Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2cccnc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2cccnc2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-3-ylmethyl-ethylamine (326 mg.; 1 mmol, from Example 3) in dichloromethane (15 mL) at 0° C. was added triethylamine (0.28 mL; 2 mmol) and 1-methyl-1-cyclohexanecarbonyl chloride (160 mg.; 1 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (5% methanol/chloroform) to yield the free base of the title compound as a clear oil (132 mg.; 29%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as an off-white amorphous solid, m.p. 150–152° C.; MS (+) FAB, [M+H]+ @ m/z 451, [M+Na]+ @ m/z 473; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2.C4H4O4.0.5H2O Calculated: C, 64.68; H, 7.53; N, 9.73 Found: C, 64.89; H, 7.18; N, 9.64.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:18][SH:19]>CN(C=O)C.O>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])[S:19][C:2]=2[CH:9]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(F)cc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2,4-difluorobenzaldehyde (50.17 g) and potassium carbonate (63.4 g) in DMF (500 ml) was added ethyl thioglycolate (38.7 ml) dropwise at 0° C. The mixture was stirred at room temperature for 18 hours, diluted with water, and extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid, water, and brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel using hexane-ethyl acetate (20:1) as an eluent to give the titled compound as colorless crystals (16.61 g).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH3:25][O:24][C:22]([N:9]1[CH2:10][CH2:11][C@@H:12]([C:14]2[O:21][NH:29][C:16](=[O:17])[CH:15]=2)[CH2:13][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A solution of trans-methyl 2-benzyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (6.35 g, 18.3 mmol) in MeOH (2 mL) was added to a solution of NaOH (0.77 g, 19.4 mmol) in MeOH/H2O (15 mL/0.9 mL) at −30° C. After 10 minutes was added a solution of hydroxylamine hydrochloride (2.54 g, 36.6 mmol) and NaOH (1.46 g, 36.6 mmol) in MeOH (18 mL) and H2O (18 mL). Stirring was continued at −30° C. for 30 minutes. The reaction mixture was then poured into concentrated HCl (20 mL) held at 80° C. The solution was stirred for 30 minutes. The organic solvent was evaporated and the aqueous phase extracted with DEE (×3). The organic phase was dried over Na2SO4 and evaporated to give a solid, 3.68 g, which was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-70% acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer, over 18 minutes with a flow of 19 mL/minutes. Trans-methyl-2-benzyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.54 g, 54.6%) was isolated as a solid. 1H NMR (600 MHz, cdcl3) δ 1.50-2.21 (m, 4H), 2.91 (m, 2H), 3.10 (m, 2H), 3.58 (d, 3H), 4.04-4.41 (m, 1H), 4.43-4.82 (m, 1H), 5.55-5.84 (m, 1H), 7.15-7.30 (m, 5H); MS m/z 317 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22]C)[C:14]([Br:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C(O)=C(C(CSC2C=CC=CC=2OC)=CC=1)[C:29](OC)=[O:30]>>[Br:24][C:14]1[C:15]([OH:22])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[O:30][CH3:29])(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2OC)ccc(Br)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 61, starting from methyl 3-bromo-2-hydroxy-6-(2-methoxyphenylthiomethyl)benzoate (Intermediate 82).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>C(O)CC(C)C.CO>[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH3:20])[CH:8]=3)[N:3]=2)=[CH:29][CH:28]=1)(=[O:24])=[O:25]
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Reactant: COc1ccc2nc(Cl)nc(Nc3ccccc3)c2c1
Solvent: CO
Solvent: CC(C)CCO
Product: CNS(=O)(=O)Cc1ccc(Nc2nc(Nc3ccccc3)c3cc(OC)ccc3n2)cc1

