Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([CH3:32])([CH3:31])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][N:20]=3)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:35]1[N:44]=[CH:43][C:42]2[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=2)[C:36]1=[O:50])(=O)C.[OH-].[Na+].C(Cl)Cl>O1CCOCC1.O>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([CH3:31])([CH3:32])[CH2:27][N:28]([CH3:30])[CH3:29])=[CH:21][N:20]=4)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:44]=[CH:43]2)([CH3:46])([CH3:47])[CH3:48]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(OC(C)(C)CN(C)C)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CC(C)(C)Oc1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 26.1 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-(dimethylamino)-2-methylpropan-2-yloxy)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-benzyl acetate (292 mg, 0.43 mmol) in dioxane (1.5 ml) was added a solution of 2N sodium hydroxide (2.5 ml, 5 mmol). The flask was heated at 50° C. (oil bath) with vigorous stirring under argon atmosphere for 3 hours. The material was cooled to ambient and the contents were taken up in water (25 ml) and methylene chloride (50 ml) and transferred to a reparatory funnel and shaken. The organic phase was collected and washed with a solution of 50% diluted brine (25 ml). The aqueous phases were back extracted with methylene chloride (2×40 ml) and the organic phases combined, dried (magnesium sulfate), filtered and stripped. The remainder was purified by preparative thin layer chromatography (3 plates), eluting with 6% methanol/dichloromethane and then re-developing the plates with first 8% and then 11% methanol/dichloromethane. The product band was collected providing the desired product as a light yellow-white solid (72 mg). MP=136-144° C.; (M+H)+=642 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 6H) 1.42 (s, 9H) 2.40 (s, 6H) 2.51 (s, 2H) 3.90 (s, 3H) 4.42 (s, 2H) 6.90 (d, J=9.06 Hz, 1H) 7.33 (dd, J=8.69, 3.02 Hz, 1H) 7.41-7.72 (m, 5H) 8.09 (d, J=3.02 Hz, 1H) 8.20-8.35 (m, 2H) 8.53 (s, 1H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:11]([O:15]C(=O)CC)(=[O:14])[CH2:12][CH3:13].C([O-])(=O)CC.[Na+].C(=O)([O-])O.[Na+]>>[CH3:13]/[C:12](=[CH:1]\[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)/[C:11]([OH:15])=[O:14]
Reactant: CCC(=O)OC(=O)CC
Reactant: COc1ccc(C=O)cc1
Agent: CCC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(/C=C(\C)C(=O)O)cc1
Temperature: 140 °C
Yield: 58 %

Procedure:
A mixture of 68 g of p-anisaldehyde (500 mmol), 81 g of propionic anhydride (625 mmol) and 48 g of sodium propionate (500 mmol, dried for 5 h at 120° C.) is heated under argon for 30 h at 140° C. This solution, cooled to 80° C., is poured slowly into 400 ml of vigorously stirred saturated aqueous sodium hydrogen carbonate solution. After extraction with dichloromethane (twice 300 ml), the organic phases are combined and then washed with saturated sodium hydrogen carbonate solution (twice 150 ml). The aqueous phases are combined and then poured slowly into a mixture of 300 ml of 12N hydrochloric acid solution and 100 g of crushed ice. The precipitate is collected after filtration, dried in a dessicator, triturated in twice 150 ml of petroleum ether, filtered again and dried in the dessicator. 55.70 g (290 mmol) of a white solid are collected. Yield=58% m.p. 178°-182° C. IR (nujol): 1665 cm-1 1H NMR (CDCl3 /TMS): 9.20 to 8.90 (broad s, 1H); 7.60 (s, 1H); 7.35 to 6.90) AB, 4H, J=8 Hz); 3.80 (s, 3H); 2.1 (s, 3H) 13C NMR (CDCl3): 170.40; 158.50, 137.60; 130.90; 128.10; 126.30; 113.50; 54.80.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:77])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1.C1(C)C=CC=CC=1>[F:8][C:6]1[CH:7]=[C:2]([NH2:77])[CH:3]=[C:4]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:5]=1
