Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)[CH2:2][CH3:3].[ClH:11].[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(O)C>[ClH:11].[CH3:3][C:2]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:18][C:1]=1[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: NNc1ccccc1
Reactant: CCC(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Product: Cc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride is synthesized based on the method described in U.S. Pat. No. 3,468,894. A flask is charged with 3-propionylpyridine (1.004 g, 7.279 mmol), phenylhydrazine hydrochloride (1.010 g, 6.915 mmol) and ethanol (15 mL). The mixture is heated to reflux for 1 h and cooled to room temperature. To a portion of the reaction mixture (2.5 mL) is added HCl (4M in dioxane, 1 mL, 4 mmol) and the mixture is heated to reflux. After 3 h, the mixture is concentrated in vacuo. The solid is dissolved in the minimum amount of boiling methanol (17 mL) and allowed to cool slowly to room temperature. A solid precipitates and after cooling to 0° C. for 30 min, the yellow solid is filtered off, washed with portions of cold methanol and dried under high vacuum to give 3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as yellow needles. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 2.56 (s, 3H), 7.09-7.13 (m, 1H), 7.23-7.26 (m, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 8.14-8.18 (m, 1H), 8.74 (d, J=5.8 Hz, 1H), 8.83-8.85 (m, 1H), 9.08 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([O:23]CC)=[O:22])=[C:6]2[C:20]=1[C:10]1[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:13][C:9]=1[CH2:8][CH2:7]2.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([OH:23])=[O:22])=[C:6]2[C:20]=1[C:10]1[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:13][C:9]=1[CH2:8][CH2:7]2
Reactant: CCOC(=O)c1sc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CSc1sc(C(=O)O)c2c1-c1nc(-c3ccccc3)sc1CC2
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylate (2.28 g) was suspended in a mixed solvent of ethanol (15 ml) and tetrahydrofuran (25 ml); a 2 N aqueous solution of sodium hydroxide (8.8 ml) was added at 50° C. After the reaction mixture was stirred at 50° C. for 4 hours, the solution obtained was poured over water (400 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzothiazole-6-carboxylic acid (2.08 g, 98.6%), which was then recrystallized from chloroform-methanol. Light-yellow prisms. Melting point 255-256° C. (decomposed).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[CH:7]=[C:2]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:3]=1
Reactant: Cc1nc(Cl)cc(-c2cccc(F)c2F)n1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(-c2cccc(F)c2F)nc(C)n1
Temperature: 25 °C
Reaction time: 11 h
Yield: 86.4 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 401 mg of 4-chloro-2-methyl-6-(2,3-difluorophenyl)pyrimidine and 152 mg of 2-butyn-1-ol, to which 87 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 11 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 395 mg of 2-methyl-4-(2,3-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (162)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.OC(C(F)(F)F)=O.[C:43]([C:47]1[N:51]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[C:50]([C:57]2([OH:63])[CH2:62][CH2:61][CH2:60][NH:59][CH2:58]2)=[N:49][CH:48]=1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][C:11]([N:59]2[CH2:60][CH2:61][CH2:62][C:57]([C:50]3[N:51]([CH2:52][CH2:53][CH2:54][O:55][CH3:56])[C:47]([C:43]([CH3:46])([CH3:44])[CH3:45])=[CH:48][N:49]=3)([OH:63])[CH2:58]2)=[O:13])=[CH:6][CH:7]=1
Reactant: COCCCn1c(C(C)(C)C)cnc1C1(O)CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCCn1c(C(C)(C)C)cnc1C1(O)CCCN(C(=O)C[C@@H](Cc2ccc(Br)cc2)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
