Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:21]C)=[CH:4][C:5]([O:19]C)=[C:6]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=3[O:10][N:9]=2)[CH:7]=1.[Li][CH2:24]CCC.IC.B(Br)(Br)Br>C1COCC1>[OH:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([CH3:24])[C:3]([OH:21])=[CH:4][C:5]=3[OH:19])=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: [Li]CCCC
Reactant: COc1ccc2c(-c3cc(Br)c(OC)cc3OC)noc2c1
Agent: BrB(Br)Br
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(-c2noc3cc(O)ccc23)c(O)cc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 3-(5-bromo-2,4-dimethoxyphenyl)-6-methoxy-1,2-benzisoxazole (200 mg, 0.55 mmol) in THF (6 mL) at −78° C. was added n-BuLi (0.24 mL, 0.60 mmol, 2.5 M in hexanes) dropwise. The solution was stirred at −78° C. for 30 min and then iodomethane (60 μL, 0.96 mmol) was added dropwise. The cooling bath was switched to an ice bath and the solution was stirred at 0° C. for 2 h. The reaction was quenched with water, most of the solvent was removed in vacuo, and extraction was conducted in EtOAc (2×30 mL) with water (20 mL). Flash chromatography with silica gel (gradient to 25% EtOAc/hexanes) provided a mixture of the desired methylated product and the protonated side product (both compounds have the same Rf). The above mixture of compounds was treated with BBr3 according to Example 2, Step i, to produce the title compound as a light orange solid (114 mg, 81% yield for two steps): mp 195° C. (dec.); 1H NMR (300 MHz, acetone-d6) δ 2.25 (s, 3H), 6.59 (s, 1H), 7.04 (dd, 1H, J=8.5, 2.1 Hz), 7.09 (d, 1H, J=1.8 Hz), 7.80 (s, 1H), 8.12 (d, 1H, J=8.8 Hz), 8.88 (broad s, 1H), 9.42 (broad s, 1H), 9.52 (s, 1H); MS m/e 258 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:15]1([CH:21]([N:28]=[C:29]=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH:21]([NH:28][C:29]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:10][CH2:11]1)=[O:30])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CN1CCC(CN2CCNCC2)CC1
Solvent: ClCCl
Product: CN1CCC(CN2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 1-(1-methyl-piperidin-4ylmethyl)-piperazine (0.5 g, 2.7 mmol) in dry CH2Cl2 (12 ml) was added diphenylmethyl isocyanate (0.56 ml, 2.7 mmol) drop wise under nitrogen. The resulting mixture was stirred at room temperature over night. Removal of solvent under reduced pressure followed by column chromatography using CH2Cl2:CH3OH (10:1) gives the desired product in 82% yield.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)[CH:2]=[CH2:3].[C:16]([O:30][CH2:31][CH:32]([CH2:37][CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])(=[O:29])[CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19].C1(C)C=CC=CC=1.N1CCCCC1>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:17]([C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[C:16]([O:30][CH2:31][CH:32]([CH2:37][CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:29])[CH:2]=[CH2:3]
Reactant: CCCCC(CC)COC(=O)CC(=O)OCC(CC)CCCC
Reactant: C=CCc1cc(C=O)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=CCc1cc(C=C(C(=O)OCC(CC)CCCC)C(=O)OCC(CC)CCCC)cc(OC)c1OC
Yield: 58.1 %