Reactant: CN1CCC(N(C)c2cc(F)cc(Br)c2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCC(N(C)c2cc(N)cc(F)c2)CC1
Reaction time: 2 h

Procedure:
The (3-bromo-5-fluorophenyl)-methyl-(1-methylpiperidin-4-yl)-amine intermediate is then aminated at the benzo 3-position, as for example, by reacting the intermediate with BINAP, Pd2dba3, benzhydrylideneamine, and sodium t-butoxide, in a suitable solvent, such as toluene or the like, under an inert atmosphere for about 1–3 hr., say about 2 hr., at about 50° C. to 100° C., say about 80° C. The resulting intermediate is treated with 1M HCL or the like in a suitable solvent, such as THF at 0° C. to ambient temperature, preferably ambient temperature for 1–2 hours, say about 1 hr. The resulting intermediate, 5-Fluoro-N-methyl-N-(1-methylpiperidin-4-yl)benzene-1,3-diamine may then be isolated and purified by common procedures such as, but not limited to, solvent removal, extraction and/or chromatography, etc.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]([NH:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:26]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:26][N:13]([CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]1[S:9][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:12][CH:11]=1
Reactant: CCOC(=O)C(=CNc1cnc(CN2CCOCC2)s1)C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C(=CN(C)c1cnc(CN2CCOCC2)s1)C(=O)OCC
Temperature: 75 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a mixture of diethyl 2-(((2-(morpholin4-ylmethyl)-1,3-thiazol-5-yl)amino)-methylene)malonate (Preparation 28, 1.51 g) and K2CO3 (1.19 g) in DMF (15 mL) at ambient temperature is added iodomethane (0.28 mL). The mixture is heated to 75° C. in a sealed pressure tube and stirred overnight. The solution is cooled to ambient temperature and the solvent is removed. The mixture is diluted with water (75 mL) and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed to afford 0.984 g (63%) of the title compound as a light brown solid. Physical characteristics: 1H NMR (CDCl3) δ 1.24-1.33, 2.60, 3.31, 3.74, 4.17-4.24, 7.60; IR (liq.) 1702, 1608, 1535, 1453, 1383, 1365, 1293, 1270, 1232, 1206, 1117, 1096, 1071, 1010, 865 cm−1; HRMS (FAB) m/z 384.1600 (C17H25N3O5S+H). Anal. Found: C, 53.18; H, 6.64; N, 10.41.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]([O:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])=[O:23])([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[C:17]([O:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-(1-Methylpiperazin-4-yl)benzoic acid (250 mg, 1.13 mmol) and 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17, 331 mg, 1.59 mmol) were dissolved in DMF (3 ml). 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (Method 18, 313 mg, 1.13 mmol) was added and the resulting solution was stirred for 20 hours at ambient temperature. The solution was poured into water and extracted several times with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (eluting with 99:1→9:1 dichloromethane:methanol) to afford the title compound as a colourless gum which crystallised on trituration (240 mg, 52%); Mass Spectrum: M+H+ 411.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[O:2]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([Cl:18])=[O:14])[CH3:1]
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(OC)c(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 196 mg (1.00 mmol) of (2,5-dimethoxyphenyl)acetic acid in 3 mL of CH2Cl2 was added 100 μL of oxalyl chloride. The mixture was stirred at ambient temperature for 1 hour then concentrated under reduced pressure to a thick liquid.