Procedure:
A solution of 2-chloro-6-methoxy-4-phenylamino-quinazoline (1.15 g) and N-methyl-(4-aminophenyl)-methanesulfonamide (prepared as described in Tetrahedron Letters 1992, 33, 8011) (0.89 g) in 5 mL of isopentylalcohol is stirred under nitrogen at 180° C. for 20 min in a sealed vessel. The warm reaction mixture is diluted with methanol and the hydrochloride salt, which is crystallizing on cooling, is filtered off. The crude product is redissolved in ethylacetate and aqueous sodium carbonate solution and extracted with ethylacetate. The organic extracts are dried and evaporated and the solid residue is titurated with diethylether to give N-methyl-[4-(6-methoxy-4-phenylamino-quinazolin-2-ylamino)-phenyl]-methanesulfonamide as light yellow crystals melting at 212-215° C.; (Rf (A2) 0.16. Recrystallisation from methanolic hydrogen chloride and diethylether yields N-methyl-[4-(6-methoxy-4-phenylamino-quinazolin-2-ylamino)-phenyl]-methanesulfonamide hydrochloride as light yellow crystals melting at 264-268° C.; Rf (A2) 0.16, FAB-MS: (M+H)+ =450. Analytical data: C23H23N5O3S+HCl.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH3:10])=[CH:4][C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][CH:12]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][CH:12]=1
Reactant: C/C=C/c1ccc(F)c(-c2cccc(C(=O)OC)n2)c1
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc(F)c(-c2cccc(C(=O)OC)n2)c1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (E)-methyl 6-(2-fluoro-5-(prop-1-enyl)phenyl)-picolinate (1.0 equiv.) in MeOH (0.04 M) was 10% Pd/C (0.5 equiv.) and the reaction was placed under an atmosphere of hydrogen and left stirring overnight. The mixture was filtered over a pad of Celite and washed with MeOH. The filtrate was concentrated in vacuo to provide methyl 6-(2-fluoro-5-propylphenyl)picolinate as a light grey oil in 97% yield. LC/MS=274.2 (M+H), Rt=0.61 min.
Reaction SMILES: Cl.Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][C@H:59]([OH:62])[C@@H:58]([CH3:63])[CH2:57]2)CC1>>[OH:62][C@H:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][C@@H:58]1[CH3:63]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6cc(Cl)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117, see example 72) and amine 14 analogously to the method described in example 1.
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=O)C1C=CC=CC=1.[CH3:19]C(C)(CC(OC)=O)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:11]([C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([O:16][CH3:19])=[O:15])=[C:9]=[O:8]
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: COC(=O)CC(C)(C)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)(C)N=C=O
Temperature: 5 °C

Procedure:
3-(Benzyloxycarbonylamino)-3-methylbutanoic Acid. A solution of 2,2-dimethyl-3-carbomethoxypropionic acid (LeMaul, Bull. Soc. Chim. Fr., 828 (1965), 20 g, 0.125 mol), diphenylphosphorylazide (34.3 g, 0.125 mol) and triethylamine was heated in toluene (150 ml) at 100° C. for 2 h After cooling to 5° C., the toluene solution was washed successively with 0.5M HCl, aqueous NaHCO3 and brine. Evaporation of the dried solution gave a residue which was chromatographed on silica gel eluting with 60/40 hexane-ether. There was obtained 13 g of methyl 3-isocyanato-3-methylbutanoate as a mobile liquid. A solution of this material in toluene (20 ml) was treated with benzyl alcohol (13 ml) and the resulting mixture heated at reflux for 40 h. Evaporation of the toluene left a residue which was dissolved in methanol (125 ml) and then treated with a solution of NaOH (6.6 g, 0.165 mol) in 22 ml of water. After 5 h, the reaction mixture was partially evaporated, washed with ether and acidified with 6N HCl. Extraction with methylene chloride and evaporation gave 21 g of the desired product. NMR (300 MHz, CDCl3): 1.42 (s,6H), 2.78 (s,2H), 5.08 (s,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]2[OH:15])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]2[O:15][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CN1CCC(c2ccc(Cl)cc2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A solution of 1.12 g (5 mmol) of (3RS,4RS)-4-(4-chloro-phenyl)-1-methyl-piperidine-3-ol in 5 ml of tetrahydrofuran was added dropwise to a suspension of 0.264 g (5 mmol) of sodium hydride (50% dispersion in refined oil) in 8 ml of tetrahydrofuran and the mixture was stirred at 50° C. for 60 minutes. Subsequently, it was cooled to room temperature and treated with 1.10 g (5 mmol) of 2-bromomethyl-naphthalene in 5 ml of tetrahydrofuran. After 2 hours at 50° C. the reaction solution was poured into 60 ml of ice-water and extracted three times with 25 ml of ethyl acetate each time. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on silica gel using a 95:5 mixture of methylene chloride and ethanol as the eluent. There was obtained 0.53 g (28% of theory) of (3RS,4RS)-4-(4-chloro-phenyl)-1-methyl-3-(naphthalen-2-ylmethoxy)-piperidine as a pale yellow oil; MS: 366 (M)+.
Reaction SMILES: [C:1]1([CH:7]2[S:11]C(=N)N[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Ba+2].[OH-]>C(O)C>[SH:11][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([OH:13])=[O:14]
Reactant: N=C1NC(=O)C(c2ccccc2)S1
Reactant: [OH-]
Agent: [Ba+2]
Solvent: CCO
Product: O=C(O)C(S)c1ccccc1
Yield: 70 %

