Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[C:12]1([CH:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][NH:11][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCC(Nc1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(NCCC(Nc1ccccc1)c1ccccc1)c1ccccc1
Yield: 27.5 %

Procedure:
A solution of N,1-diphenyl-1,3-propanediamine (5.0 g, 22 mmoles, described in Example 2) and benzoic acid (12.5 g, 105 mmoles) in dry xylene (300 ml) is refluxed for 20 hr using a Dean-Stark water separator. The mixture is cooled and washed with several portions of 2 N hydrochloric acid. The aqueous extracts are combined, basified with dilute sodium hydroxide and extracted with chloroform. The organic extract is washed with brine, dried over magnesium sulfate and evaporated. The residue is chromatographed an silica gel using chloroform and the eluates are evaporated. The residue is crystallized from benzene-hexane to obtain the title compound (2.0 g), mp 120°-121° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:38])[C:22]=1[CH:23]1[O:28][CH2:27][C:26]([CH3:37])([CH2:29][NH:30]C(=O)C(F)(F)F)[CH2:25][O:24]1)=[O:16]>CO.C([O-])([O-])=O.[K+].[K+]>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:38])[C:22]=1[CH:23]1[O:28][CH2:27][C:26]([CH2:29][NH2:30])([CH3:37])[CH2:25][O:24]1)=[O:16]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1OCC(C)(CNC(=O)C(F)(F)F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1OCC(C)(CN)CO1
Temperature: 100 °C
Yield: 4.8 %

Procedure:
2,2,2-trifluoro-N-((5-methyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)acetamide (171 mg, 0.49 mmol, intermediate 84) was dissolved in MeOH (30 mL) and ammonium formate (170 mg, 2.69 mmol) and 10% Pd/C (140 mg, 0.13 mmol) were added. The mixture was heated at reflux for 18 hr before being cooled to room temperature. The suspension was filtered, the cake washed with EtOAc (100 mL) and the filtrate concentrated under reduced pressure. The crude residue was dissolved in EtOAc (10 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (131 mg, 0.51 mmol) was then added followed by N-methylmorpholine (0.11 mL, 1.46 mmol). Propylphosphonic anhydride solution (50% wt in EtOAc, 338 mg, 0.53 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and purified via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM) to give 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide as a white solid (102 mg, 18% over three steps). A mixture of 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide (101 mg, 0.18 mmol) in MeOH (6 mL) and aqueous saturated K2CO3 solution (0.6 mL) was heated in a microwave at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified via silica gel chromatography (0-20% MeOH/DCM) to give 175 as a white solid (4 mg, 5%). 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 8.24 (s, 1H), 7.34-7.27 (m, 1H), 7.05-6.97 (m, 2H), 6.15 (s, 2H), 5.70 (s, 1H), 3.98-3.91 (m, 2H), 3.86 (s, 3H), 3.80 (d, J=11.0 Hz, 2H), 2.54 (s, 2H), 1.26 (s, 3H). Alkyl NH2 not observed. LCMS (ES+) m/z 465 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([C:20]#[N:21])[N:3]=1.COC1C=C2C(=CC=1)C(=O)NC(C#N)=C2C1C=CC=CC=1[F:43]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:43])=[C:4]([C:20]#[N:21])[N:3]=1
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3F)c2c1
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Product: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3F)c2c1

Procedure:
Following the procedure for 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using 6-methoxy-1-oxo-4-(2-fluorophenyl)-1,2-dihydroisoquinoline-3-carbonitrile in place of 6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile, the title compound was synthesized.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Na+].[Cl-]>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:15][CH2:14]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 111 °C
Reaction time: 16 h
Yield: 96.3 %