(R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (45 mg, 81 gmol), EDC (24 mg, 125 μmol), HOBt (17 mg, 125 μmol) and 3-(5-tert-butyl-1-(3-methoxypropyl)-1H-imidazol-2-yl)piperidin-3-ol TFA salt (133C) (34 mg, 83 μmol) were added to a 10 mL round bottomed flask. DMF (420 μL) was added and the reaction was stirred overnight at room temperature. The solvent was removed and the residue was purified by preparatory LC/MS (35-50% CH3CN in H2O) to give the product tert-butyl (2R)-1-(4-bromophenyl)-4-(3-(5-tert-butyl-1-(3-methoxypropyl)-1H-imidazol-2-yl)-3-hydroxypiperidin-1-yl)-4-oxobutan-2-ylcarbamate (133D) (29 mg, 55% yield). ESI-MS:m/z 635.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][NH:24][C:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[C:9]=2[S:31][CH3:32])=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:26]([C:25]1[O:22][C:21]([C:10]2[C:9]([S:31][CH3:32])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=2)=[N:23][N:24]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CSc1c(C(=O)NNC(=O)C(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CSc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 49.3 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(methylthio)-N′-pivaloyl-1H-pyrazole-3-carbohydrazide (9) (80 mg, 0.156 mmol) and Burgess reagent (111 mg, 0.468 mmol) in THF (5 mL) was irradiated in a microwave reactor (Biotage Initiator™) for 50 minutes at 155° C. The organic extract was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was subjected to flash column chromatography (Biotage SP1™) to obtain 38 mg (50%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C(N(CC)CC)C.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:19]
Reactant: OCc1cccc(O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Oc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
3-Hydroxybenzylalcohol (5 g, 40 mmol) and triethylamine (5.2 ml, 60 mmol) were dissolved in benzene (250 ml), and thionylchloride (5.2 ml) dissolved in benzene (50 ml) was added thereto at 0° C. The brownish reacting solution was stirred at room temperature for 6 hours. When the reaction was completed, the solution was washed with brine, and the water layer was extracted with methylene chloride. The organic extract was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to obtain the title compound (5.7 g, 99%).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([F:4])[F:3].[OH:15]OS([O-])=O.[K+]>CO.C1COCC1.O>[F:1][C:2]([F:4])([F:3])[S:5]([C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: CC(=O)c1cccc(SC(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1cccc(S(=O)C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
To a solution of 1-(3-trifluoromethylsulfanyl-phenyl)ethanone (1.4 g, 6.36 mmol) in methanol (30 ml) and THF (30 ml) a solution of oxone, monopersulfate compound (10.94 g, 17.8 mmol) in water (50 ml) was added dropwise over a period of 10 min. The reaction mixture was stirred at 60° C. for 3 days. The organic solvent was removed in vacuo and the aqueous phase was extracted with dichloromethane. Evaporation of the combined organic layers and purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane gave the desired product (0.66 g, 44%). 1-(3-Trifluoromethanesulfonyl-phenyl)ethanone (190 mg, 12%) was obtained as a side product which was used for the synthesis of example 77.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[CH2:17][CH2:16][CH:15]2[CH:7]([NH:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6]1)[CH3:4].[C:18](O)(=O)[CH3:19]>>[CH2:3]([N:5]1[CH2:17][CH2:16][CH:15]2[CH:7]([N:8]([CH2:18][CH3:19])[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:6]1)[CH3:4]
Reactant: CC(=O)O
Reactant: CCN1CCC2c3ccccc3NC2C1
Agent: [BH4-]
Agent: [Na+]
Product: CCN1CCC2c3ccccc3N(CC)C2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
NaBH4 (1.08 g) was added under ice-cooling to a solution of 2-ethyl-1,2,3,4,4a,9a-hexahydro-pyrido[3,4-b]indole (1.16 g) in 40 ml of acetic acid. After stirring the solution at room temperature for 4 hrs, additional NaBH4 (0.54 g) was added and the mixture was stirred for 3 hrs. After removal of acetic acid by evaporation, the residue was neutralized with ammonia, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. The solvent was evaporated off, thereby affording 1.26 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=O)[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([OH:16])=[CH:6]3)[CH:2]=1)=[O:12].Cl.[NH2:18][OH:19]>N1C=CC=CC=1>[OH:19][N:18]1[C:14](=[O:13])[C:7]2[CH:6]=[C:5]([OH:16])[CH:4]=[C:3]3[C:8]=2[C:9](=[CH:10][CH:1]=[CH:2]3)[C:11]1=[O:12]
Reactant: NO
Reactant: O=C1OC(=O)c2cc(O)cc3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3cc(O)cc(c23)C(=O)N1O
Yield: 130.2 %

