Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:7]3[C:18](=[O:20])[NH:19][C:5]([C:6]=23)=[CH:4][CH:3]=1.[C:21]([O:29][CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[C:32]=1B(O)O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:21]([O:29][CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[C:32]=1[C:2]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:7]3[C:18](=[O:20])[NH:19][C:5]([C:6]=23)=[CH:4][CH:3]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccn1)CO3
Reactant: Cc1noc(COC(=O)c2ccccc2)c1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1noc(COC(=O)c2ccccc2)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
A solution of 7-bromo-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (687 mg, 2.07 mmol) and {5-[(benzoyloxy)methyl]-3-methylisoxazol-4-yl}boronic acid (1.08 g, 4.14 mmol) in 1,4-dioxane (15.7 mL) and water (4 mL) was degassed with nitrogen. The reaction mixture was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (253 mg, 0.310 mmol), degassed with nitrogen, and heated in a sealed tube at 80° C. for 30 min, at which time the reaction mixture was treated with {5-[(benzoyloxy)methyl]-3-methylisoxazol-4-yl}boronic acid (1.08 g, 4.14 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (10 mg, 12.2 mol), degassed with nitrogen and heated at 80° C. for a further 30 min. The reaction mixture was then diluted with ethyl acetate and water. The organic layer was separated and washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (30% ethyl acetate/hexanes to 100% ethyl acetate [the ethyl acetate contained 5% methanol]) gave the desired product (0.589 g, 58%) as a racemic mixture. LCMS calculated for C26H21N4O5 (M+H)+: m/z=469.1. found: 469.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]1(O)[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.FC(F)(F)C(O)=[O:26].C(=O)([O-])[O-].[K+].[K+].I([O-])(=O)(=O)=O.[Na+]>[Cl-].O.CO>[O:26]=[S:11]1[CH2:12][CH:13]=[C:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:15][C:16](=[O:22])[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1
Reactant: CC(C)COC(=O)Nc1ccc(C2(O)CCSCC2)c(F)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)COC(=O)Nc1ccc(C2=CCS(=O)CC2)c(F)c1
Reaction time: 1 h

Procedure:
To a slurry of 2-methylpropyl [3-fluoro-4-(tetrahydro-4-hydroxy-2H-thiopyran-4-yl)phenyl]carbamate (IV, EXAMPLE 2, 64.63 g, 197.4 mmol, 90.1 wt %) in methylere chloride (194 ml) at 22° is added trifluoroacetic acid (28.0 ml, 363.5 mmol, 1.84 eq) yielding a mixture at 17° which is warmed and stirred at 35-37° for 1 hr. The mixture is cooled to 15° and a mixture of potassium carbonate (40.3 g, 292 mmol, 1.48 eq) in water (174 ml) added over 5-10 min, to control foaming, while maintaining the temperature at 15-20°. The phases are separated and the organic washed with water (100 ml). Both aqueous are serial back extracted with methylene chloride (100 ml). Methanol (500 ml) is added to the combined organic phases and the mixture concentrated under reduced pressure to give a slurry. Methanol (970 ml) is added. A mixture of sodium periodate (49.90 g, 233.3 mmol, 1.18 eq) in water (490 ml) is then added over 39 min while maintaining 23°. The slurry is stirred at 23° for 17 hr then warmed to 50° over 1 hr and stirred at 50° for 1.5 hr. The is cooled to 23° and water (733 ml) added. The slurry is cooled to −1° and the product collected by vacuum filtration, washed with water (720 ml) and dried to give the title compound, mp=212-214°; TLC Rf=0.43 (methanol/methylene chloride, 5/95); HPLC (method A) RT=3.58 min; NMR (DMSO-d6, 400 MHz) d 9.88, 7.39,7.29-7.21, 5.78, 3.89, 3.65, 3.39-2.51, 1.93 and 0.94; CMR (DMSO-d6, 100 MHz) d 159.0, 153.4, 140.1, 133.0, 129.3, 122.7, 117.7, 113.8, 105.1, 70.3, 46.2, 42.7, 27.4, 20.7 and 18.8; MS (CI, NH3) m/z (relative intensity) 345 (2.9), 344 (7.9), 343 (51), 328 (13), 327 (53) and 326 (100).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].[Na+].[Cl-]>O.C(OCC)(=O)C.CN(C)C=O>[NH:18]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:10][CH:11]=2)=[N:17][N:20]=[N:19]1
Reactant: N#CCc1ccc(OCC2CCCCC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cc(OCC2CCCCC2)ccc1Cc1nnn[nH]1
Temperature: 135 °C
Yield: 59 %

