Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.Cl.[CH:12]([N:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a stirring solution of DMSO (5.3 mL, 75 mmol) in methylene chloride (100 mL) at −78° C. under argon was added oxalyl chloride (4.6 mL, 53 mmol) dropwise. After stirring for 30 min., a solution of 1-benzhydryl-azetidin-3-ol hydrochloride (12) (10 g, 36 mmol) in methylene chloride (10 mL) was added dropwise. The reaction mixture was stirred for 1 hr at −78° C. before triethylamine (18 mL, 128 mmol) was added. The ice bath was removed and the reaction quenched with saturated ammonium chloride (75 mL) at 0° C., then extracted with ethyl acetate (3×150 mL). The combined ethyl acetate layer was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was stirred in ethyl acetate and hexane, filtered to give 1-benzhydrylazetidin-3-one (9 g, 33 mmol, 92%). To a stirring solution of the resulting 1-benzhydryl-azetidin-3-one (8.3 g, 30 mmol) in methylene chloride (120 mL) was added triethylamine (6.4 mL, 45 mmol), and carbethoxymethylene triphenylphosphorane (15.9 g, 45 mmol). This reaction mixture was stirred under argon at room temperature for 2 hrs., then quenched with acetone (1 mL), and concentrated in vacuo. The residue was stirred in 20% ethyl acetate in hexane (20 mL) as triphenyl phosphine oxide precipitated. The mixture was then filtered and concentrated. The crude product was chromatographed on silica gel, eluting with 50:40:10 methylene chloride:hexane:ether to give 9.3 g of the title compound.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([OH:19])[C:13]=3[C:12]3[CH:20]=[C:21]([Br:24])[CH:22]=[N:23][C:11]2=3)(=O)=O)C=CC=CC=1>Cl>[Br:24][C:21]1[CH:22]=[N:23][C:11]2[NH:10][C:14]3[CH:15]=[N:16][CH:17]=[C:18]([OH:19])[C:13]=3[C:12]=2[CH:20]=1
Reactant: O=S(=O)(c1ccccc1)n1c2cncc(O)c2c2cc(Br)cnc21
Agent: Cl
Product: Oc1cncc2[nH]c3ncc(Br)cc3c12
Temperature: 125 °C
Yield: 99.1 %

Procedure:
9-Benzenesulfonyl-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ol (4.0 g, 9.32 mmol) was dissolved in concentrated hydrochloric acid (100 mL) and heated in an autoclave at 125° C. for 40 hours. The mixture was allowed to cool to ambient temperature then evaporated in-vacuo. The resultant residue was loaded onto a 50 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Appropriate fractions were combined and concentrated in-vacuo to afford the title compound as a light brown solid (2.44 g, 99%). LCMS (Method B): RT=2.70 min, M+H+=264/266. 1H NMR (400 MHz, DMSO-d6): 12.25 (s, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.42 (s, 1H), 8.04 (s, 1H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@H:15]([CH3:16])[C@H:23]([C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)[OH:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Product: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](O)c1ccc(Cl)cc1
Yield: 80 %

