Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[O:30])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[Li].O>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:42]=[CH:43][CH:44]=3)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(Nc3ccc(C)c(C)c3)ccn2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed a solution of methyl 3-(3-((2-(4-(3,4-dimethylphenylamino)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate (440 mg, 0.72 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), and a solution of LiOH H2O (300 mg, 7.14 mmol, 9.89 equiv) in water (2 mL). The resulting solution was stirred for 18 h at room temperature. The reaction was then quenched with 30 mL of water. The solution was adjusted to pH 6-7 with hydrochloric acid (1 N). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (250 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 237.2 mg (55%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 13.76 (s, 1H), 10.22 (s, 1H), 10.11 (s, 1H), 8.21 (d, J=6 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.42 (m, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.16 (d, J=9 Hz, 1H), 7.08 (s, 2H), 6.94 (m, 3H), 6.81 (s, 1H), 3.80 (s, 2H), 3.24 (s, 4H), 2.55 (m, 3H), 2.17 (d, 6H), 1.63 (s, 6H). MS (ES, m/z): 595 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[CH:20]1([C:26](=O)[CH2:27][C:28]#[N:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:26]2[C:27]([C:28]#[N:29])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=3)[N:1]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N#CCC(=O)C1CCCCC1
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Product: N#Cc1c(C2CCCCC2)nc2ccc(C(F)(F)F)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-trifluoromethyl-phenyl)-phenyl-methanone and 3-cyclohexyl-3-oxo-propionitrile (prepared as described in example 110 step A). Off-white solid. MS (ESI): 381.4 (M+H)+.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([NH:10][C:11]3[N:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)[CH:7]=[CH:6][C:5]=12.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30].[Li+].CC([N-]C(C)C)C>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([N:10]3[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][N:18]=4)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)[C:29]3=[O:30])[CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1cccnc1Nc1ccc2nsnc2c1
Reactant: CCOC(=O)CCCCc1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2ccccn2)cc2cccnc2n1-c1ccc2nsnc2c1
Yield: 27 %

Procedure:
The procedure of Example 1 was repeated using 2-(2,1,3-benzothiadiazol-5-ylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1a)), ethyl 5-(pyridin-2-yl)pentanoate (1.5 eq., prepared in Synthetic Example 4) and LDA (1.5 eq.) to obtain 1-(2,1,3-benzothiadiazol-5-yl)-3-[3-(pyridin-2-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 27%). The product was purified through flash column chromatography and recrystallization (mp 169.5–170.5° C./DMF).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:7][CH2:8]O.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:7][CH2:8][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCOCc1cccc(Br)c1
Product: O=C1c2ccccc2C(=O)N1CCOCc1cccc(Br)c1

Procedure:
Mitsunobu reaction of 2-(3-bromobenzyloxy)ethanol and phthalimide following the method used in Example 134 gives 2-(2-(3-bromobenzyloxy)ethyl)isoindoline-1,3-dione.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1.[C:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>C1COCC1>[CH3:27][C:24]([C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:21]([C:17]2[C:18]3[C:13](=[CH:12][C:11]([O:10][C:4]4[C:5]5[CH:9]=[CH:8][NH:7][C:6]=5[N:1]=[CH:2][N:3]=4)=[CH:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])=[CH:33][CH:34]=1)([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)c2cccc3cc(Oc4ncnc5[nH]ccc45)ccc23)cc1
Reaction time: 14 h

