Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](OC1C=CC(O)=CC=1CCCC1C=CC(C(OC)=O)=CC=1)C1C=CC=CC=1>>[OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: COC(=O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Product: COC(=O)c1ccc(C)cc1O

Procedure:
Methyl 2-hydroxy-4-methylbenzoate was prepared from 2-hydroxy-4-methylbenzoic acid by the process described in Example 6 for the synthesis of methyl 4-(3-(2-benzyloxy-5-hydroxyphenyl)propyl]-benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:12][NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNc1nnc(Cl)c2ccccc12
Solvent: Cc1ccccc1
Product: O=C(NN=c1[nH]nc(Cl)c2ccccc12)c1ccccc1
Temperature: 25 °C

Procedure:
2.5 g (4-chloro-phthalazin-1-yl)-hydrazine (compound C1) are suspended in 250 ml toluene and treated with a solution of 1.7 ml benzoic acid chloride in 50 ml toluene at reflux temperature. After 2 h the reaction mixture is cooled to ambient temperature and filtered with suction. The filtrate is concentrated under reduced pressure and the residue is recrystallized from N,N-dimethylformamide to yield 1.2 g of benzoic acid (4-chloro-2H-phthalazin-1-ylidene)-hydrazide.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cc(I)ccn1
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1ccnc(C(F)(F)F)c1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to previously reported procedure (see pending U.S. patent application Ser. No. 11/575,187) from (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 4-iodo-2-(trifluoromethyl)pyridine (this starting material was prepared according to a procedure described in Eur. J. Org. Chem. 2003, 1559-1568).
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.[H-].[Na+].[CH2:7]([CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[CH2:7]([C:14]([CH2:3][S:2][CH3:1])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CSC)(Cc1ccccc1)C(=O)OCC
Temperature: 23 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
Chloromethyl methyl sulfide (1.4 mL, 17 mmol, 1.0 equiv) and 60% sodium hydride in mineral oil (750 mg, 19 mmol, 1.1 equiv) were sequentially added to a stirred solution of diethyl 2-benzylmalonate (4.0 mL, 17 mmol, 1.0 equiv) in N,N-dimethylformamide (34 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 18 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (150 mL) and extracted with diethyl ether (4×70 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford a yellow oil (5.3 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.13-7.30 (m, 5H), 4.22 (q, J=7 Hz, 4H), 3.36 (s, 2H), 2.94 (s, 2H), 2.11 (s, 3H), 1.27 (t, J=7 Hz, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C:30]1[CH:31]=[C:32]([CH:61]=[CH:62][C:63]=1[F:64])[C:33]([NH:35][NH:36][C:37](=[O:60])[C@H:38]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[C:52](Cl)[C:51]=1C)[C@@H:39]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH3:40])=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].[CH2:65]([Cl:67])Cl>>[Si:42]([O:41][C@H:39]([CH3:40])[C@@H:38]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]#[N:57])=[C:65]([Cl:67])[C:55]=1[CH3:54])[C:37]1[O:60][C:33]([C:32]2[CH:61]=[CH:62][C:63]([F:64])=[C:30]([O:29][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[CH:31]=2)=[N:35][N:36]=1)([C:45]([CH3:48])([CH3:46])[CH3:47])([CH3:44])[CH3:43]
Reactant: ClCCl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)c(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Triphenylphosphine (1.0 g, 3.85 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (977 mg, 3.85 mmol) and TEA (779 mg, 7.70 mmol) at 0° C. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-fluorobenzohydrazide (1.25 g, 1.93 mmol) in 35 mL DOA was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stir. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 100 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (1.10 g). 1H NMR (400 MHz, DMSO-d6, δ in ppm): 7.71 (m, 1H), 7.70 (d, J=9 Hz, 1H), 7.65 (m, 1H), 7.03 (d, J=9 Hz, 1H), 6.53 (d, J=9 Hz, 1H), 5.15 (d, J=9 Hz, 1H), 4.80 (m, 1H), 2.44 (s, 3H), 1.51 (d, J=6 Hz, 3H), 1.13 (s, 9H), 0.83 (s, 9H), 0.36 (s, 6H), 0.19 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[C:25]([C:27]1([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])[CH2:29][CH2:28]1)#[N:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:25]([C:27]1([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]4[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]5[CH2:22][CH2:21]5)=[O:19])[N:16]=4)[N:13]=3)[CH:23]=2)=[O:34])[CH2:28][CH2:29]1)#[N:26]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 78.6 %