Procedure:
A 1-L, 4-neck round bottom flask was equipped with a heating mantle, an overhead stirrer, condenser, nitrogen inlet, and thermocouple. The flask was charged with 5-chloro-2-nitroaniline (150 g, 869 mmol, 1 equiv), 1-methylpiperazine (348 mL, 386 g, 3.48 mol, 4 equiv) and 4M aqueous NaCl (247 mL). The contents of the flask were stirred and purged with N2 for at least 15 min. The reactor was then heated until an internal temperature of 110-112° C. was reached. The contents were stirred for 7-8 h until the reaction was complete as determined by HPLC. After completion, the reaction mixture was cooled to 20° C. over 2 h to precipitate the product as a slurry, and stirring was continued for an additional 16 h. The solid was vacuum filtered, and the mother liquor collected in the original reaction vessel. The solids were washed on the filter with H2O (2×250 mL), followed by soaking in heptane (200 mL) for 0.5 h. The slurry was again filtered via vacuum, and dried in vacuo (50° C., 30 in. Hg) to yield 5-(4-methyl-piperazin-1-yl)-2-nitroaniline (197.8 g, 96.3% yield). Residual N-methylpiperazine was not detected by 1H NMR.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:7])[CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:18]([CH3:19])[C:17](=[O:20])[C:16]2[C:11](=[C:12]([I:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1>C1COCC1.CCOC(C)=O>[I:21][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([NH:7][C:3]1([CH3:2])[CH2:6][CH2:5][CH2:4]1)[N:18]([CH3:19])[C:17]2=[O:20]
Reactant: Cn1c(Cl)nc2c(I)cccc2c1=O
Reactant: CC1(N)CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(NC2(C)CCC2)nc2c(I)cccc2c1=O
Temperature: 80 °C
Yield: 85 %

Procedure:
A heterogeneous mixture of 1-methylcyclobutanamine hydrochloride (Oakwood Chemical, cat #041889; 0.69 g, 5.70 mmol) (Oakwood Chemical, cat #041889), 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700) (0.96 g, 3.0 mmol) and TEA (2.1 mL, 15.10 mmol) in 2 mL of THF in a sealed glass tube was heated in an oil bath at 80° C. for 4 h. The reaction mixture was diluted with EtOAc, washed with water followed by brine. The organic extract was concentrated and the residue was purified on a silica gel column (25-55% EtOAc in hexanes) to afford 8-iodo-3-methyl-2-((1-methyl-cyclobutyl)amino)quinazolin-4(3H)-one (0.94 g, 2.55 mmol, 85% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (1H, dd, J=7.4, 1.4 Hz), 7.92 (1H, dd, J=7.8, 1.4 Hz), 7.03 (1H, s), 6.87 (1H, t, J=7.7 Hz), 3.40 (3H, s), 2.20-2.46 (4H, m), 1.88 (2H, m), 1.72 (3H, s). m/z (ESI, +ve) 370.1 (M+H)+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Na].[CH2:23](Br)[CH2:24][C:25]([CH3:27])=[CH2:26]>CCOCC>[OH:1][C:2]1[C:11]([CH2:23][CH2:24][C:25]([CH3:27])=[CH2:26])=[C:10]([O:12][CH3:13])[CH:9]=[C:8](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(C)CCBr
Reactant: COC(=O)c1c(O)cc(OC)cc1/C=C/c1ccccc1
Agent: [Na]
Solvent: CCOCC
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
Dissolve compound 7 (5 g, 0.0176 mol) in 50 ml ether, add sodium metal (0.43 g, 0.0184 mol) into the solution, stir at room temperature for 4 h, then add in isopentenyl bromide (3.2 g, 0.0211 mol), reflux to react for 4 h, stop the reaction. Wash the reaction solution successively with water and saturated brine, separate the organic layer. Desiccate the organic layer over anhydrous magnesium sulfate, filter the solution and remove the solvent by rotary evaporation to obtain a yellow oil which is then feeded to silica gel column chromatography and evaporate the solvent in the eluent to obtain 3.8 g white solid (61%). 1H-NMR (400M, CDCl3) δ (ppm): 1.61 (s, 3H), 1.71 (s, 3H), 34 (d, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.94 (s, 3H), 5.12 (t, J=6.8 Hz, 1H), 6.78 (s, 1H), 7.00 (d, J=16 Hz, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.38 (t, J=7.2 Hz, 2H), 7.52 (d, J=7.2 Hz, 2H), 7.84 (d, J=16 Hz, 1H), 11.66 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=394.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][C@@:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([O:20]CC)=[O:19])[CH:11]=1.FC1C(OC)=CC=CC=1C1C=C(CC[C@@](C)(S(C)(=O)=O)C(O)=O)ON=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][C@@:17]([CH3:27])([S:23]([CH3:26])(=[O:25])=[O:24])[C:18]([OH:20])=[O:19])[CH:11]=1
Reactant: CCOC(=O)[C@@](C)(CCc1cc(-c2cccc(OC)c2F)on1)S(C)(=O)=O
Agent: COc1cccc(-c2cc(CC[C@](C)(C(=O)O)S(C)(=O)=O)on2)c1F
Product: COc1cccc(-c2cc(CC[C@](C)(C(=O)O)S(C)(=O)=O)no2)c1F
Yield: 99.1 %