Procedure:
3-Hydroxy-1,8-naphthalic anhydride (1.4 g, 6.7 mmol) and hydroxylamine hydrochloride (0.9 g, 12.9 mmol) were reacted in pyridine (30 mL) following the procedure of Example 1 to give 2.0 g of the title compound, mp 285≧288/C.;
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:10][C:9]1[CH:11]=[CH:12][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OCCCCCCl

Procedure:
A mixture of 59.7 g (0.36 mole) of acetovanillone, 100 g (0.539 mole) of 1-bromo-5-chloropentane and 138 g (1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an oil which crystallized in petroleum ether (30°-60° C.). The solid was collected by filtration, washed with petroleum ether and dried to yield 81.4 g (84%) of fluffy, white solid. The solid was recrystallized from isopropyl ether, m.p. 57°-58° C.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][S:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4]1.P(Br)(Br)[Br:15].C([O-])(O)=O.[Na+]>CCOCC>[Br:15][CH2:2][CH:3]1[CH2:7][S:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4]1
Reactant: BrP(Br)Br
Reactant: OCC1CSC(c2ccccc2)S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: BrCC1CSC(c2ccccc2)S1
Temperature: 0 °C
Yield: 99 %

Procedure:
4-Hydroxymethyl 2-phenyl 1,3-dithiolane (30 g., 0.14 mole) was suspended in 150 ml of ether and cooled to 0°C. Phosphorus tribromide (15 g., 0.053 mole) were added over a 1.5 hour period and the mixture was stirred at ambient temperature with 5% aqueous NaHCO3 until neutral (ph = 7). After drying over MgSO4 the solvent was removed under vacuum to yield 38 g. (99%) of desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]#[N:11])[C:5]=1[Cl:12].[C:14](O)(=[O:16])C>[Pd].CO.C(O)=O.C(OC(=O)C)(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][NH:11][CH:14]=[O:16])[C:5]=1[Cl:12]
Reactant: COC(=O)c1ccnc(C#N)c1Cl
Reactant: CC(=O)O
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COC(=O)c1ccnc(CNC=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-chloro-2-cyano-isonicotinic acid methyl ester (2.9 g, 14.8 mmol) and 10% palladium on charcoal (293 mg) in acetic acid (65 mL) was degassed and backfilled with hydrogen three times. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen (1 bar) for 18 hours and then filtered. The filtrate was concentrated under reduced pressure to give a residue which was dissolved in methanol and loaded onto a 50 g Isolute® SCX-2 cartridge, eluted with methanol followed by a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated under reduced pressure to give a residue. The residue was dissolved in a mixture of formic acid (40 mL) and acetic anhydride (8 mL), which was stirred at room temperature for 30 minutes. The solvents were removed under reduced pressure to give a residue which was dissolved in dichloromethane. The resulting solution was washed with a saturated solution of sodium hydrogen carbonate, the aqueous layer was separated and extracted twice with dichloromethane. The combined organic extracts were passed through a phase separator and concentrated under reduced pressure to give a residue that was subjected to column chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane). The title compound was obtained as a white solid (1.5 g, 44%). LCMS (method B): RT=2.15 min, [M+H]+=229.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:27][CH2:26][C@:5]2([N:9]=[C:8]([C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH:13]=[CH:12][N:11]=3)[CH2:7][CH2:6]2)[C:4]1=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:2][N:3]1[CH2:27][CH2:26][C@:5]2([NH:9][C@@H:8]([C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)[CH:13]=[CH:12][N:11]=3)[CH2:7][CH2:6]2)[C:4]1=[O:28]
Reactant: CN1CC[C@@]2(CCC(c3nccc(-c4ccc(C(F)(F)F)cc4)n3)=N2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC[C@@]2(CC[C@H](c3nccc(-c4ccc(C(F)(F)F)cc4)n3)N2)C1=O
Temperature: 25 °C
Yield: 21.5 %

Procedure:
Concentrated aq. HCl (71.99 μL, 0.84 mmol) was added to a solution of (5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 9) (314 mg, 0.84 mmol) in DCM (10 mL) at 0° C. Sodium triacetoxyborohydride (533.3 mg, 2.52 mmol) was added in a single portion and the resulting mixture was stirred allowing warming to room temperature. After 90 minutes the reaction was quenched by the addition of sat. aq. Na2CO3 and the resultant mixture was filtered. The phases were separated, the organic layer was dried (Na2SO4) and the solvent was evaporated to afford a brown oil. This was purified using a Biotage SP4 with a 25 g SNAP cartridge, eluting with 0 to 20% MeOH in EtOAc. This gave two products; the first to elute: (2R,5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one (68 mg, 0.1807 mmol, 21.5% yield) was obtained as a yellow oil.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[C:37](Cl)=[O:38])=[CH:28][CH:27]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:37]([C:33]1[N:34]=[CH:35][O:36][C:32]=1[C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1)=[O:38])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ncoc1-c1ccc(F)cc1
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncoc2-c2ccc(F)cc2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 5-(4-fluoro-phenyl)-oxazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 16 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.21. LC-MS-conditions 02: tR=1.07 min, [M+H]+=472.48.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:30]4[C:25]([O:24][CH3:23])=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Product: COc1ncccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Yield: 21.3 %

