Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=2[CH3:17])[C:4](=[O:18])[NH:3]1.[OH-].[K+]>CO.O>[CH3:1][C:2]1([CH3:19])[CH2:6][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[CH3:17])[C:4](=[O:18])[NH:3]1
Reactant: COC(=O)c1ccc(N2CC(C)(C)NC2=O)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1N1CC(C)(C)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.70 g (10.3 mmol) methyl 4-(4,4-dimethyl-2-oxo-imidazolidin-1-yl)-3-methyl-benzoate are suspended in 75 ml of methanol and combined with a solution of 1.68 g (30.0 mmol) potassium hydroxide in 10 ml of water. It is stirred for 3 hours at ambient temperature and then evaporated down i. vac. The aqueous residue is diluted with water, acidified with 1-molar hydrochloric acid and the precipitate obtained is suction filtered, washed with water and dried.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[C:4]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[Na+:12].[CH2:13]([CH:25]1[CH2:30][C:29](=[O:31])[N:28]([CH2:32][C:33](Cl)=[O:34])[C:26]1=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C(C)=CC=CC=1>[CH2:13]([CH:25]1[CH2:30][C:29](=[O:31])[N:28]([CH2:32][C:33]([O:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:8]([O-:11])(=[O:9])=[O:10])=[O:34])[C:26]1=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Na+:12]
Reactant: O=S(=O)([O-])c1ccccc1O
Reactant: CCCCCCCCCCCCC1CC(=O)N(CC(=O)Cl)C1=O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCC1CC(=O)N(CC(=O)Oc2ccccc2S(=O)(=O)[O-])C1=O

Procedure:
78.5 g (400 mmol) of anhydrous sodium phenolsulfonate and 137.4 g (400 mmol) of ω-(2-dodecylsuccinimido)-acetyl chloride are reacted in 200 g of xylene at 140° C. for 25 hours and the mixture is worked up as described in Example 1. The product is recrystallized from 90% strength ethanol and then dried at 40° C. under a water pump vacuum.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][O:12][C:11](=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.F[C:19](F)(F)C1C=CC(B(O)O)=CC=1.O1CCC=CC1=O.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.IC>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:19][CH:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=2)[CH2:14][CH2:13][O:12][C:11]1=[O:15]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1CC(c2ccc(C(F)(F)F)cc2)CCO1
Agent: CC(C)[N-]C(C)C
Agent: O=C1C=CCCO1
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: CC1C(=O)OCCC1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
4-(4-Trifluoromethylphenyl)tetrahydropyran-2-one (995 mg) derived by the same method as in Preparation Example 2-10 from 4-(trifluoromethyl)phenylboronic acid (5.29 g) and 5,6-dihydro-2H-pyran-2-one was dissolved in tetrahydrofuran (10 mL). The solution was added dropwise at −78° C. to a lithium diisopropylamide solution previously prepared from n-butyllithium (3.91 mL) and diisopropylamine (1.46 mL) in tetrahydrofuran (30 mL). After stirring at the same temperature for 30 minutes, iodomethane (760 μL) and hexamethylphosphoramide (1.77 mL) were added and stirring was continued. After stirring for 30 minutes, the reaction solution was gradually heated to room temperature over three hours and 20 minutes. The reaction was terminated with saturated ammonium chloride aqueous solution. The organic layer was washed with brine and then dried over magnesium sulfate. Removal under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 50%) to obtain the title compound (500 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([O:11][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=2)[C:3]1=[O:14]
Reactant: CC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1Cc2cc(OCc3ccccc3)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred mixture of 2-methyl-5-hydroxy-6,7-dichloro-1-indanone (27.6 g., 0.12 mole), potassium carbonate (24.9 g., 0.18 mole) and benzyl bromide (21.4 ml., 0.18 mole) in dimethylformamide (100 ml.) is warmed at 55°-60° C. for 2 hrs., then poured into water (1 l.) to precipitate 35.5 g. of 2-methyl-5-benzyloxy-6,7-dichloro-1-indanone which melts at 153°-155° C. after crystallization from benzene:hexane, 3:2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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]>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: Oc1cccc(Br)c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Oc1cccc(-c2cccnc2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
3-Bromophenol (500 mg, 2.86 mmol) and pyridin-3-ylboronic acid (422 mg, 3.76 mmol) were dissolved in dimethoxyethane/water=5 mL/2.5 mL. Pd(dppf)Cl2 (118 mg, 0.14 mmol) and sodium carbonate (919 mg, 8.67 mmol) were added thereto, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (hexane:ethyl acetate=9:1) to obtain 3-(pyridin-3-yl)phenol (386 mg, 78%).
Reaction SMILES: [C:1]([C@@H:5]1[O:9][C:8](=[O:10])[C@H:7]([CH3:11])[O:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][C@:7]1([CH3:11])[O:6][C@@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][C:8]1=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H]1O[C@H](C(C)(C)C)OC1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[C@H]1OC(=O)[C@](C)(Br)O1
Yield: 98 %

