Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C)[C:2]([C:7]([Cl:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.ClCl.[C:13]([Cl:17])(Cl)([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:17])([Cl:15])[C:1]1[C:2]([C:7]([Cl:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccccc1C(=O)Cl
Agent: ClCl
Product: O=C(Cl)c1ccccc1C(Cl)(Cl)Cl
Yield: 80 %

Procedure:
Five g (0.032 mole) of o-toluic chloride was dissolved in 150 ml of carbon tetrachloride and reaction was carried by passing dry chlorine into the solution under irradiation with an ultraviolet lamp while refluxing carbon tetrachloride. From the reaction mass an amount thereof necessary for gas chromatographic analysis was occasionally withdrawn to examine the change of the peak of α,α-dichloro-o-toluic chloride by comparing with an authentic sample, the introduction of chlorine was stopped after the peak was disappeared. Part of the oily matter obtained by reduced pressure distillation for removal of carbon tetrachloride was withdrawn, and on analyzing it by gas chromatography it was possible to ascertain that 1,1,3,3-tetrachloro-1,3-dihydroisobenzofuran and α,α,α-trichloro-o-toluic chloride was formed in a mixed ratio by weight of about 6:4, yield 6.6 g (chlorination yield 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.[CH:14](O)=O.C=O>O>[CH3:14][N:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:9]1
Reactant: c1cncc(N2CCCNCC2)c1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CN1CCCN(c2cccnc2)CC1

Procedure:
A solution of 1-(3-pyridyl)-homopiperazine (0.42 g, 2.4 mmol), formic acid (3.3 g, 71.7 mmol), formaldehyde (2.1 g, 37%) and water (10 ml) was stirred at reflux for 15 hours. The mixture was evaporated and sodium hydroxide (15 ml, 4 M) was added and the product was extracted two times with ethyl acetate (15 ml). The product was obtained as an oil. Yield 0.46 g, 100%.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH3:32][NH:33][CH3:34]>>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4
Reactant: CNC
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN(C)C)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (−)-2-(2-Bromo-ethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 24b) and dimethylamine as starting materials.
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[CH:2]=3)[CH2:14][CH2:15]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: c1cc2c(cc1CC1CCNCC1)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCN2CCC(Cc3ccc4c(c3)CCCC4)CC2)cc1

