residue was purified by column chromatography, eluting with CH2Cl2/2% NH4OH. A brown oil (1-8c) was obtained in 84% yield. 1H NMR (CDCl3-d, 300 MHz) δ (ppm) 2.13 (s, 6H), 2.50-2.56 (m, 2H), 2.95-3.01 (m, 2H), 3.89 (d, 3H, J=1.9), 5.13 (s, 2H), 6.29 (dd, 1H, J=8.5, 2.8), 6.67 (dd, 1H, J=8.5, 12.1), 6.69 (s, 1H), 7.29-7.40 (m, 3H), 7.45-7.48 (m, 2H). APCI [M+1]: 327.2.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[F:23])[C:7]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]2[NH:13][C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)=[O:8].I[CH3:25]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[F:23])[C:7]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]2[N:13]([CH3:25])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)=[O:8]
Reactant: Cc1cc(C(=O)c2ccc(F)c(Br)c2)cc2oc(=O)[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccc(F)c(Br)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.175 g (4.00 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 1.33 g (3.80 mmol) 6-(3-bromo-4-fluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one in 5 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.317 mL (5.00 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then 0.100 mL (15.8 mmol) iodomethane were added and the mixture was stirred overnight at RT. After the addition of ice water the reaction mixture was extracted with EtOAc. The organic phase was washed with water, dried on sodium sulphate and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down and dried i. vac.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[CH2:1]([NH:8][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: NCc1ccccc1
Product: COc1cc(Nc2cccc(NCc3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from benzylamine and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brown solid (Yield=11%). MS ISP (m/e): 386.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=8.88 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.35-7.25 (m, 3H), 7.35-7.10 (m, 4H), 7.06 (d, 1H), 6.97 (d, 1H), 6.90 (t, 1H), 6.00 (d, 1H), 5.95 (d, 1H), 4.54 (d, 2H), 3.65 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: C[C@@H:2]1[O:9][C:7](=[O:8])[C@H:6]([CH3:10])[O:5][C:3]1=O.O.[C:12]1(C)[CH:17]=[CH:16]C(S(O)(=O)=O)=[CH:14][CH:13]=1.C(O)C1C=CC=CC=1>>[C:7]([O:9][CH2:2][C:3]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)(=[O:8])[C@H:6]([CH3:10])[OH:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Solvent: O
Solvent: OCc1ccccc1
Product: C[C@H](O)C(=O)OCc1ccccc1

Procedure:
Commercially available L-lactide 1 (16 g, 0.14 mol) and p-toluenesulfonic acid monohydrate (catalytic amount) in benzyl alcohol (40 mL, 0.38 mol) was heated to 110° C. overnight. Excess benzyl alcohol was removed under vacuum to obtain a light yellow oil. The desired product was distilled under vacuum (0.9 mm Hg, 85-95° C.) to obtain 50.3 g of 2 as a clear oil. The distilled oil was used without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1.[C:33]([O:37][C:38]([C@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].N1C(C)=CC=CC=1C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][CH2:16][C:17](=[O:18])[NH:47][C@@H:40]([C:38]([O:37][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:39])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:5][C:4]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:26][CH3:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)O)cc2S(=O)(=O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)N[C@@H](C(=O)OC(C)(C)C)c3ccccc3)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.9 %

Procedure:
To a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-carboxyethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 89; 70 mg, 0.134 mmol) and (R)-α-(t-butoxycarbonyl)benzylamine (J. Amer. Chem. Soc.; EN; 117; 44; 1995; 10879–10888; 35 mg, 0.169 mmol) in DCM (2.5 ml) was added 2,6-lutidine (29 mg, 0.268 mmol) and TBTU (56 mg, 0.174 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, then diluted with DCM. The solution was washed with NaHCO3 (aq, sat), water, dried and the solvent was evaporated under reduced pressure. The residue was suspended in ether/petroleum ether and the crystals filtered to give the title compound 85 mg (89%). NMR (500 MHz) 0.79–0.86 (m, 6H), 1.04–1.28 (m, 4H), 1.35–1.56 (m, 11H), 1.60–1.77 (m, 2H), 2.82 (t, 2H), 3.13–3.25 (m, 2H), 3.72 (brs, 2H), 4.35–4.44 (m, 2H), 5.54 (d, 1H), 6.95 (d, 1H), 7.04 (t, 1H), 7.08 (d, 2H), 7.15 (s, 1H), 7.29–7.43 (m, 6H), 7.52 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH2:17][C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=2)=[CH:13][N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:29][CH:30]=2)=[CH:13][N:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCc2cncnc2OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(CCCc2cncnc2OCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
tert-Butyl 4-[3-(4-(benzyloxy)pyrimid-5-yl)propyl]benzoate (0.36 g, 0.92 mmol) was dissolved in dichloromethane (0.7 ml) and treated with trifluoro-acetic acid (1.05 g, 9.2 mmol). The reaction was stirred at amibent temperature for 2 hours. The mixture was partitioned between EtOAc/water and the aqueous layer extracted with EtOAc. The organic layers were combined, dried (MgSO4) and evaporated and the solid was triturated with hexane and recrystallised from isopropanol/water. The cream coloured solid was taken up in THF, filtered through Celite and evaporated to give the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:12])[CH2:10]Cl)[CH:3]=1.[CH3:13][P:14](=[O:25])([O-:24])[O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1.[K+]>CC(C)=O>[CH3:13][P:14](=[O:24])([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[O:25][CH2:10][C:9]([NH:8][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)=[O:12]
Reactant: CP(=O)([O-])Oc1ccc(Cl)c(Cl)c1
Reactant: Cc1ccnc(NC(=O)CCl)c1
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccnc(NC(=O)COP(C)(=O)Oc2ccc(Cl)c(Cl)c2)c1

