Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[CH2:32][CH2:33][NH2:34].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[CH2:32][CH2:33][NH:34][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: NCCc1c(Cl)cccc1Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2c(Cl)cccc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2,6-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H27Cl2NO5 [M−H]−: 466, [M+H]−: 468.
Reaction SMILES: N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:22][C:23]1([CH3:37])[C@@H:25](/[CH:26]=[C:27](\[F:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@H:24]1[C:34]([OH:36])=[O:35].[C:38]([C@@H:40](O)[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:42]=1)#[N:39]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:37][C:23]1([CH3:22])[C@@H:25](/[CH:26]=[C:27](\[F:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@H:24]1[C:34]([O:36][C@H:40]([C:38]#[N:39])[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:42]=1)=[O:35]
Reactant: CCOC(=O)/C(F)=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)/C(F)=C/[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Yield: 72.3 %

Procedure:
1.9 ml of pyridine and 4.8 g of dicyclohexylcarbodiimide were added to a solution of 4.9 g of (1R,cis) 2,2-dimethyl-3(Z)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylic acid in 39 ml of methylene chloride and a solution of 5.3 g of (S)α-cyano-3-phenoxy-benzyl alcohol in 9.8 ml of methylene chloride was added with stirring to the mixture. After stirring the mixture for 2 hours, 30 mg of 4-dimethylamino-pyridine were added thereto and the mixture was stirred for 2 hours. The mixture was cooled to 0° C. and was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was successively eluted with a 9-1 cyclohexane-ethyl acetate mixture and with a 6-4 methylene chloride-petroleum ether (b.p.=35°-70° C.) mixture to obtain 6.73 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3(Z)-[2-fluoro-2-ethoxycarbonyl-ethenyl]-cyclopropane-1-carboxylate with the same characteristics of the compound of Example 2.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[NH:23]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][CH2:32][CH2:33][N:23]1[C:14]([C:12]1[O:13][C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)=[O:16])=[O:26])[CH3:29]
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCN1C(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Yield: 59.4 %

Procedure:
A solution of 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (of Intermediate 8; 0.098 g, 0.33 mmol), ethyl pipecolinate (Aldrich-0.139 g 0.88 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (Avocado; 0.13 g, 0.68 mmol), and N,N-dimethylaminopyridine (0.083 g, 0.68 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The solvents were evaporated under reduced pressure, and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate, and the combined organic layers were dried (sodium sulfate) filtered, evaporated, and purified using a Biotage Flash 40 purification system, eluting with methylene chloride/acetone 9:1, to give (rac)-1-[5-(biphenyl-4-yloxymethyl)-furan-2-carbonyl]-piperidine-2-carboxylic acid ethyl ester as a colorless oil (0.085 g, 59%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:35])[C:24]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:6]([O:8]C)=[O:7].C(O)(=O)C>O1CCCC1>[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:35])[C:24]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:25])[CH:18]=2)=[CH:15][CH:16]=1)/[C:6]([OH:8])=[O:7]
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)NCCc3ccccc3)c2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CO/C(=C\c1ccc(-c2cccc(N(C)C(=O)NCCc3ccccc3)c2)cc1)C(=O)O
Temperature: 68 °C
Reaction time: 4 h
Yield: 105.6 %

Procedure:
1.7 mL (1.7 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.5 g (1.1 mmol) of methyl (Z)-2-methoxy-3-[3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]acrylate in 10 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 2 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from hot ethyl acetate. 500 mg (71%) of (Z)-2-methoxy-3-[3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white solid with a melting point of 144° C.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@@H:10]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])C>C(O)=O>[CH2:1]([O:8][N:9]([C@H:10]([CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:18])([CH3:19])[NH:14][C:13]1=[O:20])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=1)[CH:30]=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)NC(=O)N(C[C@H](COc2ccc(Br)cc2)NOCc2ccccc2)C1=O
Solvent: O=CO
Product: CC1(C)NC(=O)N(C[C@H](COc2ccc(Br)cc2)N(C=O)OCc2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of Example 3H (57.7 g) in formic acid (200 mL) was treated with a mixture of acetic anhydride (35 mL) in formic acid (35 mL) over 10 minutes, stirred for 10 minutes, and concentrated. The concentrate was dissolved in ethyl acetate (500 mL), washed sequentially with 1:1/water:brine, saturated NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was dissolved in warm (60° C.) toluene, cooled, and filtered. The solid was washed with 1:1/toluene:heptane then dried under vacuum (100 mm Hg) at 50° C. with a nitrogen bleed to provide 51.7 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ8.42 (br s, 0.5H), 8.38 (br s, 0.5H), 8.32 (br s, 0.5H), 8.10 (br s, 0.5H), 7.4 (m, 7H), 6.95 (m, 2H), 5.00 (m, 1H), 4.91 (m, 1H) 4.80 (m, 0.5H), 4.55 (m, 0.5H), 4.28(m, 1H), 4.17 (m, 1H), 3.88 (dd, 1H, J=9, 14 Hz), 3.60 (m, 1H), 1.25 (s, 3H), 1.22 (s, 3H).
Reaction SMILES: [NH:1]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:27]([NH:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH2:18][O:19]CC1C=CC=CC=1)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1>>[NH:1]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:27]([NH:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[CH2:18][OH:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:27]([NH:29][C@H:30]([C:35]([CH2:37][Cl:38])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:28])[CH2:18][OH:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Solvent: COc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@@H](N)Cc1ccccc1)C(=O)CCl
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Yield: 21.1 %