Procedure:
The title compound was prepared from 4-((5,6,7,8-tetrahydro-2-naphthyl)methyl)piperidine hydrochloride (250 mg, 940 μmol), 2-(4-fluorophenoxy)ethyl bromide (216 mg, 987 μmol) and K2CO3 (266 mg, 1.93 mmol) as a colorless solid (220 mg): mp 181-183° C.; 1H NMR (CDCl3) 1.60-2.12 (m, 9H), 2.54 (d, J=7.2 Hz, 2H), 2.65-2.81 (m, 6H), 3.20-3.55 (m, 2H), 3.59-3.71 (m, 2H), 4.52 (t, J=4.2 Hz, 2H), 6.77-7.01 (m, 7H), 12.55 (bs, 1H); Anal. Calcd for C24H31ClFNO: C, 71.36; H, 7.74; N, 3.47. Found: C, 71.30; H, 7.78; N, 3.39.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH3:42])=[C:36](B(O)O)[CH:37]=1>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][C:35]([O:41][CH3:42])=[C:34]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:33]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(F)cc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 31.9 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 5-fluoro-2-methoxy-phenylboronic acid (33 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (18 mg, 32%). LC-MS m/e 435.33 (M+H+)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][CH2:27]1>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:25][CH:26]4[CH2:31][CH2:30][CH:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][CH2:27]4)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: Clc1nccc(-c2cnc3c(OCc4ccccc4)cccn23)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)NC1CCC(Nc2nccc(-c3cnc4c(OCc5ccccc5)cccn34)n2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
A mixture of 8-benzyloxy-3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.1 g), N-(4-amino-cyclohexyl)-methanesulfonamide (0.2 g), and TEA (0.21 mL) in NMP (2 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to RT, diluted with water, and the resulting solid filtered, washed with water, and dried. The product was purified by ISCO 2× using 100% DCM to 15% MeOH/DCM. Pure fractions were collected, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide N-{4-[4-(8-benzyloxy-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-ylamino]-cyclohexyl}-methanesulfonamide (compound 7, 14 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](=O)=O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5](=[O:24])[C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=1[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3Cl)c3cc(F)ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(F)cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, 7-fluoro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2'-chloro-5-fluoro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[CH:28]=[C:29]([CH:33]=O)[CH:30]=[N:31][CH:32]=1)[CH2:20][CH2:19]2.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CO>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([C:27]1[CH:32]=[N:31][CH:30]=[C:29]([CH2:33][NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:28]=1)[CH2:20][CH2:19]2
Reactant: O=Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(CNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
NaBH(OAc)3 (84 mg, 0.4 mmol) was added to a solution of 5-(6-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridine-3-carbaldehyde (28.6 mg, 0.1 mmol, example 9) and aniline (9.3 mg 0.1 mmol) in MeOH (3 mL) and the resulting reaction mixture was stirred at RT overnight before it was poured into ice-water and extracted with EtOAc (2×10 mL). The organic layers were dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by prep-HPLC to give title compound (7.2 mg, 20%) as a white solid. MS: 364.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH:17]C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>Cl.CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:15](=[O:28])[C@H:16]([CH:25]([CH3:27])[CH3:26])[NH2:17])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Product: CC(C)[C@H](N)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
1-(4-Chlorobenzyl)-4-[{(N-Boc-valyl)amino}methyl]piperidine (1.1 g, 2.51 mmol) was dissolved in 3 M HCl-CH3OH solution (25 mL) and stirred at 25° C. for 1 h. The reaction mixture was concentrated and the resulting salt was dissolved in 3:1 tBuOH—H2O (25 mL). Anion (OH−) exchange resin was added until the solution was slightly basic. Filtration and concentration afforded 1(4-chlorobenzyl)-4-{(valylamino)methyl}piperidine (819 mg, 97%) which required no further purification: RPLC (97%); ESI/MS 338.1 (M++H, C19H28ClN3O).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[H-].[Na+].[NH2:19][C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Cl:26])[N:25]=1>CN(C)C=O>[Cl:26][C:24]1[N:25]=[C:20]([NH:19][C:1](=[O:16])[O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: Cn1cc(Cl)nc(N)c1=O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Cl)nc(NC(=O)Oc2ccccc2)c1=O
Reaction time: 0.75 h
Yield: 57.9 %

Procedure:
A solution of 9.4 g of diphenyl carbonate and 65 ml of dimethylformamide is allowed to run into a mixture of 1.9 g of a 55% sodium hydride dispersion and 20 ml of dimethylformamide at 10°-15° C. 6.4 g of 3-amino-5-chloro-1-methylpyrazin-2-one are then introduced in portions at the same temperature and the mixture is stirred for a further 45 minutes. The mixture is filtered, the filtrate is poured into a mixture of 270 ml of ethyl aceate, 270 ml of ice-water and 42 ml of 7% hydrochloric acid, the organic phase is washed with water and sodium chloride solution and dried over sodium sulfate, the solution is concentrated and the product which has precipitated out is filtered off to give 6.5 g of phenyl N-(5-chloro-1-methylpyrazin-2-on-3-yl)-carbamate.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][O:7]1.O.[OH-].[Li+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(C[C@H]1CCCO1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 97.1 %