Procedure:
A mixture of 4-(cyclohexylmethoxy)phenylacetonitrile (15 g, prepared in the preceding paragraph), sodium azide (21.3 g), ammonium chloride (17.4 g) and dimethylformamide (325 mL) was heated to 135° C. under a nitrogen atmosphere for 40 hours. The mixture was then cooled to room temperature and enough water was added to dissolve all the salts. The homogeneous solution was then poured into a separatory funnel containing saturated aqueous NaCl and ethyl acetate. After extraction of the aqueous phase with additional ethyl acetate, the combined extracts were washed with saturated brine solution, dried over MgSO4 and concentrated. The dark amber oil so obtained was treated with a little water and the resulting solid filtered off and crystallized from dichloromethane-diethyl ether mixture to afford 10.5 g (59% yield) of the title compound; m.p. 156°-158° C.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[CH3:28][S:29]([NH:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:31])=[O:30]>>[OH:16][C@@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:17]=[C:2]([C:36]2[CH:35]=[CH:34][C:33]([NH:32][S:29]([CH3:28])(=[O:30])=[O:31])=[CH:38][CH:37]=2)[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]=1[C:18]([F:21])([F:20])[F:19]
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: CS(=O)(=O)Nc1ccc(-c2cc(C(=O)N[C@@H]3CCCC[C@H]3O)c(C(F)(F)F)nc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-methanesulfonylaminophenylboronic acid as starting materials, MS (ISP) 556.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>ClCCl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(Br)c1
Solvent: ClCCl
Product: ClCc1cncc(Br)c1

Procedure:
To a cooled (0° C.) solution of (5-bromopyridin-3-yl)methanol (38.8 g, 0.206 mol) in dichloromethane (0.6 L) was added a solution of thionyl chloride (149 mL, 2.05 mol) in dichloromethane (200 mL). The resulting mixture was stirred at reflux overnight. The reaction was then concentrated under reduced pressure, and the resulting residue was recrystallized from diethyl ether to provide the title compound: LCMS m/z 206 [M+H]+; 1H NMR (300 MHz, d6-DMSO) δ 12.66 (s, 1H), 8.69-8.74 (m, 2H), 8.25 (s, 1H), 4.83 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[N+:8]([C:7]1[CH:2]=[N:3][CH:4]=[CH:5][C:6]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1Nc1ccccc1
Yield: 92.9 %

Procedure:
To a mixture of 2-chloro-3-nitropyridine (15.8 g, 100 mmol) and aniline (11.1 g, 120 mmol) in dioxane (150 mL) was added was added K2CO3 (39 g, 120 mmol). The reaction was heated to reflux for 10 h and then purified by silica gel chromatography using petroleum etherethyl acetate to provide the product as a yellow solid (20 g, 93%).
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([CH3:38])[C:30]=1[S:31]([CH2:34][N+:35]([O-:37])=[O:36])(=[O:33])=[O:32])[NH2:27].Cl>O1CCCC1.O>[CH3:38][C:29]1[CH:28]=[C:26]([NH:27][S:19]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:25]=[C:24]([CH3:23])[C:30]=1[S:31]([CH2:34][N+:35]([O-:37])=[O:36])(=[O:33])=[O:32]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.7 %

