Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:34]>>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:32])=[C:19]([NH:23][S:24]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(Cl)n2)o1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (85 mg, 0.178 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as an off-white solid (74 mg, 91%). 1H-NMR (DMSO-d6): δ ppm 10.25 (br s, 1H), 8.27 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.83 (t, J=2.0 Hz, 1H), 7.44-7.36 (m, 2H), 7.25 (t, J=8.4 Hz, 1H), 6.69 (s, 1H), 6.63 (br s, 2H), 6.50 (d, J=5.2 Hz, 1H), 1.41 (s, 9H); MS: 458 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([S:22]C#N)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P([O-])(O)(O)=O.[K+].SCC(C(CS)O)O>>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([SH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#CSc1ccc2nc(NC(=O)CCCN3CCOCC3)sc2c1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Product: O=C(CCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Yield: 8.4 %

Procedure:
The 4-morpholin-4-yl-N-(6-sulphanyl-1,3-benzothiazol-2-yl)butanamide was prepared according to the method described in Example 1b, but using 906 mg of 4-morpholin-4-yl-N-(6-thiocyanato-1,3-benzothiazol-2-yl]butanamide, 14 mg of potassium dihydrogen phosphate and 1.12 g of DL-dithiothreitol. 71 mg of 4-morpholin-4-yl-N-(6-sulphanyl-1,3-benzothiazol-2-yl)butanamide are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[C:30]([CH3:31])=[N:29][N:28]=[N:27]4)=[CH:22][CH:21]=3)[C:15]2=[O:32])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>C(Cl)Cl.O1CCOCC1>[ClH:33].[CH3:31][C:30]1[N:26]([C:23]2[CH:22]=[CH:21][C:20]([O:19][C@H:16]3[CH2:17][CH2:18][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:15]3=[O:32])=[CH:25][CH:24]=2)[N:27]=[N:28][N:29]=1
Reactant: Cc1nnnn1-c1ccc(OC2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nnnn1-c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)cc1
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of tert-butyl-4-(3-(4-(5-methyl-1H-tetrazol-1-yl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (621 mg, 1.4 mmol) in DCM (15 mL) was added excess 4N HCl in dioxane (5 mL). The reaction was stirred for 4 hours and then concentrated in vacuo to yield (S)-3-(4-(5-methyl-1H-tetrazol-1-yl)phenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride salt (501 mg, 94%) as an off white solid, which was used without any further purification.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[I:61][CH2:62][C:63](=[O:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66].[OH-].[Na+]>>[I:61][CH2:62][C@@H:63]([OH:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66]
Reactant: CCOC(=O)CC(=O)CI
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: CCOC(=O)C[C@H](O)CI
Temperature: 30 °C
Reaction time: 13 h
Yield: 178.6 %

Procedure:
The recombinant E. coli HB101 (pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 0.5 g, 3.2 mg of NADP, and then 0.5 g of ethyl 4-iodoacetoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 72 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 900 mg of ethyl (S)-4-iodo-3-hydroxybutyrate. The optical purity of the ethyl (S)-4-iodo-3-hydroxybutyrate was analyzed as follows and found to be 91.6% e.e. That is, the sample was heated together with sodium cyanide in dimethyl sulfoxide to obtain ethyl 4-cyano-3-hydroxybutyrate, which was then changed to a benzoic ester using benzoyl chloride under the presence of pyridine. The optical purity of the benzoic ester was measured by an HPLC method. NMR(CDCl3) δ (ppm): 1.28(3H,t), 2.65(2H,d), 3.31(3H,m), 4.00(1H,m), 4.20(2H,q); Column: Chiralpak AS (0.46×25 cm) manufactured by Daicel Chemical Industries, Co., Ltd.; Column temperature: 25° C.; Eluent: n-hexane/ethanol of 95/5; Flow rate: 1 ml/min.; Detection: 254 nm; Elution time: 19.6 minutes for (S), 21.3 minutes for (R).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][CH2:15]CC[Sn](C=C)(CCCC)CCCC.[F-].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[CH:14]=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1ccc(F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1cc(C(=O)OCC)ccc1F
Yield: 87 %

