Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH:17]=O)[C@H:10]([OH:16])[C@@H:11]([CH2:14][OH:15])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[NH3:31]>C(O)C.[Pd]>[CH2:1]([O:8][C@H:9]1[C@H:10]([OH:16])[C@@H:11]([CH2:14][OH:15])[CH2:12][NH:31][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C[C@H](CO)[C@@H](O)[C@@H](C=O)OCc1ccccc1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: OC[C@H]1CNC[C@@H](OCc2ccccc2)[C@@H]1O
Yield: 78 %

Procedure:
To a solution of 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-xylo-pentodialdose (1.77 g) in ethanol (40 ml), 0.29M NH3 in ethanol (162 ml) and 5% palladium on charcoal (300 mg) was added. The mixture was hydrogenated at 500 Psi at 20° C. for 15 hours. The reaction mixture was filtrated and concentrated. The residue (1.85 g) was flash chromatographed using ethanol/NH4OH (25% aqueous)/trimethylamine (122:2:1) as eluent giving the product as a colourless sirup (getting coloured after storing) in 78% yield. 13C-NMR (62.9 MHz, D2O): δ138.1, 128.1, 127.3 (Ph); 80.6 (C-3), 74.9 (C-4); 71.8 (OCH2Ph); 62.5 (C-5'); 48.0 (C-2); 46.8 (C-6); 45.0 ppm (C-5). 1H-NMR (500 MHz, D2O): δ7.3 (s, 5H, Ph); 4.65, 4.51 (2 d, 2H, OCH2Ph, Jgem =12 Hz); 3.66 (dd, 1H, H-5a', J5a',5b' =10 Hz, J5',5 =5.5); 3.57 (dd, 1H, H-5'b, J5a', 5b'=10 Hz, J5b',5 =4.5); 3.41 (dd, 1H, H-4, J3,4 =11 Hz, J4,5 =9 Hz); 3.3 (broad, N--H); 3.27 (dd, 1H, H-3, J3,2zx =11 Hz, J3,2eq =4 Hz); 3.22 (dd, 1H, H-2eq, J2eq,2ax =11, J2eq,3 =4 Hz); 2.97 (dd, 1H, H-6 eq, J6eq,6ax =12 Hz, J6eq,5 =4 Hz); 2.38 (t, 1H, H-2ax, J2ax,2eq =J2ax,3=11 Hz); 2.31 (t, 1H, H-6ax, J6ax,6eq=J6ax,5 =12 Hz); 1.80 ppm (m, 1H, H-5).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[CH3:8][C:9]([CH:11]=O)=O>>[OH:6][C:5]1[C:3]([CH3:4])=[N:2][C:9]([CH3:11])=[CH:8][N:7]=1
Reactant: CC(=O)C=O
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Product: Cc1cnc(O)c(C)n1

Procedure:
The title-compound was prepared from alanine amide hydrochloride and pyruvic aldehyde as described by Karmas and Spoerri, J. Am. Chem. Soc., 1952, 74, 1580 m.p.=149.5°-151° C. (Lit. 146°-147° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][C:29]#[N:30])=[CH:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1ccc(-c2ccc(CC#N)cc2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 4-cyanomethylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=515.4 [M+H+].
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH2:10]1)=[O:8].O=CCCCNC(=O)C1C=CC=CC=1>>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH2:10]1)=[O:8]
Reactant: COc1cc2c(cc1OC)CN(C(=O)NCCCCO)CC2
Agent: O=CCCCNC(=O)c1ccccc1
Product: COc1cc2c(cc1OC)CN(C(=O)NCCCC=O)CC2