Procedure:
A mixture of 3-allyl-4,5-dimethoxybenzaldehyde (10.3 g, 0.05 mole), of di-(2-ethylhexyl) malonate (16.4 g, 0.05 mole), of toluene (20 ml), of acetic acid (0.41 ml) and of piperidine (0.77 ml) was heated at reflux for 5 hours with a Dean Stark. After cooling, washing the toluene phase with water, drying and evaporating off the solvent, an orange-colored oil was obtained, which was purified by chromatography on a column of silica 60 (eluent: 90.10 heptane/ethyl acetate) to give di-(2-ethylhexyl) 3-allyl-4,5-dimethoxybenzalmalonate (colorless oil, 15 g, yield=64%) which had the following characteristics:
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].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42](=[O:44])[CH3:43])=[CH:37][CH:36]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=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:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][C:42](=[O:44])[CH3:43])=[CH:39][CH:40]=2)[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: CC(=O)Oc1ccc(CN(c2ccc(I)cc2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccc(OC(C)=O)cc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 66 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (45.6 mg) was reacted with (4-iodophenyl)-(4-acetoxybenzyl)pyrimidin-2-ylamine (67.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-acetoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (61.7 mg). Column chromatography (silica gel, eluent: ethyl acetate/hexane=1/33/1) and thin layer chromatography (silica gel, mobile phasze: cyclohexane/ethyl acetate=1/5) were used for purification. (2) To a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-acetoxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (61.7 mg) in THF (3.0 ml), 0.1N aqueous sodium hydroxide solution (3.0 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. Water (50 ml) was added to the reaction solution and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid thereto and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-((4-hydroxy-benzyl)-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (43 mg).
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]([O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][N:14]([CH3:20])[CH2:15]3)=[O:9])[CH2:3]1.[CH3:29][I:30]>>[I-:30].[F:28][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]([O:10][CH:11]2[CH:12]3[CH2:19][CH2:18][CH2:17][CH:16]2[CH2:15][N+:14]([CH3:29])([CH3:20])[CH2:13]3)=[O:9])[CH2:3]1
Reactant: CN1CC2CCCC(C1)C2OC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Reactant: CI
Product: C[N+]1(C)CC2CCCC(C1)C2OC(=O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Product: [I-]

Procedure:
Each of the diastereomers of 3-methyl-3-azabicyclo[3.3.1]-non-9-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate was dissolved in 0.5 ml of methyl iodide and heated under reflux for 12 hours. Thereafter the excessive reagent was distilled off under reduced pressure. The residue was purified on a preparative thin layer chromatography (Aluminiumoxide™60F254, Art5713 (Merck), chloroform/methanol=20/1) to provide the title compound whose (9endo**)-body was obtained from the (9endo*)-body, and (9exo**)-body, from the (9exo*)-body, both as colorless, oily substances.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][C@@H:11]2[N:12]([CH3:23])[C:13]3[C:14]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[C@H:10]2[CH:9]1Br)=O)(C)(C)C.[CH3:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=1[NH2:30]>>[CH3:27][C:28]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:29]=1[NH:30][C:16]1[CH:15]=[C:14]([C:19]([F:21])([F:22])[F:20])[C:13]2[N:12]([CH3:23])[C@H:11]3[CH2:24][CH2:25][NH:8][CH2:9][C@H:10]3[C:18]=2[CH:17]=1
Reactant: Cc1cccc(C)c1N
Reactant: CN1c2c(cccc2C(F)(F)F)[C@H]2C(Br)N(C(=O)OC(C)(C)C)CC[C@@H]21
Product: Cc1cccc(C)c1Nc1cc2c(c(C(F)(F)F)c1)N(C)[C@H]1CCNC[C@@H]21

Procedure:
The title compound was prepared by following the general coupling procedure as a yellow solid (18 mg, 50%) from (4aS,9bR)-bromo-5-methyl-6-trifluoromethyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 45, 41 mg, 0.095 mmol) and 2,6-dimethylaniline (39 mg, 0.30 mmol). 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.87–1.98 (m, 2H), 2.20 (s, 6H), 2.30–2.70 (m, 3H), 2.78–3.20 (m, 6H), 3.33–3.45 (m, 1H), 5.07 (s, 1H), 6.46 (d, J=2.2 Hz, 1H), 6.59 (d, J=2.2 Hz, 1H), 7.00–7.18 (m, 3H).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([O:20][CH3:21])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:22]([Mg]Cl)[CH2:23]CCCC.C([Mg]Cl)CCCCCCC>>[CH3:21][O:20][C:9]1[CH:8]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:22][CH3:23])[CH:12]=[CH:11][C:10]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCC[Mg]Cl
Reactant: CCCCCCc1ccc(Oc2ccccc2)c(OC)c1
Agent: CCCCCCCC[Mg]Cl
Product: CCCCCCCCc1ccc(Oc2ccccc2)c(OC)c1