Procedure:
Using N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol), 3-(1-cyanocyclopropyl)benzoic acid (91 mg, 0.49 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) and N,N-dimethylformamide (7.0 mL) as starting materials and in the same manner as in Example 318, the title compound (178 mg, 75%) was obtained as a white powder.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[O:13][C@H:10]([O:11]C)[CH2:9][CH2:8][C@@H:7]1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-]>Cl>[C:1]([NH:4][CH2:5][C@H:6]1[O:13][CH:10]([OH:11])[CH2:9][CH2:8][C@@H:7]1[OH:14])(=[O:3])[CH3:2]
Reactant: CO[C@@H]1CC[C@H](O)[C@@H](CNC(C)=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(=O)NC[C@H]1OC(O)CC[C@@H]1O

Procedure:
Methyl 6-acetamido-2,3,6-trideoxy-α-D-erythro-hexopyranoside (1.5 g) in 0.1 M aqueous hydrochloric acid (30 ml) was heated at 100° for 0.5 h. The solution was neutralized with Amberlite IR-400 (carbonate form) resin and evaporated in vacuo to yield a syrup, 1.46 g. This syrup showed the presence of two compounds by TLC (ether-methanol, 9:1): (a) Rf 0.08 and (b) Rf 0.05. The separation of these two components was achieved by chromatography in a silica-gel column using mixtures of ether-methanol as eluants. Compound (a), 6-acetamido-2,3,6-trideoxy-D-erythro hexopyranose (Rf 0.08) was obtained as a colourless syrup (0.75 g, 50%) which reduced Fehling's reagent. [α]546125 +50°, [α]D25 +36° (c 0.5, water).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[CH2:15]1)=O)(C)(C)C>O1CCCC1>[CH3:29][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[O:21][CH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH3:12])[CH2:15]1
Reactant: Cc1cccc(C)c1OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC[C@H]1CCCN(C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.4 %

Procedure:
A solution of 1M lithium aluminum hydride in tetrahydrofuran (45 mL, 45 mmol) was added dropwise during 30 minutes to (S)-N-(tert-butoxycarbonyl)-3-(2,6-dimethylphenoxymethyl) piperidine (13.0 g, 40.6 mmol) in dry tetrahydrofuran (250 mL) under a dry nitrogen atmosphere. After the addition was complete, the reaction mixture was heated at reflux for 4 hours, stirred at room temperature for 20 hours, and quenched by the cautious addition of solid sodium sulfate decahydrate (70 g). The sodium sulfate was removed by filtration and washed with ethyl acetate (3×150 mL). The combined filtrates were concentrated, and the residue chromatographed on silica gel, eluting with dichloromethane/methanol (9.5:0.5) to give (S)-3-(2,6-dimethylphenoxymethyl)-1-methylpiperidine as a clear oil (8.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=1.[C:17]1([CH2:23][CH2:24][Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: COc1ccc(Br)cc1C1=NC(C)(C)CO1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)COC(c2cc(Br)ccc2CCc2ccccc2)=N1
Reaction time: 18 h
Yield: 103.1 %

Procedure:
To a solution of 2-(5-bromo-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (31.21 g) in THF (40 ml) was added PhCH2CH2MgBr (0.22 mol) as a solution in diethyl ether (240 ml). The mixture was stirred for 18 hours, the solvents evaporated and the residue partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was separated, evaporated and the resulting residue purified by MPLC eluting with dichloromethane to give 2-(5-bromo-2-(phenethyl)phenyl)-4,4-dimethyl-4,5-dihydrooxazole (40.56 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].[CH3:9][O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14](B(O)O)=[CH:13][N:12]=1.C(=O)(O)[O-].[Na+]>COCCOC.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]([C:14]2[C:15]([O:17][CH3:18])=[N:16][C:11]([O:10][CH3:9])=[N:12][CH:13]=2)[N:3]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1nc(Br)c(C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ncc(-c2nc(C)sc2C)c(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2,5-dimethyl-1,3-thiazole (commercially available from Apollo Scientific Ltd, 410 mg, 2.135 mmol) in 1,2-Dimethoxyethane (DME) (6.5 mL), Tetrakis(triphenylphosphine)palladium (123 mg, 0.107 mmol) was added and the mixture was stirred at rt for 30 minutes. Then [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 916 mg, 4.48 mmol) and 1M Sodium bicarbonate aqueous solution (5.83 mL, 5.83 mmol) were added. The reaction mixture was then stirred at 90° C. for 2.5 h and left stirring at rt overnight. The day after the mixture was diluted with DCM and washed with water. Organic layer was dried and concentrated under vacuum. Crude product was first purified by flash chromatography (eluent: Cy/AcOEt 65:35) and further purified by SCX cartridge affording 5-(2,5-dimethyl-1,3-thiazol-4-yl)-2,4-bis(methyloxy)pyrimidine with minor unknown impurities that was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13]C1C=C(C(OCC)=O)NC=1C>>[Cl:13][C:6]1[C:2]([CH3:1])=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][C:5]=1[CH3:7]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C

