Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[H-].[Na+].CI.[C:17]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][C:5]([NH:6][CH3:17])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (10 mmol, 2.07 g) in DMF (10 mL) was added NaH (12 mmol, 480 mg of 60% suspension in mineral oil) (exothermic, gas evolution). After 15 min MeI (20 mmol, 1.2 mL) was added. The reaction mixture was allowed to stand at ambient temperature for 1 h, then poured into a solution of saturated NaHCO3 and brine, affording the product as an orange precipitate, which was filtered, washed with water and dried in vacuo. 1H NMR (500 MHz, d6-DMSO) δ 8.27 (m, 1H), 8.22 (s, 1H), 7.25 (s, 1H), 2.96 (d, J=4.9 Hz, 3H).
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([OH:28])CO)=[O:12].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[O:28])=[O:12]
Reactant: O=C(CCCCCCCCC(O)CO)OCOC(=O)CCCCCCCCC(O)CO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=CCCCCCCCCC(=O)OCOC(=O)CCCCCCCCC=O

Procedure:
Methylene bis(10,11-dihydroxyundecanoate) (2.24 g, 5 mmol) was dissolved in 150 ml tetrahydrofuran. Sodium metaperiodate (2.06 g, 10 mmol) was dissolved in 150 ml water and added dropwise to the tetrahydrofuran solution. TLC indicated full consumption of the diol after 60 minutes, whereupon sodium chloride was added to the reaction mixture until the two phases separated. The water phase was extracted with diethyl ether (3×50 ml). The combined organic phases were dried with magnesium sulphate and evaporated to give the title product as an oil, 1.43 g (74%). 13C NMR (45 MHz) CDCl3 : δ 21.9-43.9 (16×CH2), 79.1 (O--CH2 --O), 173.0 (2×C=O), 202.6 (2×CHO).
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[O-:17][Mn](=O)(=O)=O.[K+]>O1CCOCC1.O>[C:1]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]([OH:17])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)c1cccc(CO)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
3-Pivaloylbenzyl alcohol (0.80 g, 4.16 mmol) was dissolved in dioxane (20 ml). A solution of KOH (0.35 g, 6.30 mmol) in water (5 ml) was added followed by KMnO4 (1.45 g, 9.17 mmol). The mixture was stirred at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3×50 ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (0.80 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.[OH-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:11]=3[CH:12]=[N:13][NH:14]4)=[C:2]([F:1])[CH:3]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3cccc4[nH]ncc34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
45 mg (0.19 mmol) of 3-fluoro-4-(1H-indazol-4-yloxy)aniline (from example XXVI) and 40.1 mg (0.19 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) are suspended in 2 ml of water, and 27 μl of concentrated hydrochloric acid are added. The reaction mixture is heated at reflux overnight, resulting in the formation of a brown precipitate. Using 1N sodium hydroxide solution, the suspension is adjusted to pH 10. The precipitate is filtered off from the aqueous phase, and the filtrate is discarded. The crude product is purified by HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.CCN(CC)CC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2]([NH:1][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:3][C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 40.5 %