Procedure:
The procedure as described above for synthesis of (4a) was used, except that hexyl magnesium chloride was replaced with octyl magnesium chloride. 1H NMR (300 MHz) (CDCl3): δ 7.36-6.90 (m, 8H), 3.90 (s, 3H), 2.69-2.65 (t, 2H), 1.72-1.68 (m, 2H), 1.42-1.36 (m, 10H), 1.00-0.94 (t, 3H).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.Br.[OH:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH:23]=[CH:24][C:25]=1[OH:26]>C1COCC1.C(N(CC)CC)C>[ClH:10].[OH:19][C:20]1[CH:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])[CH:23]=[CH:24][C:25]=1[OH:26]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(O)c(O)c1
Agent: Br
Agent: I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cl
Product: N=C(NCCCCc1ccc(O)c(O)c1)NC(=O)c1nc(Cl)c(N)nc1N
Yield: 51 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methyl-pseudothiourea hydroiodide (0.2 g, 0.51 mmol) was added to a suspension of 27 in a mixture of THF (35 mL) and triethylamine (3 mL). The reaction mixture was stirred at reflux for 3 h, then the supernatant was separated and the solvent was removed under reduced pressure. The brown residue was washed with ether (2×30 mL) followed by addition of 10% HCl (5 mL). The solid material was collected, dissolved in methanol and precipitated by addition of ethyl acetate. The precipitate was washed with 10% HCl and dried to give compound 28 (131 mg, 51%) as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ 1.52 (br s, 4H), 2.42 (m, 2H), 3.31 (m, 2H), 6.43 (m, 1H), 6.61 (m, 2H), 7.42 (br s, 2H), 7.90 (br s, 1H), 8.82 (br s, 1H), 8.98 (br s, 1H), 9.25 (s, 1H) 10.52 (s, 1H). APCI MS m/z=394 [C16H20ClN7O3+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:13][N:14]([CH3:22])[CH2:15][CH2:16][C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18]>CCOCC>[CH:19]1([C:17]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)([OH:18])[CH2:16][CH2:15][N:14]([CH3:22])[CH3:13])[CH2:21][CH2:20]1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CN(C)CCC(=O)C1CC1
Agent: [Mg]
Solvent: CCOCC
Product: CN(C)CCC(O)(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 25 °C

Procedure:
The Grignard reagent prepared from 64 g. (0.28 mole) of 3-bromobenzotrifluoride and 7 g. (0.28 mole) of magnesium in ether was cooled to -30° C., and 20 g. (0.14 mole) of cyclopropyl 2-dimethylaminoethyl ketone in 100 ml. of ether was added dropwise to the stirred mixture at a rate sufficient to maintain a temperature below -20° C. The mixture was allowed to warm to room temperature and then worked up as described in Preparation I. Distillation of the crude product gave 10 g. of oil which distilled at 78°-83° C./0.12 mm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[CH3:21][N:22]([CH3:32])[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[CH3:21][N:22]([CH3:32])[C:23]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:20][CH:19]=2)[CH2:30][CH2:31]1)=[O:24]
Reactant: CN(C)C(=O)NC1CCNCC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)C(=O)NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 61.5 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (200 mg, 0.76 mmol) obtained in Step 6 of Example 1, 1,1-dimethyl-3-(piperidin-4-yl)urea (0.20 ml, 1.14 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg, 1.06 mmol) and N-methylmorpholine (0.18 mL, 1.66 mmol) in a similar manner to Example 5, was crystallized from ethyl acetate to obtain Compound 132 (195 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12](=O)[CH2:13][CH3:14].C(O)(C)C.Cl>C(OCC)(=O)C>[CH2:13]([CH:14]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1)[CH3:12]
Reactant: CCC=O
Reactant: Nc1ccncc1S(N)(=O)=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCC1Nc2ccncc2S(=O)(=O)N1

Procedure:
0.5 g of 4-aminopyridine-3-sulfonamide (Preparation 2) and 0.34 g (2 equivalents) of propionaldehyde are introduced into 5 cm3 of isopropanol to which 10 drops of a saturated solution of hydrochloric acid in ethyl acetate have been added. After refluxing for 2 h, the solution obtained is concentrated to dryness and the residue is recrystallized from a 1/3 isopropanol/petroleum ether (40°-60° C.) mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O>>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccccc2Cl)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 2-chlorobenzaldehyde gave the title compound as white crystals m.p.:154° C.
Reaction SMILES: [CH3:1][NH2:2].CO[C:5]([C:7]1[N:8]=[C:9]([CH:12]([OH:37])[CH2:13][CH:14]([N:18]([CH3:36])[C:19](=[O:35])[CH:20]([NH:25][C:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])[CH:15]([CH3:17])[CH3:16])[S:10][CH:11]=1)=[O:6]>C1COCC1.CO>[OH:37][CH:12]([C:9]1[S:10][CH:11]=[C:7]([C:5](=[O:6])[NH:2][CH3:1])[N:8]=1)[CH2:13][CH:14]([N:18]([CH3:36])[C:19]([CH:20]([NH:25][C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])=[O:35])[CH:15]([CH3:16])[CH3:17]
Reactant: CN
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)OC)cs1)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)NC)cs1)C(C)C
Temperature: 100 °C
Yield: 51.9 %