Reaction SMILES: C(N(CC)C([S:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14]([C:16]1[N:21]=[C:20]([S:22][CH3:23])[N:19]=[CH:18][C:17]=1[Br:24])=O)=S)C.[OH-].[Na+]>C(O)=O>[Br:24][C:17]1[C:16]([C:14]2[S:6][C:7]3[CH:8]=[N:9][CH:10]=[CH:11][C:12]=3[N:13]=2)=[N:21][C:20]([S:22][CH3:23])=[N:19][CH:18]=1
Reactant: CCN(CC)C(=S)Sc1cnccc1NC(=O)c1nc(SC)ncc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CSc1ncc(Br)c(-c2nc3ccncc3s2)n1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A stirred solution of 4-(5-bromo-2-(methylthio)pyrimidine-6-carboxamido)pyridin-3-yl diethylcarbamodithioate (1.99 g, 4.21 mmol) in 96% formic acid (40 mL) was heated to reflux for 4 h. After cooling to r.t. the reaction mixture was poured into ice/water (400 mL), then basified with 5 N aqueous sodium hydroxide and extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried over sodium sulfate, filtered and the solvent evaporated in vacuo to yield 2-(5-bromo-2-(methylthio)pyrimidin-4-yl)thiazolo[5,4-c]pyridine (1.34 g, 94%) as a yellow amorphous solid. 1H NMR: δ (CDCl3, 400 MHz) 2.67 (s, 3H), 8.09 (d, J=5.5 Hz, 1H), 8.74 (d, J=5.5 Hz, 1H), 8.86 (s, 1H), 9.34 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH2:24]C)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:26][O:27]CCOC1N=C(C(O)=O)C=NC=1N1CCCC1.N[C@@H](CC(C)C)CO>>[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:13]([O:22][CH2:23][CH2:24][O:27][CH3:26])[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: COCCOc1nc(C(=O)O)cnc1N1CCCC1
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Agent: CC(C)C[C@H](N)CO
Product: COCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-(2-methoxy-ethoxy)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid and (S)-2-amino-4-methyl-pentan-1-ol (commercially available). m/z (ES+): 367.3 (M+H).
Reaction SMILES: Cl.OC(COC1C=CC=CC=1OC)CN1CCC([N:11]2[CH2:15][CH2:14][N:13](C3C=CC(OC)=CC=3)C2=O)CC1.[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40](N)=[CH:39][CH:38]=1.Br.BrCCN>C(C(C)=O)C>[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([CH:14]([NH2:13])[CH2:15][NH2:11])=[CH:39][CH:38]=1
Reactant: COc1ccc(N2CCN(C3CCN(CC(O)COc4ccccc4OC)CC3)C2=O)cc1
Reactant: COc1ccc(N)cc1
Agent: Br
Agent: Cl
Agent: NCCBr
Solvent: CCC(C)=O
Product: COc1ccc(C(N)CN)cc1

Procedure:
A mixture of 17.9 g of 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone and 11.7 g of 1-(2-methoxyphenyloxy)-2,3-epoxypropane in 200 ml of isopropyl alcohol is refluxed for 6 hours. The mixture is thereafter acidified with 5 N methanolic hydrochloric acid and concentrated under reduced pressure. The residue is freed from moisture still adhering to it by treatment with toluene. Recrystallisation of the residue from methanol with the addition of activated charcoal yields the 1-{1-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-4-piperidyl}-3-(4-methoxy-phenyl)-imidazolidin-2-one-hydrochloride as a white crystalline substance with a melting point of 214°-215° C. The 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone used as starting material can be prepared as follows: A mixture of 61.5 g of 4-methoxy-aniline and 51.3 g of 2-bromoethylamine-hydrobromide in 125 ml of methyl ethyl ketone is refluxed for 5 hours with stirring. The viscous suspension is thereafter evaporated to dryness under reduced pressure. The residue is suspended in 150 ml of isopropanol and then collected by filtration. The filter cake is washed with three 50 ml portions of isopropanol and with two 50 ml portions of diethyl ether. The crystalline product is made alkaline with a concentrated aqueous ammonia solution and extracted with five 50 ml portions of chloroform. The extracts are dried over sodium sulphate and concentrated under reduced pressure. The oily residue crystallises after trituration to give the 1-(4-methoxyphenyl)-ethylenediamine with a melting point of 64° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][S:20][C:12]=3[N:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=2)[CH2:6][CH2:5]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]3[C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][S:20][C:12]=3[N:13]=[C:14]([CH2:16][C:17]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:18])[N:15]=2)[CH2:6][CH2:5]1