Procedure:
N-(4-Methyl-2-pyridyl)-α-chloroacetamide (18.5 grams), potassium O-(3,4-dichlorophenyl) methylphosphonate (29.5 grams) and acetone (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is stirred and heated at reflux for a period of about 18 hours. After this time the reaction mixture is cooled, filtered and stripped of acetone on a steam bath to yield a residue. The residue is extracted with chloroform and the chloroform solution is washed with water. The washed solution is dried over magnesium sulfate, is filtered and evaporated to yield the desired product O-[2-(4-methyl-2-pyridylamino)-2-ketoethyl] O-(3,4-dichlorophenyl) methylphosphonate as the residue.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:16]1[C:15]([O:21][CH3:22])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1c(Cl)cccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(Cl)cccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of 4-(3-chloro-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (273 mg, 0.835 mmol) in CH2Cl2 (4 mL) was added TFA (4 mL) at RT. The reaction was stirred at room temperature for 1 hour and concentrated to give a reddish brown oil. Purification by SiO2 chromatography (10% MeOH/CH2Cl2 with 1% NH4OH) gave 1-(3-Chloro-2-methoxy-phenyl)-piperazine as a pale yellow solid/oil (137 mg, 0.604 mmol, 72%). MS: APCI: M+1: 227.1 (Exact Mass: 226.09).
Reaction SMILES: Cl[CH2:2][Cl:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5]1.C([N:16]([CH2:19][CH3:20])CC)C>>[Cl:3][C:2]1[N:16]=[C:19]([N:5]2[CH2:6][CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:4]2)[C:20]2[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=1
Reactant: CCN(CC)CC
Reactant: c1ccc2c(c1)CCNC2
Reactant: ClCCl
Product: Clc1nc(N2CCc3ccccc3C2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g Of the compound(50.2 mM) prepared in Preparation 2-1, 70 ml of dichloromethane and 7.8 ml of triethylamine (56 mM) were mixed and 6.4 ml of 1,2,3,4-tetrahydroisoquinoline(50.2 mM) was dropwise added slowly while maintaining the reaction temperature below 10° C., which was stirred at room temperature for 2 hours. The reaction mixture was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was crystallized to give 14.6 g of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].NCCC(O)=O>C(O)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[C:25]4[S:19][C:20](=[S:21])[NH:22][C:23]4=[O:24])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 66.2 %

Procedure:
A mixture of 4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (4.96 g, 20 mol), rhodanine (2.66 g, 20 mmol), and β-alanine (2.0 g, 22.5 mmol) in 50 mL of acetic acid was refluxed for 2 hours. The solid which was formed on cooling the solution was collected to give the title compound as a red solid (4.8 g, 66%); 1H NMR (300 MHz, CDCl3) δ 1.81 (t, J=5.5 Hz, 4 H), 3.55 (t, J=5.5 Hz, 4 H), 4.00 (s, 4 H), 6.92 (d, J=8.9 Hz, 2 H), 7.58 (d, J=8.9 Hz, 2 H), 7.38 (s, 1 H); MS (ES) m/z: 362.8 (MH+); HRMS Calcd. for C17H19N2O3S2(MH+): 363.0837. Found: 363.0852. Anal. Calcd. for C17H18N2O3S2: C, 56.33; H, 5.01; N, 7.73. Found: C, 56.28; H, 4.89; N, 7.73.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8])#[N:2].[OH:12][CH2:13][C:14](C)(CO)[CH3:15].C(#N)C=C>>[C:13]([O:11][CH:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])[C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:12])[CH:14]=[CH2:15]
Reactant: CC(C)(C)C(O)OCCC#N
Reactant: CC(C)(CO)CO
Solvent: C=CC#N
Product: C=CC(=O)OC(OCCC#N)C(C)(C)C

Procedure:
Following the procedures described in Example 1, cyanoethoxyneopentanol (bp 132°-140° C./2 mm Hg) is prepared from neopentyl glycol and acrylonitrile, acrylation of which gives the desired product.