Procedure:
In a sealed tube, 10.0 mL of a 2.0 M solution of methylamine (5.00 mmol) in THF was added to a 0.02 M solution of 23 (27.0 mg, 0.0529 mmol) in MeOH (2.50 mL). The reaction solution was heated to 100° C. for 21 h. After the solution cooled to rt, the solvent was removed under reduced pressure. Reverse-phase HPFC (20:80 to 100:0 MeCN/H2O) followed by lyophilization provided compound 25 (14.0 mg, 52%) as an amorphous solid. The 1H NMR corresponds to a 6:1 mixture of rotamers, with the major isomer reported. [α]D23=−2.9 (c=1.0, MeOH). 1R: 1070, 1499, 1551, 1646, 2876, 2961 cm−1. 1H NMR (500 MHz, MeOD): δ 0.83 (d, 3H, J=6.5 Hz), 0.90 (t, 3H, J=7.5 Hz), 0.966 (d, 3H, J=6.5 Hz), 0.974 (d, 3H, J=6.5 Hz), 1.15-1.25 (m, 1H), 1.25-1.32 (m, 1H), 1.48-1.66 (m, 4H), 1.72 (d, 2H, J=10.5 Hz), 1.81-1.99 (m, 3H), 2.00-2.10 (m, 1H), 2.16 (s, 3H), 2.19-2.37 (m, 1H), 2.53-2.58 (m, 1H), 2.87-2.94 (m, 1H), 2.92 (s, 3H), 3.17 (s, 3H), 4.16-4.58 (br s, 1H), 4.64 (dd, 1H, J=2.3, 10.3 Hz), 4.72 (d, 1H, J=9.0 Hz), 8.06 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.1, 16.1, 20.5, 20.6, 24.4, 25.9, 26.3, 26.4, 31.3, 31.7, 37.8, 38.8, 44.8, 55.4, 56.7, 70.0, 70.6, 124.2, 151.0, 164.4, 175.3, 175.7, 179.4. HRMS (FAB) calcd for C25H44N5O4S (M+H): 510.3114. Found: 510.3098.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[C@H:32]([OH:33])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Reactant: O[C@H](c1ccccc1)[C@H]1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOC[C@@H]3[C@H](O)c3ccccc3)sc21
Temperature: 95 °C
Yield: 79.3 %

Procedure:
N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1, 134 mg) and (R)-(3R)-morpholin-3-yl(phenyl)methanol hydrochloride (Preparation 6, 112 mg) in DMF (3 mL) is treated with diisopropylethylamine (0.5 mL). The mixture is heated at 95° C. overnight. After cooling to room temperature, the solution is poured into ethyl acetate (75 mL) and washed with dilute pH 4 phosphate buffer (25 mL), dilute pH 7 phosphate buffer (2×25 mL), and brine (25 mL). The organic layer is dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (methanol/CH2Cl2, 1-3%) and ethyl acetate-hexanes crystallization to afford 0.15 g of the title compound. Physical characteristics. M.p. 171-172° C.; 1H NMR(400 MHz, DMSO-d6) δ 10.63, 8.71, 7.4-7.3, 7.3, 5.42, 5.09, 4.55, 4.50, 4.15, 3.97, 3.5, 3.4, 3.04, 2.9, 2.8, 2.4; HRMS m/z 538.1558 (M+H)+. Anal. Found. C, 62.41; H, 5.17; N, 7.73.
Reaction SMILES: [CH:1]([C@H:3]1[C@H:7]2[CH2:8][CH2:9][C:10]3[C:15]([N:6]2[C:5](=[O:17])[O:4]1)=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=3)=[CH2:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.CN(C)C=O>[CH2:24]([O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:6]1[C:5](=[O:17])[O:4][C@@H:3]([CH:1]=[CH2:2])[C@H:7]1[CH2:8][CH2:9]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: C=C[C@@H]1OC(=O)N2c3ccc(O)cc3CC[C@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=C[C@@H]1OC(=O)N2c3ccc(OCc4ccccc4)cc3CC[C@H]12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 10 g (0.043 mol) of trans-3-ethenyl-7-hydroxy-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one (obtained in Step 2 of Example 1) and 12 g (0.086 mol) of potassium carbonate in 250 ml of acetonitrile and 50 ml of dimethylformamide are added 8.9 g (0.052 mol) of benzyl bromide. The mixture is stirred at 80° C. for 1 h then filtered while hot and washed with acetonitrile, and the filtrate is evaporated to dryness under reduced pressure. The residue is taken up in ethyl acetate and washed several times with water, and the organic phase is then dried over sodium sulphate and concentrated under reduced pressure. After recrystallization from diisopropyl ether, 12.8 g of product are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:9]([C:27]([O:29]C)=[O:28])=[C:8]1[CH3:31].[OH-].[K+]>O.CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:8]([CH3:31])=[C:9]([C:27]([OH:29])=[O:28])[CH:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)[C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:12]1[CH3:13]
Reactant: COCCOCN1C(C)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOCN1C(C)=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C