Procedure:
6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (4-oxo-butyl)-amide (25C) is prepared from 25B as described for 1E. The crude product is obtained in almost quantitative yield.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH2:15]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]>CN(C=O)C.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.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:15]([C:17]1[N:18]([CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=2)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]
Reactant: C#CCCCn1c(CC)nc2c(N)nc3ccccc3c21
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCC#Cc1ccccn1
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.095 g, 0.03 eq.), 3-iodopyridine (0.626 g, 1.1 eq.), triethylamine (0.923 g, 3 eq.), and copper (I) iodide (0.035 g, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(4-pentynyl) 1H-imidazo[4,5-c]quinolin-4-amine (0.85 g, 3.0 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 4/96 methanol/dichloromethane). The product was recrystallized from a mixture of ethanol and 1,2-dichloroethane. The resulting solid was dissolved in 1:1 mixture of ethanol and 1,2-dichloroethane, treated with activated charcoal, combined with a few drops of 10% sodium hydroxide, heated and then filtered while still hot. The filtrate was concentrated under reduced pressure to provide 0.2 g of 2-ethyl-1-[5-(pyridin-2-yl)-4-pentynyl]-1H-imidazo[4,5-c]quinolin-4-amine as light brown granules, mp 188.0-192.0° C. 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J=0.9 Hz, 1H), 8.55 (dd, J=4.7, 1.3 Hz, 1H), 8.06 (dd, J=8.2, 0.9 Hz, 1H), 7.82 (dd, J=8.4, 0.7 Hz, 1H), 7.71 (ddd, J=7.9, 1.7, 1.7 Hz, 1H), 7.48 (ddd, J=8.3, 7.2, 1.2 Hz, 1H), 7.25 (m, 2H), 5.46 (br s, 2H), 4.66 (t, J=7.9 Hz, 2H), 3.00 (q, J=7.4 Hz, 2H), 2.64 (t, J=6.5 Hz, 2H), 2.26 (m, 2H), 1.49 (t, J=7.4 Hz, 3H); MS (APCI) m/z 356 (M+H)+; Anal. calcd for C22H21N5.0.65H2O: C, 71.97; H, 6.12; N, 19.07. Found: C, 72.03; H, 6.06; N, 19.16.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:16])[CH:9]=[C:10]([O:14]C)[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17].B(Br)(Br)Br.C([O-])(O)=O.[Na+].[K+].[Br-]>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[C:8](=[O:16])[CH:9]=[C:10]([OH:14])[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: COc1cc(=O)c2c(C)c(C)ccc2[nH]c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: Cc1ccc2[nH]c(=O)c(O)cc(=O)c2c1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 6,7-dimethyl-3-methoxy-1H-1-benzazepine2,5-dione (300 mg, 1.30 mmol) in dry CH2Cl2 (40 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CH2Cl2 (6 mL, 1M, Aldrich) in one portion over 1 min at rt. The reaction solution immediately became orange, then an orange precipitate formed during the addition. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (50 mL) and the resulting mixture was vigorously stirred for 15 min to give a yellow aqueous phase and a near colorless organic phase. The phases were separated and the aqueous phase washed with CH2Cl2 (1×10 mL). The aqueous portion was acidified with concd HCl (pH 2). The resulting precipitate was collected by vacuum filtration, washed to neutrality with H2O (6×2 mL) and dried in vacuo to give a yellow powder. Crystallization from EtOAc (dissolved in 20 mL, hot filtered, coned to 10 mL, allowed to cool to rt) yielded fine green needles (154 mg, 55%, pure by 1H NMR); mp 206°-208° C. (dec.); 1H NMR (DMSO-d6) δ2.16 (s, 3H), 2.23 (s, 3H), 6.30 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 10.31 (bs, 1H), 11.08 (s, 1H); IR (KBr) 3260 (m), 3194 (m), 3078 (m), 2989 (m), 1643 (s), 1614 (s), 1581 (m), 1503 (m), 1479 (m), 1449 (m), 1393 (s), 1374 (m), 1347 (m), 1310 (m), 1284 (m), 1259 (m), 1238 (w), 1212 (s), 1145 (m), 1047 (m), 992 (m), 969 (w), 883 (m), 871 (m), 851 (m), 833 (m), 824 (m), 771 (m), 755 (w), 705 (m), 658 (m), 633 (m), 613 (m), 571 (m), 501 (m), 473 (m), 406 (m); Anal. Calcd for C12H11NO3 : C, 66.35, H, 5.10, N, 6.45. Found: C, 66.65; H, 4.81; N, 6.44.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:26])=[CH:28][CH:29]=1)[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(Br)c2c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2Br)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a mixture of 4-{[(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (125 mg) synthesized above, β-alanine ethyl ester hydrochloride (63.0 mg), 1-hydroxybenzotriazole monohydrate (62.9 mg), triethylamine (114 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.6 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (134 mg, 88%) as a pale-yellow oil.
Reaction SMILES: CN(C)[C:3]([S:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([O:18]C)=[O:17])[CH:10]=[CH:9]2)=O.[OH-].[K+].COS(OC)(=O)=O>CO>[CH3:3][S:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=[CH:9]2
Reactant: COC(=O)c1ccc2cc(SC(=O)N(C)C)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: CSc1ccc2cc(C(=O)O)ccc2c1
Temperature: 5 °C
Yield: 91.4 %