Procedure:
To an 8 mL screw-cap vial was added 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidin-2-one (200 mg, 0.74 mmol), CH2Cl2 (5 mL), Et3N (200 mg, 1.98 mmol), and benzoyl chloride (114 mg, 0.82 mmol). The mixture was shaken at room temperature for 2.5 h, evaporated under a stream of nitrogen, and partitioned between EtOAc and H2O. The organic phase was dried over MgSO4, filtered, and evaporated. The crude material was partially purified by normal phase chromatography (gradient, 10 to 50% EtOAc/petroleum ether), and fractions containing the major product were evaporated and recrystallized from EtOAc and petroleum ether to yield the title product as a white solid (112 mg, 41%): mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 8.31-8.25 (m, 2H), 8.24 (d, J=5.8 Hz, 1H), 8.16-8.11 (m, 2H), 7.82-7.75 (m, 1H), 7.68-7.56 (m, 3H), 7.52-7.44 (m, 2H); ESIMS m/z 374 ([M+H]+), 372 ([M−H]−).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C(O)=O.[O:9]1CCC[CH2:10]1.Cl.Cl.[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1>O>[N:16]1([CH2:21][CH2:22][CH2:23][NH:24][C:10]([C:4]2[CH:3]=[CH:2][O:1][CH:5]=2)=[O:9])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1ccco1
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: O=C(NCCCn1ccnc1)c1ccoc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.24 g. of furoic acid, 3.24 g. of N,N'-carbonyldiimidazole and 80 ml. of tetrahydrofuran was allowed to stir at room temperature for 2 hours. A 4.0 g. portion of 1H-imidazole-1-propanamine dihydrochloride was added and the mixture was stirred at room temperature overnight. The mixture was then heated for 5 hours, 5 ml. of water was added, heating resumed for 30 minutes and then the mixture was concentrated to remove most of the solvent. Dichloromethane and 60 ml. of 1N sodium hydroxide were added, the organic layer was separated, washed twice with water, dried and concentrated, giving 2.0 g. of the desired product, m.p. 127°-129° C.
Reaction SMILES: C([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)(C)(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([CH:14]([O:13][C:8]1[CH:7]=[N:6][NH:5][C:10](=[O:11])[C:9]=1[Cl:12])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH:23]([O:25][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH3:24])=[CH:19][CH:20]=1)([CH3:20])([CH3:16])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CCc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)CCc2ccc(C(Oc3cn[nH]c(=O)c3Cl)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of the product of Example 7B (200 mg, 0.548 mmol) in pyridine (10 mL) was added p-toluenesulfonyl chloride (209 mg, 1.096 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Monitoring by LC-MS showed a 1:1 mixture of starting material and product. The reaction was diluted with ethyl acetate and washed with 5% CuSO4 until a light blue aqueous solution was maintained. The organic layer was then dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (3:1 hexane:ethyl acetate to 100% ethyl acetate) to recover the starting material (90 mg) and the product as a clear oil (74 mg, 47% yield based on recovered starting material). 1H NMR (600 MHz, CDCl3): 7.80 (d, 2H, J=8.3 Hz), 7.72 (s, 1H), 7.33 (d, 2H, J=8.0 Hz), 7.30 (d, 2H, J=8.1 Hz), 7.13 (d, 2H, J=8.1 Hz), 5.27 (s, 2H), 4.66 (m, 1H), 2.65 (m, 1H), 2.54 (m, 1H), 2.45 (s, 3H), 1.94 (m, 1H), 1.81 (m, 1H), 1.63 (s, 9H), 1.26 (s, 3H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([OH:28])[CH:22]=2)[C:15]([OH:17])=O)[N:13]=1)=[O:7].[CH3:29][N+:30]([CH3:33])=[CH:31][Cl:32].[Cl-].C[Si](CC(N)=O)(C)C.[NH2:43][CH:44]1[C:54](=[O:55])[N:46]2[C:47]([C:51]([OH:53])=[O:52])=[CH:48][CH2:49][S:50][C@H:45]12>C(OCC)(=O)C.O.CN(C)C=O>[CH3:29][N+:30]([CH3:33])=[CH:31][Cl:32].[Cl-:3].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([OH:28])[CH:22]=2)[C:15]([NH:43][CH:44]2[C:54](=[O:55])[N:46]3[C:47]([C:51]([OH:53])=[O:52])=[CH:48][CH2:49][S:50][C@H:45]23)=[O:17])[N:13]=1)=[O:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=CNc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CNc1nc(C(=NOCc2ccc(Br)c(O)c2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Reaction time: 0.5 h