Procedure:
Z-Phe-Gly-Ser-LeuCH2Cl was prepared by the following procedure. First, Z-Phe-Gly-Ser(OCH2C6H5)LeuCH2Cl (0.98 g, 14.4 mmol) was deblocked by treatment with 15 mL of anhydrous HF and 1 mL of anisole (Procedure K) to yield 0.69 g of H-Phe-Gly-Ser-LeuCH2Cl.HF. This intermediate (0.59 g, 12.4 mmol) was then coupled with carbobenzoxychloride substantially according to the procedure of Procedure K to yield 0.4 g of Z-Phe-Gly-Ser-LeuCH2Cl (m.p. 146°-146.5°) after crystallization from ethyl acetate/hexane.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([F:9])([F:8])[CH2:6][NH2:7].C(N(CC)C(C)C)(C)C.Cl[C:20]([CH3:35])([CH3:34])[CH:21]([N:32]=[O:33])[CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[N+:29]([O-:31])=[O:30]>C(#N)C>[NH2:3][CH2:4][C:5]([F:9])([F:8])[CH2:6][NH:7][C:20]([CH3:35])([CH3:34])[C:21](=[N:32][OH:33])[CH2:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[N+:29]([O-:31])=[O:30]
Reactant: NCC(F)(F)CN
Reactant: CC(C)(Cl)C(CCn1ccnc1[N+](=O)[O-])N=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NCC(F)(F)CN)C(CCn1ccnc1[N+](=O)[O-])=NO
Reaction time: 0.5 h

Procedure:
To a mixture of 1,3-diamino-2,2-difluoropropane dihydrochloride (title A diamine) (1.10 g, 6.01 mmol) and N,N-diisopropylethylamine (2.72 g, 21.04 mmol) in acetonitrile (10 mL) at 40° C. was added 4-chloro-4-methyl-1-(2-nitro-1H-imidazol-1-yl)-3-nitrosopentane (Example 35 step (B)) (0.50 g, 1.90 mmol) in small portions with stirring under nitrogen atmosphere. After the addition, the stirring was continued for an additional 30 minutes and the solvent was removed on a rotary evaporator. The paste obtained was treated with silica gel and the silica gel powder impregnated with the compound was loaded onto a silica gel column and eluted with CH3OH-CH2Ch2 (5:95). The fractions containing compound were collected and evaporated to give the title product as a light yellow colored solid. Yield: 0.42 g (66%), mp. 112-114° C.; 1H NMR (CDCl3) d 1.19[s, 6H, C(CH3)2], 2.88[m, 4H, C(═N)CH2 & NHCH2], 3.71(t, 3H, JHF=13.19 Hz, CH2NH2), 4.72(t, 2H, J=7.26, CH2CH2N), 7.11 & 7.26(2s, 2H, nitroimid-H) and 10.79(s, 1H, NOH). MS m/e 335 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:19])=[CH:8][C:7]([CH2:20][OH:21])=[CH:6][N:5]2[C:22]=1[CH3:23].S(Cl)([Cl:26])=O.[C:28](=O)(O)[O-]>C(Cl)Cl>[ClH:26].[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=3[CH3:18])=[CH:8][C:7]([CH2:20][O:21][CH3:28])=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: O=S(Cl)Cl
Reactant: O=C([O-])O
Reactant: Cc1cccc(C)c1CNc1cc(CO)cn2c(C)c(C)nc12
Solvent: ClCCl
Product: COCc1cc(NCc2c(C)cccc2C)c2nc(C)c(C)n2c1
Product: Cl
Reaction time: 2 h
Yield: 11 %

Procedure:
To a stirred solution of 2,3-dimethyl-8-(2,6-dimethylbenzylamino)-6-hydroxymethyl-imidazo[1,2-a]pyridine (0.08 g, 0.26 mmol) in methylene chloride (5 ml) was added thionyl chloride (0.038 ml, 0.52 mmol) and the mixture was stirred for 2 h. A saturated bicarbonate solution was added and the organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. To the residue was added methanol (5 ml) the mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride: methanol (100:5) as eluent. Treating the residue with HCl/diethyl ether and filtration gave 0.01 g (11%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CO>[NH:3]1[C:2]2[NH:1][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:6]=2[CH:5]=[N:4]1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CO
Product: CCOC(=O)c1cc2cn[nH]c2[nH]1
Yield: 110.4 %

