Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:33]([F:36])([F:35])[F:34])=[CH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[N+:37]([CH3:40])([O-:39])=[O:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([CH2:40][N+:37]([O-:39])=[O:38])([C:33]([F:35])([F:34])[F:36])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=[O:13])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)C=C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
To a stirred solution of tert-butyl 5′-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 6, 6.54 g, 11.658 mmol) in DMF (215 mL) was added nitromethane (6.24 mL, 116.57 mmol) and DBU (1.69 mL, 11.3mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (2×300 mL). Combined organic layer was washed with aqueous LiCl solution (2×400 mL) then brine (500 mL), dried over sodium sulfate and concentrated to get as semi solid (11.23 g, crude). Crude compound was purified by column chromatography using silica gel (230-400 mesh). Desired compound was eluted in 10% ethyl acetate in n-hexane to afford light yellow sticky liquid (4.51 g, 63.7%). 1H NMR (400 MHz, CDCl3) δ: 1.48 (s, 9H), 1.85-1.88 (m, 1H), 2.16-2.17 (m, 1H), 3.40-3.44 (m, 1H), 3.95 (d, J=18.84 Hz, 1H), 4.13-4.18 (m, 2H), 4.33-4.36 (m, 2H), 5.17 (d, J=4.12 Hz, 2H), 7.13 (d, J=6 Hz, 1H), 7.26 (s, 1H), 7.63-7.65 (m, 1H), 7.76-7.78 (m, 1H), 8.00-8.02 (m, 1H). LC-MS (m/z): 605.0 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(Br)cc1C=O
Agent: O=S(=O)(O)O
Product: COc1c(C=O)cc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
5-Bromo-2-methoxybenzaldehyde (29.65 g, 138 mmol) was added to stirred concentrated sulfuric acid (160 mL) at −15° C. Nitric acid (70% w/w) (16 g) was added dropwise. Further stirring was allowed for 15 mins at this temperature before the mixture was poured onto crushed ice (2 L). The resulting precipitate was collected by filtration and partitioned between dichloromethane (800 mL) and saturated sodium hydrogen carbonate (1 L). The organic layer was dried (Na2SO4) and evaporated in vacuo to give the title compound (20.5 g) as a crude solid.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:12])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:15]=[O:16]>>[O:1]([CH2:8][CH:9]1[O:12][C:15](=[O:16])[NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: NCC(O)COc1ccccc1
Product: O=C1NCC(COc2ccccc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
422 mg of N,N'-carbonyldiimidazole were added, whilst ice-cooling, to a solution of 500 mg of 3-phenoxy-2-hydroxypropylamine in 5 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature overnight. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the resulting concentrate. The mixture was then extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using ethyl acetate as the eluent, to give 490 mg of the title compound, melting at 110° C. to 111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12](O)=O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[ClH:15].NC1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[C:22](Cl)[C:20]=2[N:21]=1>>[Cl:15][C:23]1[CH:24]=[CH:25][C:19]2[S:18][C:12]([CH2:11][C:4]3[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:21][C:20]=2[CH:22]=1
Reactant: O=C(O)Cc1cc(Cl)cc([N+](=O)[O-])c1
Reactant: Cl
Reactant: Nc1nc2c(Cl)cccc2s1
Product: O=[N+]([O-])c1cc(Cl)cc(Cc2nc3cc(Cl)ccc3s2)c1