Reactant: COCC1CCN(c2nc(CC(=O)O)nc3scc(-c4ccccc4)c23)CC1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC1CCN(c2nc(CC(=O)N3CCCC3)nc3scc(-c4ccccc4)c23)CC1
Yield: 11.1 %

Procedure:
2-[4-[4-(Methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]acetic acid (24 mg, 0.06 mmol), pyrrolidine (5 mg, 0.067 mmol), HATU (26 mg) and triethylamine (0.025 mL) were stirred in acetonitrile (2 mL) at 50° C. for 20 hrs. The reaction was partitioned between water and DCM. The organics were separated and concentrated in vacuo. The residue was purified by preparative TLC, eluting 10% methanol in DCM. The isolated band was repurified by preparative TLC, eluting ethyl acetate to give 2-[4-[4-(methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]-1-pyrrolidin-1-yl-ethanone (3 mg). LCMS RT=4.61 min. M+1=451.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.[OH2:25]>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[CH:9][C:7]([O:8][CH2:4][CH3:3])=[O:25]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(C=O)c1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 0.17 h
Yield: 81 %

Procedure:
Sodium hydride (oily, 60%, 2.40 g) was added little by little to a solution of triethyl phosphonoacetate (12.3 g) in tetrahydrofuran (200 ml) at 0° C., and the mixture was stirred at 10 minutes. Then, 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (14.7 g) was added, and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate-hexane (1:3, v/v) gave crystals of ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate (14.8 g, 81%). The crystals were recrystallized from ethanol. Colorless prisms, mp: 94-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([N:13]1[CH2:18][CH2:17][CH:16]2[S:19][C:20](=[O:22])[CH:21]=[C:15]2[CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].C(OCC)(=O)C>O1CCCC1>[CH2:34]([O:33][C:31]([O:22][C:20]1[S:19][C:16]2[CH2:17][CH2:18][N:13]([C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([O:11][CH3:12])=[O:10])[CH2:14][C:15]=2[CH:21]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1CCC2SC(=O)C=C2C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc2c(s1)CCN([C@H](C(=O)OC)c1ccccc1Cl)C2
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
(2S)-Methyl 2-(2-chlorophenyl)-2-(2-oxo-7,7a-dihydrothieno[3.2-c]pyridin-5(2H,4H,6H)-yl)-acetate (IV-1) (85 mg) was dissolved in 10 ml of anhydrous tetrahydrofuran, and 0.141 ml of triethylamine was added at room temperature and stirred for 10 min. Then, 0.167 ml of ethyl chloroformate was added dropwise at 0° C. After the addition, the reaction solution became a light yellow cloudy solution from a dark red clear solution. The ice bath was removed and the reaction was warmed to 10° C. for 1 hr. Then, 0.07 ml of triethylamine and 0.1 ml of ethyl chloroformate were additionally added in an ice bath at 0° C. The ice bath was removed and the reaction was warmed to 10° C. for 1 hr, at which the raw materials substantially disappeared. Water (20 ml) was added, the reaction solution was extracted with ethyl acetate (30 ml×3) and dried over anhydrous sodium sulfate, and the solvent was evaporated to give a crude product, which was subjected to flash column chromatography (petroleum ether:ethyl acetate=40:3) to obtain (S)-methyl 2-(2-(ethoxycarbonyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)-acetate (I-14) (77 mg). Yield 75%, mp: 42-44° C., ee=97.3% (chiral HPLC analysis conditions were the same as those in Example 4), [α]D20=+40.00° (c 0.50, MeOH); 1H-NMR (300 MHz, CDCl3) δ 1.37 (t, 3H, J=7.2 Hz), 2.76-2.78 (m, 2H), 2.86-2.90 (m, 2H), 3.52 (d, 1H, J=14.2 Hz), 3.64 (d, 1H, J=14.3 Hz), 3.72 (s, 3H), 4.32 (q, 2H, J=7.1, 14.3 Hz), 4.90 (s, 1H), 6.30 (s, 1H), 7.24-7.68 (m, 4H); 13C-NMR (75 MHz, CDCl3) δ 14.4, 25.4, 48.4, 50.5, 52.4, 65.7, 68.1, 112.7, 126.2, 127.4, 129.7, 129.8, 130.1, 130.2, 134.0, 135.0, 152.9, 157.3, 171.5; ESI-MS m/z 410.1 [M+H]+, 432.1 [M+Na]+; HRMS Calcd for C19H21NO5SCl [M+H]+ m/z 410.0836. found 410.0829.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2NN=[N:27][N:26]=2)=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[N:26][N:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Clc1ccc(-c2nnn[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccc(Cl)cc2)o1