Procedure:
In 500 ml of carbon tetrachloride, 48.0 g of the (2S,5S)-2-tert-butyl-5-methyl-1,3-dioxolan-4-one obtained in Step 1 was dissolved. To the resulting solution, 54.0 g of N-bromosuccinimide and 1.0 ml of benzoyl peroxide were added, and the solution was refluxed for 2 hours. After the reaction solution was left to have cooled, insolubles were separated by filtration and the filtrate was successively washed with an aqueous 10% sodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated brine. From the filtrate thus washed, the carbon tetrachloride was evaporated under reduced pressure, and the resulting residue was recrystallized from hexane to obtain 70.5 g of (2S,5S)-5-bromo-2-tert-butyl-5-methyl-1,3-dioxolan-4-one.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]1=[O:20])C.[OH-].[Na+]>CO>[O:20]=[C:12]1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:21])=[O:3])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13]1
Reactant: CCOC(=O)CCCCCCn1c(=O)oc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCn1c(=O)oc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
18.4 g. of 7-(2-Oxobenzoxazolin-3-yl)-enanthic acid ethyl ester are dissolved in 60 cc. of methanol. 2.52 g. of sodium hydroxide are dissolved in methanol and added to the above solution. The mixture is stirred at room temperature for 24 hours, the solvent is distilled off and the residue is dissolved in water. The aqueous solution is shaken several times with chloroform, the chloroform solution is discarded. The aqueous phase is acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform solution is washed with water and dried over Na2SO4. The solvent is distilled off and the residue is purified chromatographically on silicic acid gel using hexane/ethylacetate as eluant.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.[OH-].[Na+]>C1COCC1>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(F)cc4)nc3cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol), diisopropylethylamine (0.36 ml, 2.01 mmol) in THF (0.8 ml), 4-fluorobenzoyl chloride (114 μL, 0.97 mmol) was slowly added at rt. The mixture was stirred overnight at rt. Aqueous NaOH (2 mL, 1M) was added and the solvent was evaporated. Water (25 ml) was added and the mixture was extracted three times with ethyl acetate (3×25 ml). The combined organic layers were washed with brine, dried and evaporated to afford a residue which precipitated after addition of methanol. The precipitate was suspended in MeOH/CH3CN (1:1, 6 mL) and refluxed for 2 hours in aqueous KOH (0.50 mL, 5M). After evaporation of the solvent and addition of water, a white solid was isolated and dried under high vacuum. The title compound was obtained (77 mg).
Reaction SMILES: Cl.[O:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1>C(OCC)C>[O:27]=[C:25]1[NH:24][C:23]2[CH:28]=[CH:29][C:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([O:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:14][CH2:13]3)=[CH:21][C:22]=2[O:26]1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(O)CN1CCC(Oc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Product: O=C(CN1CCC(Oc2ccccc2)CC1)Nc1ccc2[nH]c(=O)oc2c1