Procedure:
5-Chloro-2-(3-chloro-5-nitro-benzyl)-benzothiazole (329) was synthesized (92%) from (3-chloro-5-nitro-phenyl)-acetic acid (328, 430 mg, 2.0 mmol) and 2-amino-4-chloro-benzothiazole hydrochloride (6, 392 mg, 2.0 mmol) in a similar manner as described in Example 8.
Reaction SMILES: ClCCl.[F:4][C:5]1[C:15]([N:16]2[C:20](=[O:21])[N:19]([CH3:22])[C:18]([CH3:23])=[N:17]2)=[CH:14][C:8]2[N:9]=[C:10]([S:12][CH3:13])[S:11][C:7]=2[CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:29]>O>[F:4][C:5]1[C:15]([N:16]2[C:20](=[O:21])[N:19]([CH3:22])[C:18]([CH3:23])=[N:17]2)=[CH:14][C:8]2[N:9]=[C:10]([S:12]([CH3:13])=[O:29])[S:11][C:7]=2[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2cc(-n3nc(C)n(C)c3=O)c(F)cc2s1
Solvent: ClCCl
Solvent: O
Product: Cc1nn(-c2cc3nc(S(C)=O)sc3cc2F)c(=O)n1C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
10 mL dichloromethane was charged with 0.001 mol 1-(6-fluoro-2-(methylthio)benzo[d]thiazol-5-yl)-3,4-dimethyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred for 10 mins and then 0.0011 mol m-chloroperoxybenzoic acid (MCPBA) were added. After stirring at room temperature for 2 hours, the mixture was poured into 30 mL of water, extracted with 15 mL dichloromethane twice. Organic phases were combined and dried over anhydrous sodium sulfate. Filtration and removal of solvent under vacuum gave the title compound as a white solid in a 93% yield.
Reaction SMILES: [CH3:1][C:2]([N+:16]([O-])=O)([CH3:15])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1>CO>[NH2:16][C:2]([CH3:15])([CH3:1])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1
Reactant: CC(C)(COc1ccc(O)c(C(N)=O)c1)[N+](=O)[O-]
Solvent: CO
Product: CC(C)(N)COc1ccc(O)c(C(N)=O)c1

Procedure:
11.5 g 5-(2-methyl-2-nitropropoxy)salicylamide are hydrogenated in 150 ml of methanol at 40°-50° and 80 bar over 5 g of Raney nickel until hydrogen absorption ceases. By filtration and concentration of the filtrate by evaporation, crude 5-(2-amino-2-methylpropoxy)salicylamide is obtained, which, after standing for a relatively long period, crystallises from isopropanol and melts at 115°-117°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:2]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[C:36]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:13])=[CH:2]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottom flask, (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide (50 mg, 0.14 mmol, 1.0 equivalent), and DMAP (cat, 4.0 mg, 0.14 equivalent) were introduced and dissolved in CH2Cl2, after which DIPEA (0.04 ml, 0.20 mmol, 1.5 equivalent) was introduced. After introducing benzoyl chloride (0.02 ml, 0.17 mmol, 1.2 equivalent) at 0° C. and stirring at room temperature for 24 hr, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:=1:1) and dried so that solid form of (E)-N′-(3-(1-benzoyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (48.0 mg, 77%).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]3[S:27][C:26]([C:28](N(OC)C)=[O:29])=[CH:25][C:24]=3[CH3:34])[CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH2:35]1COC[CH2:36]1>>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:23]2[S:27][C:26]([C:28](=[O:29])[CH2:35][CH3:36])=[CH:25][C:24]=2[CH3:34])=[CH:16][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2sc(C(=O)N(C)OC)cc2C)cc1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Product: CCC(=O)c1cc(C)c(-c2ccc(OC)c(-c3ccc(S(N)(=O)=O)cc3)c2)s1
Temperature: 82.5 °C

Procedure:
Grignard reagent (ethyl magnesium bromide, 1.32 g, 9.9 ml, 9.97 mmol) was added drop wise to a stirred solution of 5-(4′-(N-((dimethylamino)methylene)sulfamoyl)-6-methoxy-[1,1′-biphenyl]-3-yl)-N-methoxy-N,4-dimethylthiophene-2-carboxamide (1d, 1.0 g, 1.99 mmol) in anhydrous THF (20 ml) at 25° C. The reaction mixture was heated at 80-85° C. for 1 hour. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0° C. The cooled reaction mixture was then quenched by adding a saturated solution of ammonium chloride (10 ml). The mixture was then extracted with ethyl acetate (3×60 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product. The crude product so obtained was purified by flash chromatography using 30-40% ethyl acetate in hexane as an eluent to obtain the title compound. The compound was re-purified by dissolving 0.68 g of the compound in ethyl acetate (5 ml) and precipitating it by slow addition of diisopropyl ether. (0.180 g, 21.7%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[CH:15]>CN(C=O)C.[Cu]I.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>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:15]#[C:14][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Brc1nccs1
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#Cc1nccs1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
2-Bromo-1,3-thiazole (0.15 mL, 1.6 mmol), CuI (98 mg, o.51 mmol), PdCl2(PPh3)2 (120 mg, 0.17 mmol) and triethylamine (2.8 mL, 20 mmol) were combined in DMF (6.8 mL) and cooled in an ice bath. 3-Ethynylpyridine (520 mg, 5.04 mmol) was then added to the mixture as a solution in DMF (3.0 ML). The ice bath was removed and the reaction was allowed to stir at ambient temperature for 16 h. The reaction mixture was filtered through a pad of Celite.™, and the pad was washed thoroughly with ethyl acetate. The filtrate was washed with brine (3.times.20 mL). A partial emulsion was observed. The mixture was concentrated in vacuo and the residue was taken up in CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 80:20 followed by 30:20 hexane:ethyl acetate to afford 3-(1,3-thiazol-2-ylethynyl)pyridine (160 mg) as a mixture with another product exhibiting a mass of 204 in the GC/MS, assigned as pyridylalkyne dimer. A portion of the mixture (100 mg) was further purified by preparative reverse phase HPLC eluting with a gradient of 80:20 to 0:100 water: acetonitrile over twenty minutes. The fractions containing the desired product were collected (detection by uv at 210 nm) to afford 3-(1,3-thiazol-2-ylethynyl)pyridine as a white waxy solid (15 mg). 1H NMR (CDCl3, 300 MHz) Δ9.3-8.5 (br s, 2H), 7.92-7.90 (m, 2H), 7.50-7.30 (m, 2H). MS (ESI) 187.0 (M++H).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1nccc(-c2ccccc2)n1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc2nc(-c3ccccc3)ccn12