Procedure:
A suspension of 158 (6.36 g, 22-mmol) in a mixture of aqueous KOH (5N, 340 mL, 1.7 mol) and MeOH (205 mL) was stirred at reflux for 3 h, then cooled to 5° C. and treated dropwise with Me2SO4 (26 mL. 275 mmol). After stirring at room temperature for a further 4 h the mixture was concentrated to half volume, acidified with dilute aqueous HCl, and the precipitated product was crystallised from EtOAc/hexane to give 6-(methylsulfanyl)-2-naphthoic acid (159) (4.39 g, 91%) as a white solid: mp (MeOH) 231-233° C.; 1H NMR [(CD3)2SO] δ (CO2H not observed) 8.53 (s, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.96 (dd, J=8.6, 1.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.77 (d, J=1.7 Hz, 1H), 7.47 (dd, J=+8.7, 1.9 Hz, 1H), 2.61 (s, 3H). Anal. (C12H10O2S) C, H.
Reaction SMILES: C[O:2][C:3]([CH2:9][C@@H:10]1[CH2:13][C:12](=[O:14])[NH:11]1)=[CH:4][C:5]([O:7][CH3:8])=[O:6].[Cl-].[Na+]>Cl>[O:2]=[C:3]([CH2:9][C@@H:10]1[CH2:13][C:12](=[O:14])[NH:11]1)[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C=C(C[C@@H]1CC(=O)N1)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)CC(=O)C[C@@H]1CC(=O)N1
Yield: 86.1 %

Procedure:
A solution of methyl 3-methoxy-4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate[(E,Z)-isomeric mixture](35 mg) in 1N hydrochloric acid (2 ml) was stirred at 25° C. for two hours. The resultant solution was saturated with sodium chloride and extracted three times with chloroform. The combined extracts were dried over magnesium sulfate and evaporated. The residue (29 mg) was chromatographed on silica gel (1.5 g) eluting with 2% methanol in dichloromethane to give methyl 3-oxo-4-[(2R)-4-oxoazetidin-2-yl]butanoate (28 mg), mp. 45.0°-46.5° C.:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:28]([CH3:29])=[N:27][C:26]([NH2:30])=[N:25]1>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]1[C:28]([CH3:29])=[N:27][C:26]([NH:30][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:4]([O:14][CH3:15])[CH:3]=2)=[N:25]1
Reactant: Cc1nc(N)nn1-c1ccc(Cl)cc1Cl
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)n(-c3ccc(Cl)cc3Cl)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 1b) starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352) and 1-(2,4-dichloro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-ylamine (Synthesis 1976, 274). The title compound was obtained as a brownish solid (Yield=13%). MS ISP (m/e): 429.1 (100) [(M+H)+].
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C@H:18]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:33][CH2:34][CH2:35][CH2:36][N:37]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C@H:18]([C:39]([OH:41])=[O:40])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:33][CH2:34][CH2:35][CH2:36][N:37]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccccc2o1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccccc3o2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h
Yield: 98 %