Procedure:
1.31 ml (16.2 mmol) of pyridine, dried over potassium hydroxide, and 2.5 g (9.82 mmol) of 4-(methylsulphonyl)benzenesulphonyl chloride are successively added to a solution, maintained under a nitrogen atmosphere, of 1.6 g (6.55 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 50 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 2 days at room temperature and then poured into 200 ml of water. The mixture obtained is brought to pH 3 by addition of 1N hydrochloric acid and is then extracted with 3 times 200 ml of ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: 2/1 methylene chloride/ethyl acetate) and recrystallization from a mixture of hexane and ethyl acetate, to give 0.78 g (26%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-(methylsulphonyl)benzenesulphonamide.
Reaction SMILES: [N:1]1([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.[ClH:21].C(OCC)(=O)C>>[ClH:21].[ClH:21].[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:4]1[CH2:5][CH2:6][N:1]([CH2:13][C:14]([OH:16])=[O:15])[CH2:2][CH2:3]1)[CH3:12]
Reactant: CCOC(=O)CN1CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4.8 g of tert-butyl ethyl 2,2′-piperazine-1,4-diyldiacetate was added 20 mL of a 4M hydrogen chloride/ethyl acetate solution, followed by stirring for 2 hours at room temperature. The generated insoluble material was collected by filtration, thereby obtaining 4.0 g of [4-(2-ethoxy-2-oxoethyl)piperazin-1-yl]acetic acid dihydrochloride.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:19]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:22]=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1>O>[CH2:1]([NH:8][C:10]1[N:19]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:22]=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Reactant: NCc1ccccc1
Solvent: O
Product: Fc1ccccc1-c1cn2c(NCc3ccccc3)nc3c(c2n1)CCCC3
Temperature: 100 °C

Procedure:
To 5 mL of benzylamine was added 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (150 mg) and the resulting mixture heated at 100° C. for 20 min. After 10 mL of water was added to the mixture, it was cooled and the solid that precipitated was collected. The solid was recrystallized from ethanol/water to yield 5-(N-Benzylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 31), m.p. 144°-145° C.
Reaction SMILES: [CH3:1][C:2](=O)[C:3]#[C:4][CH2:5][CH3:6].[C:8]([CH2:10][C:11]([NH2:13])=[O:12])#[N:9].C(O)(=O)C.N1CCCCC1.N1CCCCC1>C(O)C.O.C(O)(=O)C>[CH2:5]([C:4]1[C:10]([C:8]#[N:9])=[C:11]([OH:12])[N:13]=[C:2]([CH3:1])[CH:3]=1)[CH3:6]
Reactant: N#CCC(N)=O
Reactant: CCC#CC(C)=O
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCc1cc(C)nc(O)c1C#N
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a solution of hex-3-yn-2-one (1.5 g, 15.6 mmol) in 90% ethanol (30 mL), cyanoacetamide (1.58 g, 18.72 mmol) and piperidine acetate {prepared by the addition of piperidine to a solution of acetic acid (0.258 mL) in water (0.65 mL) till pH 8} were added and reaction heated at 90° C. for 12 h. On completion, ethanol was evaporated and water was added to residue. Solid obtained was filtered and washed with water. Then this solid was stirred with acetonitrile for 10 min and filtered again to obtain the desired intermediate (1.5 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:22][OH:23])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH2:32][CH3:33].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:22][O:23][CH2:31][CH2:32][CH3:33])[CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(=NO)c1ncc(Cl)cc1Cl
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
To 265 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]phthalimide in 2 ml of N,N-dimethylformamide, 310 mg of potassium carbonate and 387 mg of 1-iodopropane were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 30 ml of water and extracted with ethyl acetate (50 ml×1), the resulting organic layer was washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 15:85 to 25:75) as the eluent to obtain 235 mg of the desired product as a yellow resinous substance.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:5][C@:4]1([NH:18]C(=O)OC(C)(C)C)[C:6](=[O:17])[NH:7][S:8]([C:11]1([CH2:14][O:15][CH3:16])[CH2:13][CH2:12]1)(=[O:10])=[O:9])=[CH2:2].[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:18][C@:4]1([C:6]([NH:7][S:8]([C:11]2([CH2:14][O:15][CH3:16])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[O:17])[CH2:5][C@H:3]1[CH:1]=[CH2:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1(COC)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1(COC)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of the product of Step 1 (120 mg) in DCM (1 mL) at 0° C. was added TFA (1 mL). The mixture was slowly warmed to room temperature and stirred for 3 hours. The solvent was removed in vacuo and the crude product was used in the next step. 1H NMR (400 MHz, CDCl3): δ (ppm) 5.82 (ddd, 1H), 5.44 (d, 1H), 5.43 (d, 1H), 3.67 (d, 1H), 3.63 (d, 1H), 3.35 (s, 3H), 2.64 (dt, 1H), 1.92 (dd, 1H), 1.83 (dd, 1H), 1.76-1.70 (m, 1H), 1.67-1.60 (m, 1H), 1.14-1.02 (m, 2H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)=[CH:23][CH:24]=1)#[N:29]
Reactant: NN
Reactant: N#Cc1ccc(CCC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 90 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(4-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (270 mg, 0.69 mmol, prepared in Synthetic Example 8) in DMF (5 ml) was added hydrazine monohydrate (80%, 102 μl, 2.55 mmol, 3.7 eq.), and the mixture was treated in the same manner as in Example 9 to give 3-[2-(4-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (243 mg, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C:17](=[O:21])[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[Cl:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C@@H:17]([OH:21])[C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CC(=O)C(=O)O)cc(Cl)c1OCc1ccccc1
Agent: Cl
Product: Cc1cc(C[C@@H](O)C(=O)O)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-2-hydroxy-propionic acid was prepared analogously to Example 7d from 15.5 g (48.6 mmol) 3-(4-benzyloxy-3-chloro-5-methyl-phenyl)-2-oxo-propionic acid and 27.6 g (86.1 mmol) (1R)-B-chlorodiisopinocampheylborane. The crude product was combined with 150 mL methanolic HCl (1.25 M) and stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue was combined with 70 mL 15% K2CO3 solution and extracted twice with 50 mL EtOAc. The combined organic extracts were dried, filtered and evaporated down i.vac.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([OH:20])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([NH:22][CH2:23][C:24]([OH:26])([CH3:27])[CH3:25])=[O:20])[CH2:15][CH2:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(O)CNC(=O)C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Yield: 102.1 %