Procedure:
Vilsmeier reagent was prepared from N,N-dimethylformamide (0.44 g.) and phosphoryl chloride (0.92 g.) in an usual manner. 2-(2-Formamidothiazol4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetic acid (syn isomer, 2.0 g.) was added to the stirred suspension of Vilsmeier reagent in ethyl acetate (18 ml.) under ice-cooling, and stirred at the same temperature for 30 minutes to give a solution [hereinafter referred to solution A]. Trimethylsilylacetamide (3.9 g.) was added to a stirred suspension of 7-amino-3-cephem-4-carboxylic acid (1.0 g.) in ethyl acetate (10 ml.) and the mixture was stirred at 40° C. for 30 minutes. To the solution was added the solution A all at once at -30° C., and stirred at -10° to -20° C. for an hour. Water (100 ml.) and ethyl acetate (100 ml.) were added to the resultant mixture at -10° C. After separating the organic layer, water (100 ml.) was added to the organic layer and adjusted to pH 7.0 with a sodium bicarbonate saturated solution. The aqueous layer was separated, and ethyl acetate was added thereto. The mixture was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling. The organic layer was separated, washed with a sodium chloride saturated solution and dried over magnesium sulfate. The solution was concentrated in vacuo to give 7-[2-(2-formamidothiazol-4-yl)-2-(4-bromo-3-hydroxybenzyloxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.0 g.).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1>S(Cl)(Cl)=O.C(OCC)C>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([NH:10][C:4](=[O:5])[C:3]([C:2]([F:9])([F:8])[F:1])=[CH2:7])=[CH:12][C:13]=1[C:19]([F:20])([F:21])[F:22])#[N:16]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: C=C(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
2-Trifluoromethyl-acrylic acid (36.0 mmoL) in thionyl chloride (2.86 mL) was refluxed for 30 min. Excess thionyl chloride was removed in vacuo to yield a residue. 4-Amino-2-trifluoromethyl-benzonitrile (36.0 mmoL) in diethyl ether (50 mL) was added dropwise to the residue at −40° C. The reaction mixture was slowly warmed to room temperature. The reaction mixture was then partitioned between diethyl ether and water. The diethyl ether layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the brown oil) was then purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compound as yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.Cl[P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(OCC)C>[C:23]1([P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)n1
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C(=O)Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
1.00 g (3.89 mmol) of 6-bromo-2-pivaloylaminopyridine from example 14.2.1 was dissolved in 10 ml of diethyl ether and admixed at 0° C. with 3.64 ml (8.00 mmol) of (iso-C3H7)MgBr (2.2M in Et2O). The suspension was stirred at 0° C. for 18 h and then admixed with 0.7 ml (0.86 g, 3.89 mmol) of chlorodiphenylphosphine. The mixture was allowed to warm to ambient temperature overnight and was then hydrolyzed by adding 10 ml of dist. H2O. The resulting phases were separated and the aqueous phase was extracted twice with 50 ml each time of ethyl acetate. The organic phases were combined and dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was filtered together with dichloromethane through a short silica gel column (2×10 cm) and the solvent was removed under reduced pressure. The resulting oil was crystallized by digesting with petroleum ether/diethyl ether (40/60). The crystals were filtered off and washed with petroleum ether/diethyl ether (40/60). 0.38 g (1.05 mmol, 27.0%) of 6-(diphenylphosphino)-2-pivaloylaminopyridine was obtained as a solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[CH3:15][CH2:16][O:17][C:18](OCC)(OCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:18]([O:17][CH2:16][CH3:15])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1ccccc1

Procedure:
A solution of 41.9 g 1-acetyl-6-chloro-2-indolinone (educt V.1) and 136 ml triethyl orthobenzoate in 150 ml acetic anhydride is stirred for six hours at 120° C. After cooling the mixture is evaporated down by half, the crystals precipitated are suction filtered and dried at 100° C. in vacuo.
Reaction SMILES: C(OC(=O)[C@H]1C[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)CN1C(OCC1C=CC=CC=1)=O)C.[C-]#N.[Na+].C(Cl)(Cl)Cl.[CH2:39]([O:41][C:42](=[O:60])[C@@H:43]1[CH2:47][C@H:46]([C:48]#[N:49])[CH2:45][N:44]1[C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH3:40]>CS(C)=O>[CH2:39]([O:41][C:42](=[O:60])[C@H:43]1[CH2:47][C@@H:46]([C:48]#[N:49])[CH2:45][N:44]1[C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH3:40]
Reactant: CCOC(=O)[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Agent: CCOC(=O)[C@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H]1C[C@@H](C#N)CN1C(=O)OCc1ccccc1

Procedure:
The tosylate 12 (2.02 g, 4.53 mmol) was treated with NaCN in DMSO at 80° C. to provide, after workup, the cis nitrile ester (0.88 g, 64%) as a colorless oil: [α]25D +32° (c 1.04, CHCl3); Spectra were identical in all respects to those of the enantiomer N-(benzyloxycarbonyl)-cis-4-cyano-L-proline ethyl ester; HRMS (EI, 22 eV) m/e 302.1255 (302.1266 calcd for C16H18NO4).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>CN(C=O)C.O>[C:50]([O:49][C:47](=[O:48])[CH2:46][NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: Cc1ccc(-c2nc(CCN)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(CCNCC(=O)OC(C)(C)C)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 49.6 %

Procedure:
A solution of 2-{1-[4-(2-Amino-ethyl)-2-p-tolyl-imidazol-1-yl]-2-methyl-propyl}-3-benzyl-7-chloro-3H-quinazolin-4-one (181 mg, 0.343 mmol), potassium carbonate (47 mg., 0.343 mmol), and tert-butyl bromoacetate (67 mg., 0.343 mmol) in DMF (2.0 mL) was stirred at room temperature for 4.5 h. The reaction was diluted with water and the resulting white precipitate was filtered and purified by flash chromatography (silica gel, 95:5 methylene chloride:methanol) to provide the title compound as a white solid (109 mg., 50%). MS(ES+) m/e 640 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[CH3:35])=[CH:32][CH:33]=3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(Br)nc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1ccccc1-c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)OC(C)(C)C)cn1