Procedure:
The title compound (1.32 g, 80%) was prepared from 4-(S)-benzyl-3-propionyl-oxazolidin-2-one and 4-chlorobenzaldehyde as in Example 55, Part B. 1H NMR (400 MHz, CDCl3): 7.37-7.26 (m, 7H), 7.23-7.17 (m, 2H), 5.12-5.08 (m, 1H), 4.69-4.62 (m, 1H), 4.22-4.13 (m, 2H), 4.03 (dq, J=7.0, 3.6, 1H), 3.25 (dd, J=13.4, 3.3, 1H), 3.20 (d, J=2.5, 1H), 2.79 (dd, J=13.4, 9.4, 1H), 1.18 (d, J=7.0, 3H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][Br:20])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.[C:21]([NH:28][C@H:29]([C:38]([OH:40])=O)[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:24]([O:23][C:21]([NH:28][C@H:29]([C:38]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][Br:20])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:40])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCBr
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound (U) (3.51 g, 10 mmol) was dissolved in a solution of 25% TFA in DCM (10 ml) and stirred at room temperature for 30 mins. The solution was evaporated to dryness in vacuo and the residue evaporated from DCM three more times to remove residual traces of TFA. This residue was coupled to Boc-tyrosine (2.8 g, 10 mmol) using the procedure described for the synthesis of compound (U). The resultant product was purified by column chromatography (silica; 50% ethyl acetate in hexane (Rf =0.19)) as a colourless powder (4.9 g, 96%), mp 96-100° C. 1H NMR (CDCl3): δ 6.7-7.1 (m, 6H, ArH, Ile-NH, NH), 5.15 (d, J=8.2 Hz, 1H, Tyr-NH), 4.30 (m, 1H, αCH), 4.2 (m, 1H, αCH), 3.35-3.50 (m, 1H, NCH), 3.40 (t, J=6.0 Hz, 2H, CH2Br), 3.25 (m, 1H, NCH), 3.01 (dd, J=6.1, 13.6 Hz, 1H, Tyr-βCH), 2.93 (dd, J=6.1, 13.6 Hz, 1H, Tyr-βCH), 2.05 (m, 2H, CH2), 1.9 (m, 1H, Ile-βCH), 1.4 (m, 10H, Ile-γCH, (CH3)3), 1.05 (m, 1H, Ile-γCH), 0.89 (d, J=6.32 Hz, 3H, Ile-γCH3), 0.83 (t, J=7.37 Hz, 3H, Ile-δCH3). ISMS 514/516 (M+H). HRMS calcd for C23H35N3O5 (M-HBr), 433.2577; found 433.2573.
Reaction SMILES: Cl[CH2:2][C:3]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[CH:4]([O:6]C(=O)C(C)(C)C)[CH3:5].C[O-].[Na+].O.C(OCC)(=O)C>CO>[O:13]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])([CH:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)C1(c2ccc(F)cc2F)CO1
Reaction time: 16 h
Yield: 39.2 %

Procedure:
A solution of 0.45 g (1.4 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(pivaloyloxy)butan-2-ol ((2S,3R)/(2R,3R)=93/7)) in 3 mL of methanol was cooled to 0° C., and 0.33 g (1.7 mmol) of a 28% solution of NaOMe in methanol was added. The reaction was performed for 1 hour and at room temperature for another 16 hours. Then, 5 mL of water was added to stop the reaction, and extraction was performed with ethyl acetate (20 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 0.31 g of a crude product. The resulting product was purified by column on silica gel to obtain 0.11 g of the title compound (yield: 40%) ((2R,3R)/(2S,3R)=96/4 (the diastereomeric ratio was measured by HPLC under the same HPLC measurement conditions as those in Example 10)).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C(Cl)Cl.[I:15]N1C(=O)CCC1=O>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[C:10]([I:15])=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Clc1nc(Cl)c2c(I)c[nH]c2n1
Temperature: 16 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A 50-L jacketed reactor was charged with 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (950 g, 5053 mmol) and DCM (16 L). The resulting tan suspension was cooled to 16° C., and N-iodosuccinimide (1598 g, 7104 mmol) was added portionwise over 20 min. The reaction mixture was stirred at room temperature for 16 h, after which time TLC analysis (2:1 hexane/ethyl acetate) indicated complete reaction. The resulting precipitate was filtered, washed with DCM (3×1.5 L), and dried under reduced pressure at 40° C. for 64 h to afford 1447 g (Yield: 91%) of target compound as a beige solid. MS (ESI) m/z 314.0 [M+1]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[C:23]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CS(C)=O>[N:32]([CH2:12][C@@H:13]1[O:14][C:15]2[C:23]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[CH:22][CH:21]=[CH:20][C:16]=2[CH2:17][CH2:18][CH2:19]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
A solution of [(2R)-9-(2,6-dichlorophenyl)-2,3,4,5-tetrahydro-1-benzoxepin-2-yl]methyl 4-methylbenzenesulfonate (381 mg, 0.798 mmol) and sodium azide (208 mg, 3.192 mmol) in anhydrous dimethyl sulfoxide (10 mL) was heated at 70° C. under nitrogen for 19 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 5 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a colorless syrup. Purification by flash chromatography using 3% ethyl acetate in hexane as eluant gave 240 mg (86%) of (2R)-2-azidomethyl-9-(2,6-dichloro-phenyl)-2,3,4,5-tetrahydro-benzo[b]oxepine as a colorless syrup.
Reaction SMILES: Cl[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][CH:4]=O.[NH2:12][C:13]1[C:17]([C:18]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:19])=[CH:16][NH:15][N:14]=1>C(O)(=O)C>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[C:18]([C:17]1[CH:16]=[N:15][N:14]2[C:2]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)=[CH:3][CH:4]=[N:12][C:13]=12)=[O:19]
Reactant: O=CC=C(Cl)c1cccnc1
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Solvent: CC(=O)O
Product: O=C(c1ccco1)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 0.02 mole of 3-chloro-3-(3-pyridinyl)-2-propenal and 0.02 mole of (3-amino-1H-pyrazol-4-yl)-2-furanyl-methanone in 30 ml of glacial acetic acid was refluxed for 5 hours. The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was dried over sodium sulfate and passed through a short pad of hydrous magnesium silicate. The eluent was concentrated and the residue crystallized from dichloromethane:hexane to give the desired product as crystals, mp 228°-229° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][C:10]=2[C:11](Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:33]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:33]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:11](=[O:12])[C:10]1[CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=[CH:17][C:9]=1[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:39]
Reactant: CCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)Cl)c1
Reactant: CCOC(=O)CNCC(=O)OCC
Product: CCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Yield: 82 %