Procedure:
Hydrolysis of 142 g of 5-phenyl-2-imino-4-thiazolidinone with barium hydroxide in 20% aqueous ethanol gave 55 g of α-mercaptophenylacetic acid (70% yield).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C[O-].[Na+].O>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][OH:18]
Reactant: O=C1CCCCCCCCCCCCCCCO1
Reactant: OCCNCCO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=C(CCCCCCCCCCCCCCCO)N(CCO)CCO
Temperature: 80 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A 200-ml flask equipped with a stirrer was charged with 16.6 g (158 mmol) of diethanolamine and 20.1 g (79 mmol) of cyclohexadecanolide, to which 0.21 g (3.9 mmol) of sodium methoxide was added. The contents were stirred at 80° C. for 18 hours. After completion of the reaction, water was added, and solids deposited were collected by filtration and recrystallized from methanol, thereby obtaining 23.3 g (yield: 82%) of N,N-bis(2-hydroxyethyl)-16-hydroxyhexadecanamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cc(NC(=O)C(CC(C)C)NC(=O)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.4 %

Procedure:
A mixture of 2-(benzyloxycarbonylamino)-4-methylpentanoic acid (1 g, 3.8 mmol), methyl 5-amino-2-hydroxybenzoate (0.66 g, 3.95 mmol) and Et3N (0.76 g, 7.6 mmol) were dissolved in CH3CN (10 mL) and HATU (1.503 g, 3.95 mmol) was added. The mixture was stirred (RT, 16 h). The solvent was removed under reduced pressure. Brine (50 mL) was added to the resulting residue, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed successively with 2N aq. HCl (3×50 mL), brine (50 mL), 5% NaHCO3 (50 mL×3), brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica chromatography on (CH2Cl2) to give methyl 5-(2-(benzyloxycarbonylamino)-4-methylpentanamido)-2-hydroxybenzoate as a white solid (0.81 g, 51.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([OH:22])=O)[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:22])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: C1COCCN1
Product: C[C@H]1C(=O)N(CCC(=O)N2CCOCC2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 45 %

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and morpholine gave the titled compound in 45% yield as white foam. MS: 441.1 (M−H−, 2Cl).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH:9]([OH:13])[CH2:10][O:11][CH3:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:14]OS(OC)(=O)=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>O.[OH-].[K+]>[CH3:14][O:7][C:6](=[O:8])[CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:9]([OH:13])[CH2:10][O:11][CH3:12]
Reactant: COCC(O)C(NC(C)=O)C(=O)O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COCC(O)C(NC(C)=O)C(=O)OC
Reaction time: 2 h

Procedure:
The crude carboxylic acid was dissolved in 250 ml of water and the solution neutralized (pH 7 as indicated by pH paper) in 1 N KOH. Dimethylsulfate (30 ml) was added and the resultant two phase system was stirred vigorously for 21/2 hrs. During this time, the pH was maintained at approximately 7 by the periodic addition of saturated sodium bicarbonate solution. The temperature was then brought to 60° for 45 min and solid sodium bicarbonate was added in order to maintain pH 7. The reaction mixture was cooled, saturated with sodium chloride, and extracted 3 times with chloroform (250 ml). The extracts were dried over anhydrous sodium sulfate and concentrated in vacuo yielding 2-acetamido-3-hydroxy-4-methoxybutanoic acid methyl ester (8) as a beige solid. Crystallization from methylene chloride/petroleum ether (bp 35°-60°) gave one of the diastereomers as a white solid: mp 131°-134.5°; IR (CHCl3) 3580, 3442, 1750, 1680, 1509, 1125 cm-1 ; NMR (CDCl3) δ6.5 (broad, 1H, NH), 4.7 (m, 1H, CHNH), 4.3 (m, 1H, CH2CH), 3.7 (s, 3H, CH3O2C--), 3.3 (singlet superimposed on a multiplet, 6H, CH3OCH2 --and HO--), 2.0 (s, 3H, CH3CONH--). (Calcd. for C8H15NO5 : C, 46.82; H, 7.37; N, 6.83. Found: C, 47.03; H, 7.48; N, 6.85).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5].[Cl-].[CH2:23]1[CH2:27]OC[CH2:24]1>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4](=[O:5])[CH2:24][CH2:23][CH3:27])[CH2:7]2)=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CN2CCCC(C(=O)N(C)OC)C2)cc1
Agent: [Cl-]
Product: CCCC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Yield: 94 %