Procedure:
3-Aminopyrazole (1.203 mmol, 0.1 g), ethyl bromopyruvate (1.504 mmol, 0.293 g) and methanol were added into a flask and refluxed for 1.5 h. The solvent was evaporated and the residue was dissolved in DCM and washed with Na2HCO3. The organic phase was dried, filtered and evaporated. 0.238 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.30 (t, 3H), 4.26 (q, 2H), 6.76 (d, 1H), 7.68 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[N:10]([O-])=O.[Na+].[ClH:14]>>[ClH:14].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(NN)ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-3-methylaniline (10.2 g) was suspended in 6N HCl (85 mL) and cooled to 0° C. A solution of sodium nitrite (4 g in 40 mL H2O) was added over 10 min. The reaction was stirred for 15 min at 0° C. followed by the addition of stannous chloride dihydrate (36 g in 25 mL 12N HCl). The reaction was stirred for 2 hours at 0° C. The reaction was filtered, and the filter cake was washed with cold H2O to afford 4-bromo-3-methylphenylhydrazine hydrochloride (compound 2a, 20 g) as a tan solid.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[C:18](=[O:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Nc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)C(=O)C1
Temperature: 119 °C
Yield: 86.6 %

Procedure:
A suspension of p-iodo-aniline (918 mg, 4.8 mmol), 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (960 mg, 4.2 mmol) (1R,2R)-cyclohexane-1,2-diamine (0.05 mL, 0.42 mmol), copper (I) iodide (14.9 mg, 0.0042 mmol) and K2CO3 (1.19 g, 2.04 mmol) in dioxane (4 mL), is purged with nitrogen for 5 min in a reaction tube. The tube is sealed and the reaction mixture is heated at 119° C. for 15 hours. After cooling to room temperature, the reaction mixture is filtered through a silica cartridge washing with ethyl acetate (40 mL). The filtrate is concentrated in vacuo to afford the title compound as a brown liquid (1.06 g, 87%). LCMS: Rt 0.88 min (91%).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-])=O)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH4+].[Cl-].O>C1(C)C=CC=CC=1.CCOC(C)=O.[Fe]>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:19][CH2:20]1)=[O:34]
Reactant: O=C(c1ccccc1[N+](=O)[O-])N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 115 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
N-Cyclopropyl-N-[1-(2-nitro-benzoyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide (10) (0.403 mg, 0.81 mmol) was taken up in 7 ml of toluene. To the mixture, Fe (0.230 mg, 4.1 mmol), NH4Cl (0.440 g, 8.2 mmol) and H2O (0.8 ml) was added. The reaction mixture was heated at 115° C. and stirred for 3 hours. The reaction mixture was diluted with 30 ml of EtOAc, then filtrated by Celite. The filtration was concentrated and dryness under reduced pressure. The crude product was purified through a column of silica gel with a gradient of 35% to 80% EtOAc in hexane to afford the title compound 11 (pale yellow solid, 335 mg, 88%). LC: 100%. MS: m/z=467.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH2:18])[CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2].[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:24]2[N:25]=[CH:26][C:21]([Br:20])=[CH:22][N:23]=2)[CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](N)C[C@H]1C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Br)cn2)C[C@H]1C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
(2R*,4S*)-4-Amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (3.80 g), 5-bromo-2-chloropyrimidin (6.92 g) and N,N-diisopropylethylamine (6.23 ml) are dissolved in 1,4-dioxane (50 ml) and the mixture is heated under reflux for 4 hours. After cooling to room temperature, the reaction solution is partitioned by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→6:4) to give (2R*,4S*)-4-(5-bromopyrimidin-2-yl)amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (5.92 g). MS (m/z): 422/424 [M+H]+
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8](=[O:18])[CH:9]([CH:11]1[CH2:16][CH:15]2[CH2:17][CH:12]1[CH:13]=[CH:14]2)[OH:10]>C(OCCO)C.C(O)(=O)C>[CH:12]12[CH2:17][CH:15]([CH:14]=[CH:13]1)[CH2:16][CH:11]2[C:9](=[O:10])[C:8]([CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)=[O:18]
Reactant: O=C(C(O)C1CC2C=CC1C2)C1CC2C=CC1C2
Solvent: CCOCCO
Solvent: CC(=O)O
Product: O=C(C(=O)C1CC2C=CC1C2)C1CC2C=CC1C2