Procedure:
The N-protected diester is then mono-saponified, e.g., by heating with an alkali metal hydroxide or alkoxide (for example, NaOH, KOH, t-BuOK) or an alkali metal carbonate (for example K2CO3) in a water miscible solvent containing 10-45% water (preferably MeOH containing 15-40% water) at reflux temperature (or between 50° C. and reflux temperature for solvents other than MeOH) for 10 to 24 hours to yield an N-protected mono-ester. For example, 1-(2-methoxyethoxy)methyl-2,6-dimethyl-3,5-di(carbomethoxy)-4-(3-nitrophenyl)-1,4-dihydropyridine in 20% H2O/MeOH is heated at reflux with aqueous KOH for 16 hours to yield racemic (RS)-1-(2-methoxyethoxy)methyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine ((RS)-18). (Scheme VI, Step 2)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:8](OCC)OCC)(=[O:7])[OH:6].[CH2:15]([SH:18])[CH2:16][SH:17].Cl>C(O)(=O)C>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:8]1[S:18][CH2:15][CH2:16][S:17]1)(=[O:7])[OH:6]
Reactant: SCCS
Reactant: CCOC(OCC)P(=O)(O)CCCN
Agent: Cl
Solvent: CC(=O)O
Product: NCCCP(=O)(O)C1SCCS1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.90 g (4.0 mmol) of 3-aminopropyl(diethoxymethyl)phosphinic acid in 10 ml of glacial acetic acid at 0° there are added 0.38 ml (4.4 mmol) of ethane-1,2-dithiol, followed by addition of 2 ml of concentrated hydrochloric acid over a period of 5 min. The mixture is allowed to warm to room temperature and is then stirred for 18 hours. After removal of acetic and hydrochloric acids under high vacuum, the residue is chromatographed (Opti-Up® C12 50%, water) and recrystallized from methanol to yield 3-aminopropyl(1,3-dithiolan-2-yl)phosphinic acid, m.p. 272°-274°.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:13]1C3.Cl>C(Cl)(Cl)Cl.C(O)C>[ClH:11].[NH2:13][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCC(=O)c1cccc(Cl)c1
Temperature: 55 °C
Yield: 239.4 %

Procedure:
2-Bromo-1-(3-chlorophenyl)ethanone (2.0 g, 8.57 mmol) was added to a solution of hexamethylenetetramine (1.201 g, 8.57 mmol) in CHCl3 (60 mL), and the resulting mixture was heated at 55° C. for 1 hour. The mixture was cooled to room temperature, and the white precipitate was collected by filtration, washed with CHCl3, and dried in vacuo to afford 3.1 g. This white solid was suspended in a mixture of ethanol (50 mL) and hydrochloric acid (0.25 mL, 8.30 mmol) and heated at 105° C. for 1.5 hours. The mixture was cooled to 0° C., filtered and washed by ethanol (30 mL). The organic phase was concentrated to afford an HCl salt of the title compound (1.74 g) as a pale yellow solid. LC-MS (ES) m/z=170 [M+H]+.