Procedure:
3 ml of trifluoroacetic acid is added to 200 mg of ester 6-2 in 10 ml of dichloromethane, agitation is carried out for 2 hours at ambient temperature then 10 ml of toluene is added. After evaporating under reduced pressure, taking up in dichloromethane and crystallizing by adding an Et2O/pentane mixture, 175 mg of 6-3 is obtained.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:11]=2[CH:32]=1)C.[OH-].[Na+:35]>C(O)C>[CH2:18]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:13]1[CH2:12][C:11]2[CH:32]=[C:7]([O:6][CH2:5][C:4]([O-:33])=[O:3])[CH:8]=[CH:9][C:10]=2[CH2:16][CH2:15][CH2:14]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+:35]
Reactant: CCOC(=O)COc1ccc2c(c1)CC(N(Cc1ccccc1)C(=O)OC(C)(C)C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(OCC(=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid ethyl ester (2.5 g) in ethanol (25 ml) was added 1N sodium hydroxide aqueous solution at 5° C., and the solution was stirred at room temperature for 1 hour. The resulting solution was evaporated in vacuo to afford sodium [8-(N-benzyl-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetate (2.35 g).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15][C:14]2=[O:21])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]#[N:25]>>[C:24]([CH2:23][CH:8]1[C:7](=[O:10])[NH:6][C:5]2[CH:11]=[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[NH:15][C:14]3=[O:21])[C:2]([F:1])=[CH:3][C:4]=2[O:9]1)#[N:25]
Reactant: Cc1cc(=O)n(-c2cc3c(cc2F)OCC(=O)N3)c(=O)[nH]1
Reactant: N#CCCl
Product: Cc1cc(=O)n(-c2cc3c(cc2F)OC(CC#N)C(=O)N3)c(=O)[nH]1

Procedure:
Analogously to the procedure described in Example 81, by alkylating 3-(3,4-dihydro-7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-6-methyl-2,4(1H,3H)-pyrimidinedione (see Example 21) with chloroacetonitrile there is obtained 3-(2-cyanomethyl-3,4-dihydro-7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p.>230° C.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH2:26][CH2:25][N:24]([C:35]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:36])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:47].O1CCOCC1>>[ClH:47].[F:34][C:30]1[CH:29]=[C:28]([CH:27]2[CH2:26][CH2:25][N:24]([C:35]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([C:42]([OH:44])=[O:43])=[CH:45][CH:46]=3)=[O:36])[CH2:23][CH:22]2[CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Nc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(C(=O)Nc2ccc(C(=O)O)cc2)CCC1c1cccc(F)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 354 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(3-fluorophenyl)piperidin-1-yl]carbonyl}amino)benzoic acid was added 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added isopropanol, followed by heating for dissolution. Diisopropylether was added dropwise thereto, and the precipitate was isolated by filtration, and dried under reduced pressure to obtain 180 mg of 4-({[4-(3-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]carbonyl}amino)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@@H:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:13]3[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Sn](CCCC)(CCCC)[C:47]1[S:48][CH:49]=[CH:50][N:51]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:47]3[S:48][CH:49]=[CH:50][N:51]=3)=[CH:9][N:8]([C@@H:12]3[O:32][C@H:31]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@@H:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:13]3[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(-c3nccs3)c3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
An argon purged mixture of the compound 4 from Step 1 (544 mg, 0.74 mmol), 2-(tributylstannyl)thiazole (554 mg, 1.48 mmol) and PdCl2(PPh3)2 (22 mg, 0.03 mmol) in DMF (3 ml) was stirred at 100° C. for 48 h. Volatiles were evaporated under diminished pressure, the residue was co-evaporated with water (3×), twice with MeOH, twice with hexane and then co-evaporated with silica from hexane. Column chromatography on silica (hexanes then hexanes/AcOEt, 10:1→6:1) afforded title compound 5 as foam (454 mg, 89%). 1H NMR (500.0 MHz, CDCl3): −0.36, −0.10, 0.11, 0.13, 0.17 and 0.18 (6×s, 6×3H, CH3Si); 0.74, 0.95 and 0.99 (3×s, 3×9H, (CH3)C); 3.79 (dd, 1H, Jgem=11.4, J5′b,4′=2.7, H-5′b); 3.96 (dd, 1H, Jgem=11.4, J5′a,4′=3.2, H-5′a); 4.11 (ddd, 1H, J4′,5′=3.9, 2.7, J4′,3′=1.8, H-4′); 4.23 (dd, 1H, =4.7, J3′,4′=1.8, H-3′); 4.55 (dd, 1H, J2′,1′=6.9, J2′,3′=4.7, H-2′); 5.96 (bs, 1H, NHaHb); 6.31 (d, 1H, J1′,2′=6.9, H-1′); 7.21 (d, 1H, J5,4=3.4, H-5-thiazolyl); 7.72 (d, 1H, J4,5=3.4, H-4-thiazolyl); 7.74 (s, 1H, H-6); 8.26 (s, 1H, H-2); 9.79 (bs, 1H, NHaHb). 13C NMR (125.7 MHz, CDCl3): −5.35, −5.33, −5.19, −4.65, −4.61 and −4.47 (CH3Si); 17.82, 18.13 and 18.57 (C(CH3)3); 25.61, 25.86 and 26.15 ((CH3)3C); 63.37 (CH2-5′); 73.03 (CH-3′); 76.26 (CH-2′); 86.28 (CH-4′); 87.01 (CH-1′); 100.52 (C-4a); 112.19 (C-5); 116.76 (CH-5-thiazolyl); 122.24 (CH-6); 141.71 (CH-4-thiazolyl); 151.57 (C-7a); 151.94 (CH-2); 157.52 (C-4); 163.53 (C-2-thiazolyl). MS (ESI) m/z 692 (M+H), 714 (M+Na). HRMS (ESI) for C32H58N5O4SSi3 [M+H] calcd: 692.3512. found: 692.3512.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N+:8]1([CH3:7])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: C[N+]1(CCOc2ccccc2[N+](=O)[O-])CCOCC1
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: C[N+]1(CCOc2ccccc2N)CCOCC1
Reaction time: 2 h