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester (338.7 mg, 0.9 mmol) and 2-methoxy-3-pyridineboronic acid [163105-90-6] (169.4 mg, 1.1 mmol) to afford 76.0 mg of yellow powder as a free base, mp. 131-132° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.06 Hz, 6 H) 3.47-3.56 (m, 4 H) 3.71-3.80 (m, 4 H) 4.00 (s, 3 H) 4.82 (spt, J=6.23 Hz, 1 H) 6.81 (d, J=8.08 Hz, 1 H) 7.08 (dd, J=7.45, 4.93 Hz, 1 H) 7.98 (dd, J=4.93, 1.89 Hz, 1 H) 8.51 (s, 1 H) 8.76 (d, J=7.83 Hz, 1 H) 8.82 (dd, J=7.58, 2.02 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 21.95, 42.85, 44.06, 53.10, 68.16, 97.21, 98.90, 116.40, 117.17, 134.55, 136.43, 141.99, 144.65, 144.71, 154.26, 155.46, 158.89. LRMS (ESI) m/z 397.1 [(M+H)]+, calc'd for C20H24N6O3: 396.45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:27][NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30].C(O)(=O)C.O>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][C:12]([C:14]3[CH:21]=[CH:20][C:17](/[CH:18]=[N:27]/[NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])=[C:16]([CH3:22])[CH:15]=3)=[N:11][CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NNC(=O)NCC(F)(F)F
Reactant: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/NC(=O)NCC(F)(F)F
Temperature: 70 °C
Yield: 73 %

Procedure:
A mixture of 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]-2-methyl-benzaldehyde (i.e. the product of Step 5, 200 mg), 1-amino-3-(2,2,2-trifluoroethyl)urea (145 mg) and acetic acid (0.1 mL) in EtOH (5 mL) was heated at 70° C. for 4 h. Water was added, the reaction cooled to room temperature and the solid was collected by filtration. Recrystallization from diisopropylether yielded the title compound (198 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>C(O)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([N:1]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc(O)c1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1cccc(O)c1
Temperature: 25 °C
Yield: 24.4 %

Procedure:
A 54.57 gram portion of m-aminophenol (0.50 mole) and 1000 milliliters of acetic acid were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was maintained at 25° C., then 49.03 grams of maleic anhydride (0.50 mole) dissolved in 100 milliliters of acetic acid was added to the reactor and heating to 115° C. commenced. The 115° C. reaction temperature was maintained for 18 hours (64,800 s), then the product was dried under vacuum by rotary evaporation at 120° C. for 30 minutes (1800 s) to a dark brown solid. The crude product was extracted with two 250 milliliter portions of o-dichlorobenzene at 120° C. The combined extracts were maintained at 2° C. for 24 hours (86,400 s) then the light yellow orange colored crystalline product was recovered by filtration and dried under vacuum at 60° C. for 24 hours (86,400 s) to provide 23.1 grams of N-(3-hydroxyphenyl)maleimide. Infrared spectrophotometric analysis of a film sample, nuclear magnetic resonance spectroscopy and mass spectroscopy (m/Z=214) all confirmed the product structure.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]([O:29][CH3:30])=[O:28].N1C=CC=CC=1.C(OC)(C)(C)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:5])=[O:4]
Reactant: COC(=O)c1c(O)ccc2ccccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoromethanesulfonic anhydride (492 g, 1.74 mol, 1.1 eq) in dichloromethane (0.5 L) was added over 1.5 hours to a suspension of methyl 2-hydroxy-1-naphthoate (319 g, 1.58 mol) and pyridine (330 ml, 4.08 mol, 2.6 eq) in dichloromethane (1.7 L) maintained at an internal temperature between −70 and −50° C., under nitrogen. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 hours, after which time all solids had dissolved. Methyl tert-butyl ether (MTBE, 2.5 L) was added, causing precipitation. The solids were removed by filtration and washed with MTBE (0.5 L). The MTBE solutions were combined and washed with 2 N HCl(aq) (0.3 L then 0.2 L), water (2×2.5 L) and brine (2 L). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in toluene (2.5 L) and washed with 1 N NaOH (aq) (0.5 L), water (2.5 L) and brine (1 L). The toluene solution was dried (MgSO4), filtered and concentrated under reduced pressure. Initially a slightly brown oil, the product crystallised on standing. Yield 438.5 g, 83%