Yield: 84.3 %

Procedure:
The title compound (1.65 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.26 g), 5-(4-chlorophenyl)tetrazole (1.08 g) and dicyclohexylcarbodiimide (1.15 g) according to the method of description 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=[O:13])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:14][Mg]Br>ClCCl.C1COCC1>[OH:13][CH:12]([CH3:14])[CH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(CC(C)O)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 1.48 g (8.47 mmol) of 2-methoxy-4-(2-oxoethyl)benzonitrile in dichloromethane (30 mL) at 0° C. was added 2.82 mL (8.47 mmol) of a 3.0 M solution of methylmagnesium bromide in THF. The reaction mixture was allowed to warm up to RT and stirred for 12 h. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid and extracted with dichloromethane (2×30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified on silica (30% EtOAc/hexanes as eluent) to afford 4-(2-hydroxypropyl)-2-methoxybenzonitrile as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.47 (d, 1H, J=7.8 Hz), 6.85 (dd, 1H, J=3.4 Hz), 6.82 (s, 1H), 4.05 (m, 1H), 3.93 (d, 2H), 3.91 (s, 3H), 1.25 (d, 2H, J=6.1 Hz). LC-MS (IE, m/z): 192.3 [M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)Cl.CN([CH:24]=[O:25])C>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:24]=[O:25])=[CH:12][CH:11]=[C:10]([Cl:15])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O

Procedure:
The title compound is prepared according to a published literature procedure (see J. Med. Chem. 2005, 48, 995-1018.) A solution of 6-chloro-1H-indole-2-carboxylic acid ethyl ester (5.0 g, 22.4 mmol) (commercially available from 3D Medical Systems Inc.) and POCl3 (2.46 mL, 26.8 mmol) in DMF (15 mL) is heated at 50° C. for 28 h. After completion, the reaction mixture is quenched by aqueous NaHCO3, Et2O is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless powder; ES-MS: M−=250.1; HPLC: AtRet=4.67 min.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1.N([O-])=O.[Na+].[ClH:16]>O>[Cl:16][C:2]1[S:3][C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1
Reactant: Nc1nc2cn[nH]c(=O)c2s1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]ncc2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (822 mg) obtained in Step 5 was suspended in 6N aqueous hydrochloric acid solution (6.6 ml), and sodium nitrite (1.69 g) was added in several portions at room temperature. After stirring the obtained suspension at room temperature for 30 min, the reaction mixture was diluted with water, and the solid was collected by filtration, washed with water and a small amount of acetone, and dried to give the title compound (770 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](O)=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.B>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][OH:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: B
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCO)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.10 g of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1 carboxylic acid benzyl ester (from example 9b) in 8.0 ml of tetrahydrofuran are added 0.31 ml of a solution of borane tetrahydrofuran (1M) at 50° C. The reaction mixture is stirred for 2 hours at this temperature, allowed to cool to room temperature and quenched by addition of methanol. The mixture is concentrated under reduced pressure and the obtained residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.50 (EtOAc-heptane 5:1); Rt=4.95.