Procedure:
Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid methoxy-methyl-amide (401.0 mg, 1.37 mmol) and THF (10 mL) at 0° C. under a Nitrogen atmosphere. By dropwise addition, add Propylmagesium chloride (4.0 mL, 8.22 mmol). Reflux the reaction for 5 hours then cool the reaction to room temperature and quench the reaction mixture with sat NH4Cl (aq) and extract product from the water using Ethyl acetate. Wash the organic layer with brine and then dry over Na2SO4. Concentrate under reduced pressure and add to an SCX (5 g) column pre-treated with 5% AcOH/MeOH. Wash with MeOH and elute product using 1N NH3 MeOH to give 356.0 mg (94% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.8 (3H, t), 1.3 (1H, qd), 1.4-1.5 (3H, m), 1.6-1.8 (1H, n), 1.9 (1H, dd), 2.0 (1H, td), 2.1 (1H, t), 2.4 (2H, t), 2.5-2.6 (1H, m), 2.7 (1H, d), 2.9 (1H, d), 3.4 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); TLC 4% 1N NH3 MeOH:CH2Cl2 Rf=0.42.
Reaction SMILES: [Br:1][CH:2]1[CH2:31][C@@H:30]([CH3:32])[CH2:29][O:28][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:27])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@H:11]1[O:26][C@@H:10]31.[Cl:33][C:34]([Cl:39])([Cl:38])[C:35]([OH:37])=[O:36]>C1(C)C=CC=CC=1>[Br:1][CH:2]1[CH2:31][C@@H:30]([CH3:32])[CH2:29][O:28][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:27])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@@H:11]([OH:26])[C@@H:10]3[O:36][C:35](=[O:37])[C:34]([Cl:39])([Cl:38])[Cl:33]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@H]5O[C@H]5[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Solvent: Cc1ccccc1
Product: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](OC(=O)C(Cl)(Cl)Cl)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1

Procedure:
Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α,11β,12β,25R)-23-bromo-11,12-epoxyspirostan-3-ol was treated with trichloroacetic acid in toluene at room temperature for 3 days to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CSc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CSc1ccc(F)cc1
Yield: 87.6 %

Procedure:
A mixture of 5.3 g of (4-fluorophenylthio)acetic acid and 6.8 g of thionyl chloride is refluxed for 2 hours. Excess of thionyl chloride is evaporated in vacuo and the residue distilled. There are obtained 5.1 g (88%) of oily (4-fluorophenylthio)acetyl chloride, b.p. 76°-77° C./0.25 Torr.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:12]([CH3:14])[CH3:13])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=1>>[CH3:14][CH:12]([C:4]1[S:3][C:2]2[N:1]=[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][N:21]3[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:13]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1cc(C(C)C)sc1N
Product: CC(C)c1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Temperature: 142 °C
Yield: 20.8 %

Procedure:
A mixture of 21.33 g (0.1 mol) of 2-amino-5-(1-methylethyl)-3-thiophenecarboxylic acid, ethyl ester (Tetrahedron, Vol. 33, pages 2089-2092, 1977) and 17.16 g (0.1 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in a wax bath at 178°-182° C. for one hundred eighty-seven minutes and then at 182°-205° C. for ninety minutes under nitrogen. The distillate is collected in a Dean-Stark Trap attached to the reaction flask. The mixture is cooled, dissolved in methanol, cooled and 16.2 g of a mixture of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester and the ring-opened diester, 6-[[3-(ethoxycarbonyl)-5-(1-methylethyl)-2-thienyl]amino]-3-pyridinecarboxylic acid, methyl ester, is collected; mp 112°-114° C. A suspension of 11 g of the previous mixture in 250 ml of concentrated hydrochloric acid and 250 ml of water is refluxed in a wax bath at 142° C. for twenty-two hours under nitrogen. The suspension is cooled to room temperature, filtered and the precipitate washed with 300 ml of water and dried to give 6.0 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid; mp 264°-266° C. after recrystallization from ethanol.