Procedure:
The title compound (0.46 g, 95%) was prepared from ethyl(2R)-4-[5-(2-fluoro-3-methoxyphenyl)isoxazol-3-yl]-2-methyl-2-(methylsulfonyl)butanoate (0.50 g, 1.25 mmol) by following the procedure described for the synthesis of (2R)-4-[3-(2-fluoro-3-methoxyphenyl)isoxazol-5-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (Example 1, Step B). MS (GCMS) m/z 372.1 (M+1). 1H NMR (400 MHz, METHONAL-d4) δ1.69 (s, 3H) 2.45-2.56 (m, 2H) 3.14 (d, J=9.95 Hz, 5H) 3.93 (s, 3H) 6.70-6.82 (m, 1H) 7.19-7.30 (m, 2H) 7.37-7.52 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[Cl:37][C:38]1[CH:39]=[C:40]([CH:51]=[CH:52][C:53]=1[Cl:54])[O:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][NH2:50])[CH2:44][CH2:43]1.C(N(CC)CC)C>CN(C=O)C.CCOCC.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:50][CH2:49][CH2:48][N:45]2[CH2:46][CH2:47][CH:42]([O:41][C:40]3[CH:51]=[CH:52][C:53]([Cl:54])=[C:38]([Cl:37])[CH:39]=3)[CH2:43][CH2:44]2)=[O:8])=[C:4]([O:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
The product from step (vi) (0.3 g) and N,N-carbonyldiimidazole (0.19 g) were dissolved in DMF (20 ml) and the solution stirred at room temperature for 1 hour. The product from step (iv) (0.42 g) and triethylamine (0.32 ml) were added. After 20 hours water and ether were added, the organic phase separated, dried and concentrated to a gum which was purified by chromatography (dichloromethane: methanol, 93:7) to give the titled product as a solid (0.38 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][CH3:13])[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C.O1CCCC1>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:12]([C:10]1[CH:11]=[C:2]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16])[CH3:13]
Reactant: CCc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure D and using 6-bromo-8-ethyl-2,2,4,4-tetramethyl chroman (Intermediate 46, 0.5 g, 1.61 mmol), (trimethylsilyl)acetylene (1.57 g, 16.1 mmol), triethyl amine (8 mL), anhydrous tetrahydrofuran (10 mL), copper(I)iodide (0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol), followed by flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.137 g, 27%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>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.O.C(O)C>[C:14]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])[CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCNC(=O)c1cc(Br)ccn1
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: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)c1cc(-c2ccccc2)ccn1
Temperature: 150 °C
Yield: 87.7 %

Procedure:
A mixture of 4-bromo-N-propylpyridine-2-carboxamide (450 mg), phenylboronic acid (330 mg), potassium carbonate (380 mg), tetrakis(triphenylphosphine)palladium (210 mg), dimethylformamide (6.5 mL) and ethanol (3.5 mL) was stirred under irradiation with microwave while heating at 150° C. for 10 min. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was washed with water and brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=67:33-50:50) to afford 4-phenyl-N-propylpyridine-2-carboxamide (390 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and morpholine (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (10 mg, 13%) which was obtained as a white solid. MS: m/e=398.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([N:9]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:5][CH:6]([CH3:8])[CH3:7].O.NN.Cl>CO>[CH3:1][O:2][CH2:3][C@H:4]([NH2:9])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC[C@@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: COC[C@H](N)CC(C)C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of (R)-2-(1-methoxy-4-methylpentan-2-yl)isoindoline-1,3-dione (example 9b) (3.87 g, 14.84 mmol) in methanol (30 mL), was added hydrazine hydrate (0.866 ml, 17.81 mmol) and the reaction mixture was warmed up to 45° C. for about 3 hours. The mixture was acidified with 2N HCl and stirred at 45° C. for 30 min. The solution was cooled to room temperature, filtered and evaporated. The residue was taken up with 2N NaOH and extracted with ether, dried over MgSO4, filtered and evaporated to give 1.51 g of (R)-1-methoxy-4-methylpentan-2-amine. Yield 77%. 1H NMR (500 MHz, CDCl3): 0.91 (m, 6H); 1.17 (m, 2H); 1.58 (s, 2H); 1.71 (m, 1H); 3.02 (m, 1H); 3.10 (m, 1H); 3.32 (m, 1H); 3.35 (s, 3H).
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([C:14]#[C:15][C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(N=C=NC2CCCCC2)CCCCC1.O>ClCCl>[C:1]1([NH:7][C:16](=[O:17])[C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C#Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: ClCCl
Product: O=C(C#Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61 %