Procedure:
A mixture of compound ethyl 3-bromo-4-fluorobenzoate (Preparation 53, 81 g, 328.8 mmol, 1 eq) and bis(triphenylphosphine)palladium (II) chloride (7 g, 9.9 mmol, 0.03 eq) in dioxane (600 mL) was charged with nitrogen. Tin vinyltributyl (115 g, 361.6 mmol, 1.10 eq) was added and the mixture was heated to reflux overnight. The mixture was filtrated and the filtrate was concentrated in vacuum. The residue was dissolved in ether (2 L) and water (1 L). Then potassium fluoride (10 g, 1.7 mol, 5.17 eq) was added to the mixture and much of solid precipitated. The mixture was filtrated and the filtrate was separated. The aqueous phase was extracted with ether (200 mL×2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by chromatography (petroleum ether) to title compound as a colorless oil (55.8 g, 286 mmol, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]([CH3:13])[CH:7]=[C:6]2[C:14]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1.[H-].[Na+].Br[CH2:36][CH2:37][Cl:38].C1CCCCC1.C(OCC)(=O)C>CN(C)C=O.O.C(OCC)(=O)C>[Cl:38][CH2:37][CH2:36][O:12][C:11]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:22]([S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[CH:15]=3)=[CH:7][N:8]2[CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: ClCCBr
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCl
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A solution of 5-methoxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-ol (0.8 g; 1.788 mmol) in solution in dimethylformamide (5 ml) is placed in a 50 ml round-bottomed flask rendered inert with argon, and sodium hydride (0.064 g; 2.146 mmol) is then added. The reaction mixture becomes brown in color and 1-bromo-2-chloroethane (0.308 g; 2.146 mmol) is added. The reaction mixture is agitated for 1 hour 30 minutes at 20° C. and then sodium hydride (0.064 g; 2.146 mmol) and 1-bromo-2-chloroethane (2×0.5 ml) are again added. Analysis by thin layer chromatography (50/50 cyclohexane/ethyl acetate) shows that the reaction has come to an end. The reaction mixture is diluted with water (150 ml) and ethyl acetate (50 ml), and extracted with ethyl acetate (2×50 ml). The organic extracts are combined, dried over magnesium sulfate, filtered, and evaporated under reduced pressure, resulting in the crude compound, which is purified by chromatography on silica gel (AIT cartridge FC 25 Si-BP-Sup, eluent: 65/35 cyclohexane/ethyl acetate at 10 ml/min). The fractions containing the expected compound are combined and then evaporated under reduced pressure, giving the expected 2-[6-(2-chloroethoxy)-5-methoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.66 g; 72%) in the form of a powder, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[CH3:20][N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])=[N:7][C:2]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([CH3:21])[N:23]=[CH:24]4)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1nc(-c2ccc3c(cnn3C)c2)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (35 mg, 0.119 mmol) and 1-methyl-1H-indazol-5-ylboronic acid (23 mg, 0.131 mmol), (R)-4-((R)-1-(3-methyl-6-(1-methyl-1H-indazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.29 was isolated, following column chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([C:10]#N)=[CH:3]1.[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=[O:24].[Na+].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10]=[O:24])=[CH:3]1
Reactant: CC1(C)C=C(C#N)C(C)(C)CC1
Reactant: O=S(=O)([O-])[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)C=C(C=O)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
To the mixture of the product of Example 10f (500 mg, 3.07 mmol) in dry dichloromethane (12.5 mL) at −78° C. was added diisobutyl aluminum hydride (6.5 mL, 6.14 mmol) and the reaction was warmed to room temperature and stirred for approximately 2.5 hours. Wet sodium sulfate was added to quench the reaction. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a colorless oil. (360 mg, Yield: 71%). 1H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 6.33 (s, 1H), 1.55-1.49 (m, 4H), 1.20 (s, 6H), 1.10 (s, 6H) ppm.
Reaction SMILES: Cl.[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:36]=[C:35]([CH:37]=O)[O:34][N:33]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:36]=[C:35]([CH2:37][N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:13]3[N:14]=[N:15][CH:16]=[C:11]4[O:10][N:9]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:12]=34)[CH2:20][CH2:21]2)[O:34][N:33]=1
Reactant: O=Cc1cc(-c2ccccc2Cl)no1
Reactant: c1ccc(-c2noc3cnnc(NCC4CCNCC4)c23)cc1
Agent: Cl
Product: Clc1ccccc1-c1cc(CN2CCC(CNc3nncc4onc(-c5ccccc5)c34)CC2)on1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 84 instead of the compound obtained in Example 11 and 3-(2-chlorophenyl)isoxazole-5-carbaldehyde instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [O:1]=[C:2]([Cl:8])[O:3][C:4](Cl)(Cl)Cl.[Cl:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])CO.CCN(CC)CC>C1COCC1>[Cl:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:4][O:3][C:2]([Cl:8])=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1C(Cl)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)OCC(Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A solution of diphosgene (1.7 ml, 14 mmol) in THF (10 ml, dist. over CaH2) was cooled by means of an ice bath to about 0° C. A solution of 2-chloro-2-(2-nitrophenyl)ethanol (705 mg, 3.5 mmol) and Et3N (354 mg, 0.485 ml, 3.5 mmol) in THF (10 ml, dist. over CaH2) was dropped thereto for about 30 min. After the solution had been stirred for a further hour, the ice bath was removed. The mixture was stirred for another 3 h at room temperature. The mixture was filtered over Celite. The precipitate was rewashed with THF (10 ml, dist. over CaH2). The combined filtrates were concentrated under reduced pressure and then dried in a high vacuum at room temperature. 2-chloro-2-(2-nitrophenyl)ethoxycarbonyl chloride (896 mg, 97%) was obtained as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(N(C(C)C)CC)(C)C.CN(C(O[N:45]1[N:53]=[N:52][C:47]2[CH:48]=[CH:49]C=N[C:46]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC(N)=CN=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:52][C:47]1[CH:48]=[CH:49][N:53]=[N:45][CH:46]=1)=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccnnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)c1cc(Cl)c(C(=O)N2CCC(F)(F)C2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-4-[(3,3-difluoro-1-pyrrolidinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 65; 90 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.46 mmol), HATU (156 mg, 0.41 mmol) and 4-pyridazinamine (26.0 mg, 0.27 mmol). The solution was stirred for 18 hours. The solvent removed in vacuo and purified by MDAP to give the title compound as a white solid. 68 mg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]([CH3:17])[C:7]([C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:8][N:9]=1)(=[O:4])=[O:3].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=O)([O-])[O-].[Ag+].[Ag+]>[CH2:18]([O:16][C:12]1[CH:11]=[C:10]([C:7]2[N:6]([CH3:17])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:9][N:8]=2)[CH:15]=[CH:14][N:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1c(-c2cc[nH]c(=O)c2)nnc1S(C)(=O)=O
Reactant: BrCc1ccccc1
Agent: [Ag+]
Agent: O=C([O-])[O-]
Product: Cn1c(-c2ccnc(OCc3ccccc3)c2)nnc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound from example 27.1 (0.95 g, 3.7 mmol) and silver (1) carbonate (1.23 g, 4.48 mmol) were combined in a round bottom flask and purged with nitrogen. Toluene (10 mL) was added, followed by benzyl bromide (0.53 mL, 4.48 mmol) and the reaction was stirred for 72 h at room temperature. The silver salts were then removed by filtration through diatomaceous earth, which were then washed with dichloromethane. The filtrate was concentrated then purified by column chromatography on silica gel with 0-10% ethyl acetate in dichloromethane to give the title compound (off-white solid, 549 mg, 43
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH2:14]([CH2:18][C:19](=O)[CH3:20])[C:15]([CH3:17])=O.O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[C:15]([CH3:17])=[CH:14][CH:18]=1
Reactant: CC(=O)CCC(C)=O
Reactant: COC(=O)C=Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=Cc1ccc(-n2c(C)ccc2C)cc1
Reaction time: 16 h