Procedure:
A mixture of 2.0 g. of 2-hydrazino-4-phenylpyrimidine and 25 ml. of triethyl orthoacetate is refluxed for 8 hours. On cooling the desired compound is removed by filtration, m.p. 303°-306° C.
Reaction SMILES: CS(O[C@@:6]1([CH3:44])[CH2:10][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])(=O)=O.[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1.C(N(CC)CC)C>CN(C)C=O>[OH:45][CH2:46][C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[CH2:44][C@@H:6]1[CH2:10][C@H:9]([S:11][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:8][N:7]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32]
Reactant: C[C@]1(OS(C)(=O)=O)C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCC[C@H]1CO
Temperature: 100 °C
Reaction time: 5 h
Yield: 65.1 %

Procedure:
To a solution of (2S,4S)-2-(methanesulfonyloxy)-methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (8.76 g) in dimethylformamide (80 ml) were added (2S)-2-(hydroxymethyl)pyrrolidine (8.72 g) and triethylamine (3.86 ml) and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was poured into ice-water (300 ml) and extracted twice with ethyl acetate (200 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (2:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.75 g).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15]([C:16]3[N:20]=[C:19]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[C:24]#[N:25])[O:18][N:17]=3)=[C:10]2[CH:9]=[CH:8]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].CO>[OH-].[NH4+]>[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[NH:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15]([C:16]3[N:20]=[C:19]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[C:24]#[N:25])[O:18][N:17]=3)=[C:10]2[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3noc(-c4cccc(C#N)c4)n3)ccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#Cc1cccc(-c2nc(-c3ccnc4[nH]ccc34)no2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
The crude 3-[3-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1,2,4-oxa-diazol-5-yl]benzonitrile (0.08 g, 0.0002 mol) was dissolved in TFA (3.0 mL, 0.039 mol) under nitrogen and then heated to 60° C. After heating for 2 h the reaction was allowed to cool to rt and concentrated in vacuo. The resulting residue was taken up in methanol and concentrated to remove as much of the TFA as possible. The residue was taken up in methanol (2.0 mL, 0.049 mol) and ammonium hydroxide (1 mL). This mixture was stirred at rt for 2 h and the reaction was then complete. The reaction was concentrated in vacuo to give the crude product which was purified by prep HPLC on a C-18 column eluting with a ACN:water gradient with 0.2% TFA to give the title compound (0.025 gm, 43%) (M+H)+ 288. 1H NMR (DMSO-d6) δ 12.1 (bs, 1H), 8.65 (s, 1H), 8.48 (d, 1H, J=6.4), 8.39 (d, 1H, J=4.8), 8.16 (d, 1H, J=6.4), 7.84 (t, 1H, J=6.4), 7.75 (d, 1H, J=4.8), 7.68 (m, 1H), 6.99 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:14]=3[O:15][C@H:16]([CH3:20])[C:17](O)=[O:18])=[N:7][CH:8]=[N:9]2)=[C:4]([F:26])[CH:3]=1.CCN(C(C)C)C(C)C.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:14]=3[O:15][C@H:16]([CH3:20])[C:17]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])=[O:18])=[N:7][CH:8]=[N:9]2)=[C:4]([F:26])[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: C[C@@H](Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Oc1cc(F)ccc1Nc1ncnc2cc(Br)cc(F)c12)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 300 mg (0.78 mmol) (2R)-2-[2-[(7-bromo-5-fluoro-quinazolin-4-yl)amino]-5-fluoro-phenoxy]propanoic acid and DMF, 0.3 ml (1.8 mmol) DIPEA, 105 mg (0.89 mmol) 2,2,2-trifluoro-ethylamine and 344 mg (0.9 mmol) HATU are added. The mixture is stirred at RT for 3 h, water is added and the precipitate is filtered and dried.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under atmosphere of argon, to a suspension of sodium hydride (63%, 57.1 g) in anhydrous N,N-dimethylformamide (540 ml) was added a solution of 3,4-dihydroxybenzaldehyde (103.5 g) in anhydrous N,N-dimethylformamide (500 ml) dropwise slowly under cooling with ice. The reaction mixture was stirred for 30 minutes at room temperature, and to the mixture was added benzyl chloride (104 ml) under cooling with ice and it was stirred for 15 hours at room temperature. To the mixture was added water under cooling with ice, and was concentrated under reduced pressure. The residue was diluted by water and it was washed by methylene chloride. The methylene chloride layer was extracted by a 1N aqueous solution of sodium hydroxide. Combined aqueous layers were acidified by 2M hydrochloric acid and it was extracted by ethyl acetate. The organic layer was washed by a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from chloroform to give the title compound (99.4 g) having the following physical data.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5.00 g, 26.8 mmol) in DCM (200 ml) was added DIPEA (9.85 ml, 56.4 mmol) and then 4-(trifluoromethyl)benzenesulfonyl chloride (7.22 g, 29.5 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then reduced to dryness in vacuo, to yield 1,1-dimethylethyl 4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate, (crude yield 100%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[H][H]>C(O)C.C1COCC1.[Pd]>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C2CCN(CC3CC3)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(C2CCN(CC3CC3)CC2)cc1