Procedure:
The title compound is prepared from (4-phenoxy-piperidin-1-yl)-acetic acid hydrochloride and 6-amino-3H-benzoxazol-2-one according to the method described in Example 161c. Melting Point: 193-195° C. (diethylether)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]2[C@H:27]([CH2:28][CH3:29])[CH2:26][O:25][C@H:24]([C:30]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:23]2)[CH:15]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:14]2[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]3[C@H:27]([CH2:28][CH3:29])[CH2:26][O:25][C@H:24]([C:30]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:23]3)[CH:15]=2)=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1c1cc(Cl)nc(NC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(NC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(4-Cyano-3-fluorophenyl)boronic acid (0.266 g, 1.61 mmol) was added to a 20 mL microwave vessel followed by the addition of Pd(PPh3)4 (0.047 g, 0.040 mmol) and (2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-ethyl-N-(phenylmethyl)-2-morpholinecarboxamide (0.314 g, 0.805 mmol) dissolved in 1,4-dioxane (5 mL). Saturated aqueous NaHCO3 (2.5 mL) was added and the reaction was irradiated at 130° C. for 30 minutes. SiliaBond® Thiol (3.10 g, 4.03 mmol) was added to the reaction and it was stirred at room temperature for 2 hours and then filtered. The filtrate was then diluted with H2O and extracted with EtOAc (×2). The organics were dried and concentrated to afford the title compound (0.365 g) as a dark brown oil. LC-MS (ES) m/z=475 [M+H]+.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[ClH:1].[CH2:10]1[C:11]2[C:16](=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)[CH2:17][NH:9]1
Reactant: COC(=O)c1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CNC2
Yield: 84 %

Procedure:
10% Pd/C (4.3 g) was added to a solution of methyl 2-benzylisoindoline-5-carboxylate hydrochloride (43 g; 1 equiv.) in 800 ml of methanol. The mixture was hydrogenated for 90 minutes at 60 mm hydrogen. When the conversion was complete, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the crude product was recrystallised from chloroform. In this manner the desired product (25.39 g; 84%) was obtained in the form of a white solid having a purity of 98.63%.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[N:16]/[NH:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[N:16]/[NH:17][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CN/N=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C=N/NCC(=O)O)cc1OC1CCCC1
Yield: 70.77 %

Procedure:
A reaction as in Example 6 was carried out using 0.80 g (3.63 mmole) of compound prepared in Reference Example 1 and 0.63 g of ethylhydrazinoacetate as starting materials to obtain 0.98 g of white ethyl (E)-2-[3-cyclopentyloxy-4-methoxyphenylmethylene]hydrazinoacetate. The prepared ester compound was hydrolysed in the mixture of methanol and 1.0 N aqueous sodium hydroxide solution to afford 0.75 g (70.77%) of white title solid. m.p. 165° C. (decomposed) 1H NMR(DMSO-d6): 1.59(2H, m) 1.71(4H, m) 1.87(2H, m) 3.74(3H, s) 3.83(2H, brs) 4.77(1H,m) 6.90(1H, d J=8.5 Hz) 6.96(1H, dd, J=8.3, 1.7 Hz) 7.09(1H, d J=1.7 Hz) 7.57(1H, s)
Reaction SMILES: [CH2:1]([O:3][PH:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[CH2:1]([O:3][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5])[CH3:2]
Reactant: BrCC1CCCCC1
Reactant: CCOC(OCC)[PH](=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)P(=O)(CC1CCCCC1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon, a solution of 221 g of diethoxymethylphosphinic acid ethyl ester in 1000 ml of tetrahydrofuran is added dropwise in the course of 3 hours to a suspension of 26.4 g of 99% sodium hydride in 1500 ml of tetrahydrofuran, the temperature being maintained at 200°-25°. The reaction is exothermic and is associated with the evolution of gas. The mixture is stirred for 2 hours at room temperature and then 177.1 g of bromomethylcyclohexane are added in the course of 20 minutes; the mixture is stirred at reflux for 24 hours, then cooled to 0°, and 200 ml of water are carefully added. The solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and water. The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation under reduced pressure. The oil that remains behind is distilled under reduced pressure and yields diethoxymethyl(cyclohexylmethyl)phosphinic acid ethyl ester having a boiling point of 85° (6×10-4 bar).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:21])=[O:20].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=O)[CH:27]=[CH:28][CH:29]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:31]([CH2:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=3)=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5]1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.2 %