Procedure:
49.9 g (204 millimoles) of VII in 130 ml of 2-ethoxyethanol and 40 ml of glacial acetic acid are heated to 105° C., while stirring. 25.0 g (53.6 millimoles) of Bi2O3 are then added all at once. After a reaction time of 2 hours, the elemental bismuth is filtered off and washed with 300 ml of chloroform. The organic phase is washed neutral with water. The solvent is stripped off and the residue subjected to fractional distillation. The product is then recrystallized from petroleum ether.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:20])=O)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([C:13](=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:20]
Reactant: COC(=O)CC(=O)N1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CC(=O)N1C(=O)[C@@H](N)[C@@H]1C
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 155 %

Procedure:
(3S-trans)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-methyl-β,2-dioxo-1-azetidinepropionic acid, methyl ester (0.3 g) was dissolved in 10 ml of dichloromethane/trifluoroacetic acid (7:3) and stirred for 15 minutes at -10° C. After evaporation and treatment with ether, 0.31 g of the title compound was obtained as a crystalline material, melting point 75° C. dec.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]=[CH2:11])[C:5]([NH2:12])=[CH:4][CH:3]=1.CN([CH:16]=[O:17])C.O=C1CCC(=O)C1OC(=O)OC1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][CH:10]=[CH2:11])[C:16](=[O:17])[NH:12][C:5]2=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: C=CCNc1nc(Cl)ccc1N
Agent: O=C(OC1C(=O)CCC1=O)OC1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CCn1c(=O)[nH]c2ccc(Cl)nc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
6-Chloro-N-(prop-2-en-1-yl)pyridine-2,3-diamine (71-3, 9.52 g, 51.8 mmol, 1.0 equiv) was added to anhydrous DMF (55 mL) to give a dark purple solution. Bis(2,5-dioxocyclopentyl)carbonate (13.18 g, 51.8 mmol, 1.0 equiv) was added in one portion to give a dark green solution. The resulting reaction mixture was then heated to 80° C. After 18 h, the reaction contents were cooled to RT, diluted with EtOAc (100 mL) and added slowly to saturated aqueous NaHCO3 (200 mL). The layers were separated and the aqueous layer was back-extracted with 3×100 mL EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give a dark purple residue. Purification by normal-phase HPLC provided 5-chloro-3-(prop-2-en-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (71-4) as a tan solid. LRMS (M+H)+: observed=210.0, calculated=209.6.
Reaction SMILES: [CH3:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O.[C:14]([OH:18])(=[O:17])[CH:15]=O.P(=O)(O)(O)O>C(OCC)C.ClCCl>[O:12]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:1]=[CH:15][C:14]([OH:18])=[O:17]
Reactant: CCCCCCCCCC(C)=O
Reactant: O=CC(=O)O
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCC(=O)C=CC(=O)O
Temperature: 25 °C

Procedure:
A mixture of 2-undecanone (10 g, 58.7 mmol), glyoxylic acid monohydrate (5.15 g, 56 mmol) and 85% phosphoric acid (10 ml) was warmed at 80° for 18 hours. On cooling to room temperature, the mixture was diluted with ethyl ether/dichloromethane (50 ml each) and washed thoroughly with brine. Evaporation of the dried (magnesium sulphate) organic phase gave a yellow oil which on crystallization from ethyl ether/petroleum ether gave 4-ketotridec-2-enoic acid as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>O1CCCC1>[CH2:13]([NH:20][C:10]1[C:5]2[S:4][CH:3]=[C:2]([Br:1])[C:6]=2[N:7]=[C:8]([Cl:12])[N:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Reactant: NCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccccc2)c2scc(Br)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine (500 mg, 1.77 mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) and stirred at 60° C. for 2 hours after adding benzylamine (0.58 mL, 5.32 mmol). The reaction mixture was cooled to room temperature and added to water (30 mL). Thus prepared solid was filtered and dried with nitrogen gas. The resultant target compound (580 mg, 92% yield) was used in the following reaction without purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[N:13][OH:14])[CH:10]([CH3:12])[CH3:11].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:14][N:13]=[C:9]([C:3]1[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH:10]([CH3:12])[CH3:11])(=[O:17])[CH3:16]
Reactant: CC(C)C(=NO)c1c(O)cccc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)ON=C(c1c(O)cccc1O)C(C)C
Yield: 32.7 %

Procedure:
1-(2,6-dihydroxyphenyl)-2-methyl-1-propanone oxime (Intermediate 38, 320 mg) was stirred in acetic anhydride (0.928 ml, 9.84 mmol) at room temperature for 1 hour. After removal of the volatiles, the crude was washed with water, filtered and dried. The residue obtained was charged on a silica gel column (Biotage SP1 system) and eluted with Cyhexane/ethyl acetate (from 100/0 to 0/100) to afford the title compound (127 mg).