Procedure:
Phenylamine (1.86 g, 20 mmol) and phenylpropiolic acid (3.22 g, 22 mmol) were dissolved in dichloromethane (50 ml) and 1,3-dicyclohexylcarbodiimide (4.8 g, 23.2 mmol) was added in one portion at 0° C. The mixture was stirred room temperature for 14 h. The mixture was poured into water and extracted with dichloromethane (3×15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenylamide 2.7 g (62%).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:3]=1[NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:6]=1.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:25][C:22]1[CH:23]=[CH:24][C:2]([CH3:1])=[C:3]([CH:21]=1)[NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:6]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Yield: 61.4 %

Procedure:
To a solution of 4-(2-methyl,5-nitroanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (377 mg, 1.00 mmol) in anhydrous ethanol (20 ml) was added slowly anhydrous tin chloride (758 mg, 4.00 mmol). The mixture was refluxed for 1 h and then rotary evaporated to leave a brown oil. The brown oil was basified with aqueous 2N NaOH to give a final pH of 8. The resulting precipitate was filtered and washed with ethyl acetate. The aqueous phase and organic phase was combined and washed with water (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness to give a brown solid (212 mg, 57%). 1H NMR (CDCl3): 8.76 (dd, J=1.8, 4.8 Hz, 2H), 8.26 (dd, J=1.8, 4.8 Hz, 2H), 7.11 (d, J=7.8 Hz, 1H), 7.12 (s, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.66 (s, 1H), 6.63 (dd, J=2.4, 8.1 Hz, 1H), 3.72 (bs, 2H), 2.16 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:20])[CH2:3]1.[H-].[Na+].Cl[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O.O>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:4](=[O:20])[CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)CC(=O)Nc2c(COC3CCCCO3)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)N(COCC[Si](C)(C)C)c2c(COC3CCCCO3)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.4 g of 4,4-dimethyl-8-(tetrahydropyran-2-yloxymethyl)-3,4-dihydro-1H-quinolin-2-one in 10 ml of N,N-dimethylformamide is admixed at 0° C. with 0.2 g of sodium hydride dispersion (60%). After stirring for 1 hour, 0.94 ml of (2-chloromethoxyethyl)trimethylsilane are added and the reaction mixture is warmed to room temperature. After 17 hours and 22 hours, 0.1 g of sodium hydride dispersion (60%) and 0.5 ml of (2-chloromethoxyethyl)trimethylsilane are again added. After a total of 24 hours, the reaction mixture is admixed with a few drops of water and subsequently partitioned between tert-butyl methyl ether and saturated aqueous sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.37 (2:1 EtOAc-heptane); Rt=6.01.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[CH:11]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2nc(C(C)(C)C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc2cc(C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a solution of methyl 2-tert-butylquinoline-6-carboxylate (347 mg, 1.43 mmol) in methanol (4 ml) and THF (4 ml) was added 2N aqueous sodium hydroxide (2 ml) at room temperature. The mixture was stirred at room temperature for 1.5 hours, then evaporated, diluted with water (5 ml), and neutralized to pH 5˜6 by 2M aqueous hydrochloride. The formed precipitate was collected and washed with water to furnish the title compound (282 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.49 (9H, s), 7.62 (1H, d, J=8.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 8.31-8.34 (1H, m), 8.64-8.66 (1H, m). MS (ESI): m/z 230 (M+H)+.