Procedure:
Part C: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 204-205° C., Mass Spec: 477(M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=O)[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O(Cl)Cl.[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[N:12][CH2:11][CH2:10]2
Reactant: COc1ccc(CCNC(=O)CCc2ccc(Cl)cc2)cc1C
Agent: ClOCl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1cc2c(cc1C)CCN=C2CCc1ccc(Cl)cc1
Yield: 52.3 %

Procedure:
Heat a mixture of the amide from step A (10.0 g), phosphorous pentoxide (25 g), phosphorour oxychloride (15 mL) and xylene (250 mL) at reflux for 2 h. Cool the reaction mixture, slowly add water (500 mL), basify using NaOH and extract with benzene. Concentrate the benzene extract to a residue and triturate with diethyl ether to give 6-methyl-7-methoxy-1-[2-(4-chlorophenyl)ethyl]-3,4-dihydroisoquinoline (4.95 g), mp=122°-124° C.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]2[C@@H:29]([CH3:30])[C@@H:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][C:26]2=[O:37])[C:9]([O:12]C)=[CH:10][CH:11]=1)C>Br.C(O)(=O)C>[OH:12][C:9]1[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]2[C@@H:29]([CH3:30])[C@@H:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][C:26]2=[O:37])=[CH:7][C:6]([CH2:5][C:4]([OH:38])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Agent: Br
Solvent: CC(=O)O
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O

Procedure:
A solution of [6-methoxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.740 g, 1.41 mmol) in hydrogen bromide (3 mL) and acetic acid (3 mL) was stirred at 100° C. overnight. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:27][CH2:28][CH:29]([C:32]6[NH:39][N:38]=[N:37][N:33]=6)[CH2:30][CH2:31]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: N#CC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCC(c7nnn[nH]7)CC6)c45)ccc32)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 24.2 %

Procedure:
A mixture of 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl }-piperidine-4-carbonitrile (145 mg, 0.3 mmole), sodium azide (59 mg, 3 equiv.) and ammonium chloride (48 mg, 3 equiv.) in DMF (0.6 mL) in a sealed vial was stirred at 100° C. for 20 h. The reaction mixture was cooled to RT, diluted with DCM, washed with water, and dried (Na2SO4). Removal the solvent followed by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 2 to 7% 2 M NH3 in MeOH) afforded the title compound as a solid (38 mg, 24%); MS: 524 (M+H+); HPLC Ret Time: 1.13 min (Xterra 3.0×50 mm S7 C18 column, 2 min gradient, 5 ml/min).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[O:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)=[CH:18][C:17]=2[CH3:35])=[N:13][CH:14]=1.CCOC(C)=O.C1COCC1>O.C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[O:27][CH2:26][CH2:25][NH:24][CH2:23]3)=[CH:18][C:17]=2[CH3:35])=[N:13][CH:14]=1
Reactant: Cc1cc(C2CN(C(=O)OC(C)(C)C)CCO2)ccc1Nc1ccc(Br)cn1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc(C2CNCCO2)ccc1Nc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a stirred solution of trifluoroacetic acid (67.0 μl) in water (6 ml) was added a solution of tert-butyl (RS)-2-(4-(5-bromopyridin-2-ylamino)-3-methylphenyl)morpholine-4-carboxylate (39 mg) in acetonitrile (2 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 2 h. The reaction mixture was then cooled to room temperature and poured into EtOAc/THF (1:1) and washed with 1 M aq. NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/EtOAc/MeOH) to afford (RS)-5-bromo-N-(2-methyl-4-(morpholin-2-yl)phenyl)pyridin-2-amine (17 mg, 56%) as a light yellow amorphous solid. MS (ISP): 350.1 ([{81Br}M+H]+), 348.2 ([{79Br}M+H]+).