Procedure:
Title compound was synthesized from ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (commercially available) by an analogous method to Intermediate 9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[N:9]1[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]2.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[N:9]1[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]2
Reactant: O=C1CC=C[C@@H]2CCC[C@H](c3ccccc3F)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CCC[C@H](c3ccccc3F)N12
Yield: 83.3 %

Procedure:
Platinum oxide (16 mg) was added to a solution of (6R*,9aS*)-6-(2-fluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (368 mg) in methanol (8 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 309 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].CCN=C=NCCCN(C)C.Cl.[CH3:40][S:41]([NH2:44])(=[O:43])=[O:42]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:44][S:41]([CH3:40])(=[O:43])=[O:42])=[O:24])=[CH:21][CH:20]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([C:10]([F:11])([F:13])[F:12])[C:14]([F:17])([F:16])[F:15]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 73.8 %

Procedure:
To a solution of 4-(5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridin-3-ylamino)benzoic acid (Preparation 259, 116 mg, 0.27 mmol) in dichloromethane (5 mL) was added 4-dimethylaminopyridine (50 mg, 0.41 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (77 mg, 0.41 mmol). The solution was stirred for 25 minutes at room temperature and methanesulfonamide (39 mg, 0.41 mmol) was added. The reaction mixture was stirred for 18 hours at room temperature. The solution was concentrated in vacuo and the material was purified by reverse phase chromatography eluting with acetonitrile:water (from 5:95 to 95:5, 30 minutes gradient followed by 5 minutes isocratic) to afford the title compound as a white solid (98 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([OH:28])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([O:28][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@@H](O)CCc1cc(Br)c(C)s1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A dichloromethane (6 mL) solution of 6 (497 mg, 1.03 mmol) was treated with 2,6-lutidine (143 μL, 1.22 mmol) and TBSOTf (0.26 mL, 1.13 mmol). After 1.5 h, 50 mL saturated NaHCO3 was added and the resulting mixture was extracted with 25 mL CH2Cl2. The CH2Cl2 layer was washed with 50 mL 1 M HCl and 50 mL brine. The CH2Cl2 solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (8% ethyl acetate/hexanes→10%) gave 7 (553 mg, 0.93 mmol, 90%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (679 mg, 1.69 mmol) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.498 mL, 1.69 mmol) dissolved in water (0.800 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.104 mL, 1.69 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8.71 mL, 52.27 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (311 mg, 50%) was isolated. MS m/z 371 (M+H)+
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][NH:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[O:20]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:22]3[CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21]3)[CH:19]=[CH:18][C:17]=2[NH:16]1
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1Cc2ccccc2C1)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and isoindoline. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-acetamide (45 mg) in N,N-dimethylformamide (10 mL) was added potassium phosphate (68 mg) and isoindoline (0.025 mL). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered (35 mg). 1H-NMR (300 MHz, DMSO-d6), 11.67 (br s, 1H), 9.97 (br s, 1H), 8.69 (s, 1H), 8.31 (d, J=9.0 Hz, 2H), 7.84 (m, 2H), 7.65 (t, J=9.0 Hz, 1H), 7.27 (m, 5H), 4.11 (s, 4H), 3.60 (s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34])[CH3:37]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A155) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].C(N(CC)CC)C>CN(C)C=O>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(O)CCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(O)cc1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
1.66 g (10 mmol) of 3-(4-hydroxyphenyl)-propionic acid in 80 ml of dimethylformamide are treated at room temperature and while stirring with 2.16 g (10 mmol) of 4-nitrobenzyl bromide and 1.4 ml (10 mmol) of triethylamine. After 12 hours, the mixture is evaporated in vacuo and the residue obtained partitioned between ethyl acetate and water. The organic phase is separated, washed with 10% potassium hydrogen carbonate solution and water, dried over sodium sulphate and then evaporated to dryness. The residue crystallizes from diisopropyl ether/petroleum ether. There is obtained 3-(4-hydroxyphenyl)-propionic acid 4-nitrobenzyl ester in the form of colourless needles of melting point 80°-82° C. The product is chromatographically pure in cyclohexane/chloroform/acetic acid (45:45:10). The yield amounts to 1.6 g (53% of theory).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 95 °C

Procedure:
5-Fluoro-2-nitrobenzotrifluoride (400 mg, 1.91 mmol) and trans-4-aminocyclohexanol (220 mg, 1.91 mmol) are dissolved in dimethylsulfoxide (10 mL) and the reaction is then heated at 95° C. for 3.5 hours. After cooling to room temperature, the mixture is diluted with dichloromethane (15 mL) and washed with water (3×10 mL). The organic phase is collected and dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is recrystallised from petrol ether. The desired product is finally isolated as a yellow solid (84% yield).