Procedure:
2.08 g (5.5 mmol) of the compound from Step 5.2 was dissolved in 80 mL of ethanol and hydrogenated in the presence of 0.25 g of Pd/C (10%) under 9 bar of hydrogen pressure. After 2 hours, the catalyst was filtered off and the filtrate was evaporated to dryness. This gave 1.9 g (99% of the theoretical) of a colorless oil which was subjected to further reaction without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4](F)[CH:3]=1.[CH3:11][S-:12].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([S:12][CH3:11])[CH:3]=1
Reactant: C[S-]
Reactant: CSc1ccc(Br)cc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cc1SC
Temperature: 0 °C
Reaction time: 48 h
Yield: 87.9 %

Procedure:
Combine 4-bromo-2-fluoro-1-methylsulfanyl-benzene (4.8 g, 22 mmol) and sodium methanethiolate (1.6 g, 22 mmol) in DMF (50 mL). Stir for 48 hours. Pour the reaction mixture into ice (10 g). Separate the layers and wash the organic layer with aqueous saturated NaHCO3 and brine. Dry with MgSO4, filter and concentrate in vacuo. Chromatograph the residue on a column eluting with diethyl ether in hexane (0 to 5%) to give 4.82 g of 4-bromo-1,2-bis-methylsulfanylbenzene (89%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][O:7][CH:8]=1.[CH2:9]([O:11][C:12](=[O:32])[N:13]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:10]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:9]([O:11][C:12](=[O:32])[N:13]([C:21]1[CH:26]=[C:25]([C:6]2[O:7][CH:8]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:10]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: COCc1cocn1
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(-c2nc(COC)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-methoxymethyl-oxazole (114 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (200 mg) and palladium bis(triphenylphosphine)dichloride (71 mg), giving the product (160 mg) as a yellow gum.