Procedure:
2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid methyl ester (180 mg, 0.52 mmol) was dissolved in ethanol (5 mL) and treated with a solution of lithium hydroxide monohydrate (54 mg, 1.3 mmol) in water (1 mL) at 25° C. It was stirred at 25° C. until the starting material was all consumed by TLC. The reaction was then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was then acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (168 mg, 98%) as a reaction of two diastereomers as a white foam: ES-HRMS m/e calcd for C14H17O5SCl (M+H)+ 333.0558, observed 333.0553; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.35-1.49 (m, 1H, CH of CH2), 1.66-1.99 (m, 4H, 4×CH of CH2), 2.06-2.23 (m, 1H, CH of CH2), 3.34, 3.35 (2×s, 3H, SO2CH3), 3.42-3.85 (m, 4H, OCH2 and OCH and ArCH), 7.54 (2×dd, Jo=8.1 Hz, Jm=1.7 Hz, 1H, Ar), 7.66 (2×d, Jm=1.7 Hz, 1H, Ar), 7.99 (2×d, Jo=8.1 Hz, 1H, Ar), 12.69 (brs, 1H, CO2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:12][C:13]1[O:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][C:14]=1[CH2:24][CH2:25]OS(C)(=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:25][CH2:24][C:14]1[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:17][C:13]=1[CH3:12])[CH:10]=[O:11]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], vanilline was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride then gave 2(Z,E)-methoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-2-methoxy-3-{3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:40]=[CH:39][C:19]2[C:20](=[O:38])[CH2:21][C:22]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[O:23][C:18]=2[C:17]=1[CH2:41][CH2:42][CH3:43].ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:40]=[CH:39][C:19]2[C:20](=[O:38])[CH2:21][C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[O:23][C:18]=2[C:17]=1[CH2:41][CH2:42][CH3:43]
Reactant: CCCc1c(OCCCOc2ccc3ccccc3c2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Product: CCCc1c(OCCCOc2ccc3ccccc3c2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O

Procedure:
The title compound was prepared by the method of Example 22 substituting 539 mg of the title product of Example 23 for the title product of Example 21. Crystallization from 5:1 ethyl acetate:hexane yielded 303 mg, m.p. 157.5°-158° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH2:21][N:22]([CH2:33][C:34]([O:36][CH3:37])=[O:35])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO>[CH3:37][O:36][C:34]([C:33]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:21][N:22]=1)[N:7]([C@@H:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:35]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1[C@H](C)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2[C@H](C)c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
(R)-5-Bromo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (3.5 g, 5.92 mmol) was dissolved in 120 mL of MeOH and placed in ice bath. NaOMe solution (4.1 mL, 17.8 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (30-100% CH2Cl2/hexanes) to give 2.13 g of the title compound as a yellow solid. MS: (−) m/z 401.18, 403.19 (M−1, 79/81Br).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C>[ClH:33].[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCCC(c2ccccc2)c2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCCC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The ester prepared in Example 15 (0.9 g, 2.3 mmol) was dissolved in ethanol (10 ml) and a 12 N sodium hydroxide solution (0.6 ml) was added. The reaction mixture was stirred at room temperature for 4 h. Concentrated hydrochloric acid solution (0.7 ml) was added with cooling of the reaction vessel in an ice-bath and dichloromethane (300 ml) was added. The resulting emulsion was dried (Na2SO4) and the solvent evaporated in vacuo to give an oily residue which was crystallised from acetone. This afforded 0.5 g (54%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([OH:26])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([OH:26])[CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=3)=[CH:10][C:9]=2[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCC(O)c2cc3cc(C(C)(C)C)ccc3o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc2oc(C(O)COc3ccc(C(=O)O)cc3)cc2c1
Yield: 82 %