Procedure:
The reaction of 2-(phenylmethoxy)-5-(tetradecyloxy)benzoic acid chloride with diethyl iminodiacetate under conditions described in Example 80 gave N-(2-ethoxy-2-oxoethyl)-N-[5-(tetradecyloxy)-2-(phenylmethoxy)benzoyl]glycine ethyl ester (82% yield, mp 49°-50°).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH:13](OC)OC)[CH3:12]>>[CH3:10][N:11](/[CH:13]=[N:9]/[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccccc1
Product: CN(C)/C=N/C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of benzamide (1-135) in DMF-DMA was stirred for 3 h at 110° C., then cooled to rt. The solid was collected by filtration, the filter cake washed with PE and air dried to give the desired (E)-N-((dimethylamino)methylene)benzamide (compound II-135).
Reaction SMILES: [I:1]N1C(C)(C)C(=O)N(I)C1=O.[CH3:12][C:13]([NH:19][C:20]([C:22]1[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=1[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[O:21])([CH3:18])[CH2:14][S:15]([CH3:17])=[O:16]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C(=O)C>[CH3:12][C:13]([NH:19][C:20]([C:22]1[C:34]([I:1])=[CH:33][CH:32]=[CH:31][C:23]=1[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[O:21])([CH3:18])[CH2:14][S:15]([CH3:17])=[O:16]
Reactant: CC1(C)C(=O)N(I)C(=O)N1I
Reactant: CCCCOC(=O)c1ccccc1C(=O)NC(C)(C)CS(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1cccc(I)c1C(=O)NC(C)(C)CS(C)=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Into the same reactor as in Example 1 were charged 1.32 mg of palladium acetate, 0.78 g of 1,3-diiodo-5,5-dimethylhydantoin, n-butyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)benzoate and 5 ml of N,N-dimethylacetamide. After stirring the mixture at 90° C. for 30 minutes, 0.56 g of 1,3-diiodo-5,5-dimethylhydantoin was added, and the mixture thus obtained was stirred at 90° C. for 3.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous solution of sodium thiosulfate was added, and the mixture thus obtained was extracted twice with toluene. The organic layer was washed successively with 0.5N aqueous hydrochloric acid, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product thus obtained was washed with hexane-ether mixture to obtain 2.26 g of n-butyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)-3-iodobenzoate (yield 82%, melting point 57.5–66.3° C.). Regioselectivity of iodination into the 3-position was 100%.
Reaction SMILES: I[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.C(O[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1)(C)C.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].C(O)(=O)C>C1COCC1.CC(OC)(C)C>[CH3:7][C:4]1[CH:3]=[C:2]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[S:6][N:5]=1
Reactant: Cc1cc(I)sn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg+]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)sn1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a cooled (−25° C.) solution of 5-iodo-3-methylisothiazole (59.5 g, 264 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.2 g, 270 mmol) in anhydrous THF (300 mL) was added dropwise 1.3 M isopropylmagnesium lithium chloride in THF (218 mL, 283 mmol) at a rate which maintained the temperature at −15° C. to −25° C. The reaction mixture was stirred at −10° C. for 5 minutes after the addition was completed. HPLC analysis indicated that the starting material was consumed. A solution of acetic acid (16.19 mL, 283 mmol) in THF (40 mL) was added slowly to the reaction solution at 0° C. Hexanes (250 mL) and MTBE (150 mL) were sequentially added to the reaction mixture. A solid precipitate was formed, which was filtered off by passing the reaction mixture through a pad of Celite. The filtrate was concentrated via rotary evaporation to afford an oil residue, which was dispersed in MTBE (500 mL) through vigorous stirring. Additional precipitate was formed, which was filtered off using a pad of Celite. The filtrate was again concentrated to an oil, and MTBE (200 mL) was added, which formed additional solid precipitate that was filtered off using a pad of Celite. The process was repeated two more times until no more solid was formed when MTBE was added to the oil residue. The oil was dried in a rotary evaporator under high vacuum overnight with a bath temperature of 20° C., which afforded the title compound as an oil (49.55 g, 83%). 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 12H), 2.56 (s, 3H), 7.41 (s, 1H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].N(OC(C)(C)C)=O.N[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cu](F)F.N1C=CC=CC=1>[O:1]([N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1Oc1ccccc1
Yield: 55237.1 %