Procedure:
To a stirred slurry of 1.75 g (3.35 mmol) of (S)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(6-bromo-pyridin-3-yl)propanoate and 913 mg (6.70 mmol, 2 eq.) of 2-methylphenylboronic acid in 50 mL of 1:1 isopropanol/toluene was added 25.0 mL of 2 M aqueous sodium carbonate solution. The reaction mixture was purged twice with argon and evacuated and then 124 mg (0.167 mmol, 0.05 equivalents) of bis(tricyclohexylphosphine)palladium (II) chloride was added and the mixture again purged with argon and evacuated.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]([O:20]CC)=[O:19])[CH:16]=2)[CH:4]=1.[OH-].[Li+].[ClH:27]>C1COCC1.O>[ClH:27].[F:23][C:2]([F:1])([F:24])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]([OH:20])=[O:19])[CH:16]=2)[CH:4]=1
Reactant: CCOC(=O)Cn1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Reaction time: 1 h
Yield: 93 %

Procedure:
To a mixture of ethyl 2-(4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)acetate (0.14 g, 0.414 mmol) and THF—H2O (5:1, 4 mL) was added lithium hydroxide (0.621 mL, 1.242 mmol) at room temperature. The reaction mixture was stirred for 1 hour, then acidified with concentrated HCl, and concentrated in vacuo to give an HCl salt of the title compound as a light brown solid (0.12 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.97 (s, 2H), 7.58 (s, 1H), 7.76 (s, 1H), 8.22 (s, 1H), 8.54 (s, 1H), 8.59 (s, 1H), 13.70 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C13H9F3N4O2, 311.1. found 311.15.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:19][CH2:20][OH:21].CCN(C(C)C)C(C)C.CN(C=O)C>O>[OH:21][CH2:20][CH2:19][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][C:2]([F:1])([F:16])[F:17])[CH2:11][CH2:12]1
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Reactant: OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2ccccc2OC(F)(F)F)CC1
Temperature: 65 °C
Yield: 63 %

Procedure:
A stirred mixture of 1.23 g of 1-(2-trifluoromethoxyphenyl)piperazine, 0.73 mL of 97% 2-bromoethanol, 1.25 mL of DIPEA and 4 mL of DMF was heated at 65° C. for 6 h. After cooling to r.t., the mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (3×30 mL). The organic layer was dried (anhydrous Na2SO4) and evaporated to dryness in vacuo. The residue was purified by flash chromatography (CH2Cl2-MeOH 100:1.5) affording 0.911 g (63%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[CH:14]1([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([CH:3]3[CH2:2][N:1]([C:24]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:25])[CH2:4]3)=[O:6])[CH2:8][CH2:9]2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)N1CCCCC1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Solvent: ClCCl
Product: O=C(C1CN(C(=O)N2CCCCC2)C1)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a stirred 0° C. solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (20 mg, 0.084 mmol) in DCM (1 ml) and TEA (0.023 ml, 0.17 mmol) was added dropwise piperidine-1-carbonyl chloride (14.9 mg, 0.013 ml, 0.10 mmol). The reaction was stirred for 1 h and then allowed to warm to RT and the progress monitored by LCMS. After 1 h the reaction was quenched with water (5 ml), extracted with DCM (2×10 ml), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 99:1 to 96:4 gradient of DCM/2M NH3 in MeOH) provided impure title compound (22 mg, 78%) as brown oil. Re-purification by preparative HPLC provided the title compound (3 mg, 10% yield) as a colourless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[CH2:12]1[O:20][C@@H:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:12][C@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:20]
Reactant: c1c[nH]cn1
Reactant: c1ccc([C@@H]2CO2)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: O[C@H](Cc1ncc[nH]1)c1ccccc1
Yield: 32 %

Procedure:
In a manner similar to that of Example 49, step 1, imidazole (2.83 g, 41.6 mmol) is dissolved in absolute ethanol (45 mL). Pyridine (0.11 mL) is added followed by addition of (R)-(+) styrene oxide (5.0 g, 41.6 mol, Aldrich Chemical Co.), followed by heating at reflux for 18 hours. The mixture is evaporated in vacuo to a syrup and suspended between ethyl ether (250 mL) and water (100 mL) to give a solid precipitate. The suspension is filtered and washed with ethyl ether. The solid is recrystallized from hot ethyl acetate and dried in vacuo (2.52 g, 32% yield). MS: APCI: M+1, 189.1 (M: 188.2). NMR spectrum is consistent with structure.