Procedure:
5-tert-Butyl-2-[1-hydroxy-2-(4-methoxycarbonylphenoxy)ethyl]benzofuran (112 g) obtained in Example 1 was dissolved in 1.5 liters of methanol, a solution of 24.3 g of sodium hydroxide dissolved in 400 ml of water was added thereto and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo, ice water was added to the residue and the mixture was acidified with concentrated hydrochloric acid to give crystals. The crystals collected by filtration were dissolved in ethyl acetate, the solution was washed with water and dried over anhydrous magnesium sulfate followed by concentrating in vacuo whereupon the residue is crystallized. This was dried and recrystallized from acetonitrile to give 88.3 g of crystals. M.p. 175°-177° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([CH:27]([NH2:33])[CH2:28][CH2:29][N:30]=[N+]=[N-])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>C1COCC1>[C:20]([CH:27]([NH2:33])[CH2:28][CH2:29][NH2:30])([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)C(N)CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(N)CCN
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A triphenylphosphine (4.8 g; 18.3 mmol) solution in THF (15 mL) is added dropwise to a stirred solution of the above azide in THF (30 mL)/H2O (0.3 mL; 18.3 mmol); the stirring is continued for 24 hrs at r.t. After removal of the solvents to dryness in vacuum, the residue is taken up with a few of EtOH to separate a white precipitate of triphenylphosphine oxide by stirring for 6 hrs at r.t. The final EtOH removal to dryness, at low pressure, gives 3.22 g (18 mmol) of 1-BOC-propane-1,3-diamine as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:2]1=2.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Br:25])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([Br:25])[C:22]=1[O:23][CH3:24])[C:17]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][C:2]1=2)=[O:18]
Reactant: N#Cc1cnc2c(c1)NCCO2
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(C#N)cc32)cc1Br
Yield: 73.9 %

Procedure:
By the same method as in the step d) of Example 2, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-carbonitrile (7 mg, 0.043 mmol) was reacted with 3,5-dibromo-4-methoxy-benzoyl chloride (21 mg, 0.065 mmol) to obtain 1-(3,5-dibromo-4-methoxy-benzoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-carbonitrile as white solid (14.4 mg, 74%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.[C:37]([O:41][C:42](=[O:52])[C@H:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[NH2:44])([CH3:40])([CH3:39])[CH3:38]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:44][C@H:43]([C:42]([O:41][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:52])[CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: CC(C)c1cc(C(=O)N2CCC(CCN[C@@H](Cc3ccccc3)C(=O)OC(C)(C)C)CC2)c(O)cc1O

Procedure:
Prepared from Intermediate D and L-phenylalanine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 7.46-7.21 (5H, m), 6.95 (1H, s), 6.34 (1H, s), 4.32-4.09 (3H, m), 3.27-2.88 (6H, m), 1.84-1.63 (5H, m), 1.34 (9H, s), 1.19 (6H, d, J=7.0 Hz). LC/MS: purity 97.5%, m/z 511 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)#[N:2].ClN1C(=O)CCC1=O.[CH:20]([CH2:22][C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])=[CH2:21].C(N(CC)CC)C.Cl>O.CN(C=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:21][CH:20]([CH2:22][C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[O:9][N:8]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=CCC(=O)OCC(C)C
Reactant: N#Cc1ccc(C=NO)cc1
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)CC1CC(c2ccc(C#N)cc2)=NO1
Temperature: 4 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of DMF (262.0 L), 4-cyanobenzaldoxime (46 kg, 342.1 mol), and N-chlorosuccinimide (54 kg, 389.4 mol) was added isobutyl vinylacetate (95 kg. 665.7 mol). The solution was cooled to 2-6° C., and triethylamine (40 kg. 388.6 mol) was slowly added over a period of 4 h. The reaction was stirred at the same temperature for an addition 1 h. Water (330.0 L) and hydrochloric acid (1 N, 49 L) were added. The crude product was collected by filtration, washed with water (555.0 L), and redissolved in toluene (500.0 L, 40° C.). The organic layer was washed with water (291.0 L) and dried by azeotropic distillation (removing about 250 L of toluene). Heptane (300.0 L) was added, and the reaction was cooled at 0-5° C. for 3 h. The product was collected by filtration and washed with toluene/heptane (150.0 L, 1/2 ratio). The product was dried under vacuum at 55-60° C. to constant weight: 81.8 kg, 90% yield, mp 98-100° C.; 1H NMR (CDCl3) ∂ 0.96 (6H), 1.96 (1H), 2.70 (1H), 2.92 (1H), 3.15 (1H), 3.56 (1H), 3.90 (2H), 5.20 (1H), 7.70 (2H), 7.80 (2H). Anal. Calcd. for C16H18N2O3: C, 67.12; H, 6.34; N. 9.78. Found: C, 67.06; H, 6.20; N, 9.76.