Procedure:
The procedure of Example 1 is repeated using 5.79 g (0.021 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 5.05 g (49 mmol) of tert-butyl nitrite, 12.6 mg (0.125 mmol) of copper(II) fluoride, 120 mL of pyridine and 3.91 g (42 mmol) of aniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 4.10 g of the title compound as a yellowish oil in 55.3% yield. The structure is confirmed by mass spectrographic analysis. MS [M+1]354.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[I:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]([N:20]3[CH:21]=[C:17]([I:16])[N:18]=[CH:19]3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (1.67 g, 7.0 mmol) and commercially available 4-iodo-imidazole (2.04 g, 10.5 mmol) according to the general procedure IVa. Obtained as a light yellow solid (1.97 g, 71%). MS (ISP) 397.1 [(M+H)+]; mp 184° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23][N:22]=3)=[C:17]([F:28])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[F:28][C:17]1[CH:16]=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[C:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3)c(F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccc(OC3CCNCC3)cc2F)=NN1
Yield: 144.2 %

Procedure:
In a 10 mL round bottom flask, 4-[3-fluoro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (410 mg, 1.0 mmol) in trifluoroacetic acid (3 mL) was stirred 2 h. The solvent concentrated under vacuum to produce 420 mg (100%) of the salt as an oil. MS m/z=292 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=O)=[CH:4][C:3]=1[F:16].C1([SiH2]C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C=O.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.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:4][C:3]=1[F:16]
Reactant: O=C(c1ccc(Br)c(F)c1)N1CCOCC1
Agent: [Rh]
Agent: C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cc(CN2CCOCC2)ccc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 250 ml flask was charged with (4-bromo-3-fluorophenyl)(morpholino)methanone (4.569 g, 15.86 mmol) and dissolved in 16 mL of THF. Diphenylsilane (6.2 ml, 33.4 mmol) was added followed by carbonyltris(triphenylphosphine)rhodium(I)hydride (100 mg, 0.109 mmol) and the reaction stirred at room temperature for 20 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[C:20]([C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][NH:27][CH:28]3[CH3:31])=[CH:23][CH:22]=2)=[CH:19][CH:18]=[CH:17][N:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][C:21]([C:20]5[C:15]([F:14])=[N:16][CH:17]=[CH:18][CH:19]=5)=[CH:22][CH:23]=4)[CH:28]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3cccnc3F)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3cccnc3F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(O[N:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1)(=O)C>C(O)(=O)C.[Pt]=O>[NH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1
Reactant: CC(=O)ON=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: NC1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1

Procedure:
10 Grams of 6-(4-acetyloxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril and 0.5 g of platinum oxide were dispersed in 150 ml of acetic acid, then the mixture was catalytically reduced at room temperature under normal pressure. The catalyst was removed by filtration, then the filtrate was concentrated under reduced pressure by evaporating the solvent, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol =10:1) to yield 3 g of 6-(4-amino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[C:21]1([OH:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:31][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1cccc2ccccc12
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc3ccccc23)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with Naphthalen-1-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C23H24O5 [M+Na]+: 403, [M+H]+: 381.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:20])(C(C)(C)C)(C)C.CCN(CC)CC>CC#N>[OH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ccccc2)c(O)c1
Yield: 76.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-phenyl-2-thiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N′-phenyl-thiourea (103 mg, 0.248 mmol) in CH3CN (1 mL) with Et3N.HF (100 uL, 0.62 mmol) in acetonitrile for 10 minutes at 23° C. The solution was concentrated and flushed through a silica pIug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%). mp: 144-145° C.; 1H NMR (CD3OD/CDCl3): d 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).