Procedure:
3.3 g (12.5 mmol) 1-cyclopropylmethyl-4-(4-nitro-phenyl)-piperidine are dissolved in a mixture of 40 ml of ethanol and 40 ml THF, combined with 1.3 g palladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Then the reaction mixture is suction filtered and the filtrate is concentrated by evaporation. Yield: 2.7 g
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:15][CH2:16][CH2:17][CH3:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[O:25][C:26]=1[CH3:27]>>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[N:23][C:22]=1[CH2:21][N:11]1[C:12]2[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][CH2:16][CH2:17][CH3:18])[C:3]([OH:2])=[O:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Product: CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3C)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid methyl ester (preparation 6) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole to give rac-3-[1-(5-methyl-2-o-tolyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-2-propoxy-propionic acid as light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:37]O)[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:37][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][OH:36])=[CH:31][CH:30]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(CO)cc1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OCc2ccc(CO)cc2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 57.4 %

Procedure:
The named compound was synthesised from 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (541 mg, 1.37 mmol, 1 equiv.) and 1,4-benzenedimethanol (946 mg, 6.85 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (405 mg, 78%). 1H NMR (300 MHz, CDCl3): 8.01-7.85 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.61-7.53 (m, 2H, Ar—H), 7.37-7.18 (m, 9H, Ar—H), 6.93 (d, J=7.8 Hz, 2H, Ar—H), 4.85 and 4.67 (d: AB, J=15.0 Hz, 2H, N—CH2), 4.66 (d, J=5.7 Hz, CH2—OH), 3.90 and 3.68 (d: AB, J=11.7 Hz, 2H, OCH2), 2.12 (t, J=6.0 Hz, 1H, OH). 13C NMR (75 MHz, CDCl3): 168.52, 147.63, 145.39, 144.90, 141.16, 137.34, 136.39, 135.37, 133.42, 131.73, 130.57, 130.32, 129.19, 128.38, 127.30, 127.11, 124.34, 123.69, 95.52, 65.26, 65.12, 42.89. m/z (ES): 515 [M+H]+. HPLC: Rt=3.56 min. Anal.: calc. for C29H23ClN2O5: C, 67.64; H, 4.50; N, 5.44, Found: C, 67.38; H, 4.43; N, 5.26.