Procedure:
A mixture of 21.4 g of methyl 4-aminocinnamate and 50 g of acetonylacetone in 500 ml of toluene is heated under reflux using a Dean Stark water separator for 16 hours. The solution is washed with ice cold dilute hydrochloric acid, brine, and then dried over magnesium sulfate. The organic phase is filtered through silica gel, evaporated at 60° under reduced pressure and the residue is crystallized from hexane to yield methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-cinnamate, m.p. 73°-75°. A solution of the ester in 150 ml of methanol and 100 ml 1N aqueous sodium hydroxide is stirred at room temperature for 16 hours. Methanol is evaporated at 60° under reduced pressure. The basic solution is washed with ethyl acetate, then made acidic with ice cold 5N aqueous hydroxhloric acid, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, treated with charcoal, and evaporated to dryness at 60° under reduced pressure. The residue is crystallized from ether/hexane (2:1) to yield (E)-4-(2,5-di-methyl-1H-pyrrol-1-yl)-cinnamic acid, m.p. 189°-191°, also named (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-2-propenoic acid.
Reaction SMILES: B(Br)(Br)Br.ClCCl.ClCCl.C[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]2.O>ClCCl.CO.CO>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]2
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
A 1.0M boron tribromide/dichloromethane solution (8.5 ml) was added at 0° C. to a dichloromethane solution (50 ml) of 6-methoxy-2H-isoquinolin-1-one (1.0 g). The mixture was stirred at room temperature overnight. Water and methanol were added to the reaction mixture and extraction was carried out with a dichloromethane/methanol mixed solvent (dichloromethane:methanol=10:1). The organic layer was dried with anhydrous sodium sulfate, followed by condensation to dryness under reduced pressure, thereby obtaining the title compound (0.4 g) as a pale yellow solid.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][C:15]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([C:17]([OH:19])=[O:18])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)C1C=CC=CC=1>CO.[Pd]>[C:24]([O:23][C:21]([NH:20][C:15]1([C:17]([OH:19])=[O:18])[CH2:16][CH:9]2[NH:8][CH:13]([CH2:12][O:11][CH2:10]2)[CH2:14]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC2COCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CC2COCC(C1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
A mixture of compound 139d (0.050 g, 0.13 mmol) and Pd/C (20 mg) in MeOH (5 ml) was stirred under H2 balloon at room temperature overnight. The mixture was filtered and the filtrate was concentrated to give 40 mg of the crude 7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid 139a, which was used directly in next step without further purification. MS: calc'd (MH+) 287, measured (MH+) 287.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[I:10])=[O:4].[Li]>O1CCOCC1.O>[I:10][C:9]1[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1I
Agent: [Li]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1sc(-c2ccccc2)cc1I
Reaction time: 21.5 h
Yield: 97.6 %