Procedure:
A solution of [4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetic acid (Example 44, 0.300 g, 1.03 mmol), 1-amino-2-methylpropan-2-ol (0.111 g, 1.24 mmol), EDCI (0.238 g, 1.24 mmol) and HOBt (0.168 g, 1.24 mmol) in acetonitrile (5 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-N-(2-hydroxy-2-methylpropyl)-2-oxoacetamide (0.380 g, quant) as a white amorphous.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([O:27]C)=[O:26])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO>Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=3)[O:23][CH2:24][C:25]([OH:27])=[O:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.08 h
Yield: 79.2 %

Procedure:
A mixture of methyl 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate (2.25 g, 5.5 mmol), 3N sodium hydroxide solution (5.5 mL) and methanol (50 mL) was heated to reflux on a steam bath. After 5 minutes, the mixture was cooled, the methanol evaporated and the residue diluted with water. Warming provided a solution which was diluted with 1N hydrochloric acid solution to pH 3 to give an oily precipitate. The mixture was extracted with CH2Cl2 and the organic extracts washed twice with water and once with saturated sodium chloride solution. Concentration, after drying over sodium sulfate, left a pale yellow solid which was recrystallized twice from a mixture of hexanes and CH2Cl2 (2:1) to give 2-[3-[2-(4,5-diphenyl-2-oxazolyl)-ethyl]phenoxy]acetic acid (1.74 g, 80%), m.p. 153.3°-154.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([F:9])=[CH:4][N:3]=1.[H-].[Na+].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:14]=1[C:15](Cl)=[O:16].O>CN(C)C=O>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:14]=1[C:15]([NH:8][C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)=[O:16]
Reactant: Nc1cc(Cl)ncc1F
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Cl)ncc1F)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a solution of 2-chloro-5-fluoropyridin-4-amine (200 mg, 1.36 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium hydride (65.5 mg, 2.73 mmol) in one portion at room temperature under N2. The reaction mixture was then stirred for 15 min and then a solution of 2,4,6-trichlorobenzoyl chloride (320 uL, 2.0 mmol) in N,N-dimethylforamide (400 uL) was added dropwise. The mixture was stirred at room temperature for 10 mins, and then poured into water (30 mL). The mixture was extracted with ethyl acetate (2×50 mL), and combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-5% methanol/dichloromethane) to give 2,4,6-trichloro-N-(2-chloro-5-fluoropyridin-4-yl)benzamide (260 mg, yield: 54%). 1H NMR (DMSO-d6, 400 MHz): δ 11.52 (s, 1H), 8.49 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.84 (s, 2H). LCMS (ESI) m/z: 354.9 [M+H+].