Procedure:
A solution of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid methyl ester (4.4 g, 12.78 mmol) in dioxane/water 4/1 (50 ml), at 21° C., under N2, was treated with lithium hydroxyde (2N, 19.3 ml, 38 mmol) and the solution left to stir for 21.5 h. The reaction mixture was evaporated to dryness and the residue partitioned between EtOAc (75 ml) and water (25 ml) and acidified with 2N HCl to pH 5.5. The aqueous phase was separated and extracted with EtOAc (3×50 ml). The combined organic extract were washed with brine, dried and evaporated to give 4.12 g (97%) of 3-Iodo-5-phenyl-thiophene-2-carboxylic acid as a pale yellow solid. NMR 1H (CD3OD, 400 MHz): 7.69-7.67 (m, 2H); 7.55 (s, 1H); 7.46-7.39 (m, 3H).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:27])[CH:11]=[CH:12][N:13]2[CH2:18][CH:17]([O:19][CH3:20])[O:16][CH:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]=12)C1C=CC=CC=1.C(OC1C(=O)C=CN(CC(OC)OC)C=1C(C1C=CC=CC=1)OC1CCCCO1)C1C=CC=CC=1.C(OCC)(=O)C.C(O)C>CO.Cl>[OH:8][C:9]1[C:10](=[O:27])[CH:11]=[CH:12][N:13]2[CH2:18][CH:17]([O:19][CH3:20])[O:16][CH:15]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:14]=12
Reactant: COC1Cn2ccc(=O)c(OCc3ccccc3)c2C(c2ccccc2)O1
Agent: COC(Cn1ccc(=O)c(OCc2ccccc2)c1C(OC1CCCCO1)c1ccccc1)OC
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: COC1Cn2ccc(=O)c(O)c2C(c2ccccc2)O1

Procedure:
9-Benzyloxy-3-methoxy-1-phenyl-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazin-8-one: 2.13 g of 3-benzyloxy-1-(2,2-dimethoxy-ethyl)-2-[phenyl-(tetrahydro-pyran-2-yloxy)-methyl]-1H-pyridin-4-one are boiled under reflux for 2 hours in 5 ml of methanol and 8.8 ml of 2N hydrochloric acid. The methanol is distilled off using a rotary evaporator and the residue is diluted with water and neutralised with 8.8 ml of 2N sodium hydroxide solution. Extraction is carried out with ethyl acetate and the extracts are washed twice with water. The extracts are dried, filtered and concentrated by evaporation. Chromatography yields: 1.3 g of 9-benzyloxy-3-methoxy-1-phenyl-3,4-dihydro-1H-pyrido[2,1-c][1,4]oxazin-8-one in the form of a diastereoisomeric mixture. Yellow resin. Rf value: 0.45 (silica gel 60, ethyl acetate/ethanol 9/1).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[C:33]([C:37]1[CH:70]=[CH:69][C:40]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:58]=[C:57]4[C:53]([CH2:54][N:55]([C@@H:60]([CH:65]([CH3:67])[CH3:66])[C:61]([O:63]C)=[O:62])[C:56]4=[O:59])=[CH:52][CH:51]=3)=[C:46]([F:68])[CH:45]=2)=[O:42])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:37]1[CH:70]=[CH:69][C:40]([C:41]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]3[CH:58]=[C:57]4[C:53]([CH2:54][N:55]([C@@H:60]([CH:65]([CH3:66])[CH3:67])[C:61]([OH:63])=[O:62])[C:56]4=[O:59])=[CH:52][CH:51]=3)=[C:46]([F:68])[CH:45]=2)=[O:42])=[CH:39][CH:38]=1)([CH3:34])([CH3:36])[CH3:35]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3F)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3F)cc2C1=O
Yield: 87 %

Procedure:
The compound of example 604 was prepared analogous to compound of example 98 by hydrolysis of compound of example 603.