Procedure:
THF (1.3 mL) was added to 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-1-naphthoyl chloride (84.0 mg, 0.259 mmol) in a 10 mL round bottom flask, followed by 4-t-butyl aniline (62.4 mL, 0.389 mmol) and Hunig's base (45.1 μL, 0.259 mmol). The resulting solution was stirred for 14 h and then transferred to a 50 mL flask. To this solution was added ˜5 g of silica gel. The resulting slurry was concentrated by reduced pressure. The impregnated silica gel was loaded into a dry pack column cartridge and the crude mixture was purified through Biotage chromatography (Hex:EtOAc). The collected product was repurified through trituration with DCM. MS (ESI, pos. ion) m/z: 437.1 (M+1). Mass Calc'd for C18H15NO3: 436.51.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH3:34])=[C:11]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[C:16]2[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=2)[N:7]=1)(=O)C.C(OCC1C=CC2C(=CC(C)=C([C@H](OC(C)(C)C)C(OCC)=O)C=2C2CCCCC=2)N=1)(=O)C>>[C:30]([O:29][C@@H:23]([C:11]1[C:12]([C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:34])[N:7]=[C:6]([CH2:5][OH:4])[CH:15]=[CH:14]2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1-c1ccc(Cl)cc1
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1C1=CCCCC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1C1=CCCCC1

Procedure:
(S)-Ethyl 2-tert-butoxy-2-(5-cyclohexenyl-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate was prepared following the procedure used to prepare compound (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate of Example 16, except that (S)-ethyl 2-(2-(acetoxymethyl)-5-cyclohexenyl-7-methylquinolin-6-yl)-2-tert-butoxyacetate was used instead of (S)-ethyl 2-(2-(acetoxymethyl)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyacetate. LCMS-ESI+ (m/z): 412.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]([CH3:18])[S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:17]=[CH:16][S:13]([N:12]([CH3:18])[CH3:11])(=[O:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CS(=O)(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: CN(C)S(=O)(=O)C=Cc1ccc2[nH]ccc2c1
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A mixture of 5-bromoindole (7.7 g), N,N-dimethylethenesulphonamide (5.3 g) triethylamine (15 ml), acetonitrile (5 ml), palladium (II) acetate (0.35 g) and tri-o-tolylphosphine (0.95 g) was heated at 100° C. in an autoclave for 3 h. The resulting cooled mixture was partitioned between hydrochloric acid (2N, 300 ml) and ethyl acetate (2×150 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by `flash` chromatography (V, 7 cm col.) to give the title compound as a crystalline solid (3.8 g) m.p. 148°-150° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]2[C:24]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=CC=4)C=3C=CC=2)=[O:10])[CH2:4]1.N1CCCCC1.C(N(C(C)C)CC)(C)C.ClC(OCC1C=CC=CC=1)=O>C(Cl)Cl.CCOC(C)=O>[OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:24]2[CH:23]=[CH:22][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH2:4]1
Reactant: O=C(Oc1cccc2c1Cc1ccccc1-2)N1CCOC(CO)C1
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCOC(CO)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.5 %

Procedure:
To a solution of 2.20 g of 2-hydroxymethyl-4-fluorenyloxycarbonyl-morpholine in 25 mL of CH2Cl2 was added 1.29 g of piperidine. The mixture was stirred at room temperature for 2 days. Diisopropylethylamine (7.15 g) and 6.30 g of benzyl chloroformate were added and the mixture was stirred overnight at room temperature, then diluted with 100 mL of EtOAc and washed with 50 mL each of 1N HCl, saturated NaHCO3, and brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with a gradient system of 20:1 CH2Cl2-acetone to 9:1 CH2Cl2-acetone, to yield 638 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ7.30-7.40 (m, 5H), 5.15 (ABq, J=12.4 Hz, 2H), 3.93 (br s, 3H), 3.68 (br s, 1H), 3.47-3.63 (m, 3H), 3.02 (br s, 1H), 2.85 (br s, 1H), 1.90 (br s, 0.6H). IR (neat) 3427, 2862, 1693, 1432, 1354, 1236, 1129 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Cl.[CH2:11](Br)[CH:12]=[CH2:13].C(=O)(O)[O-].[Na+]>ClCCl.C1COCC1.[Cl-].[Cl-].[Cl-].[V+3]>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:13][CH:12]=[CH2:11])[C:2]=1[CH3:1]
Reactant: C=CCBr
Reactant: Cc1c(Cl)cccc1[Mg]Cl
Agent: [V+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCc1cccc(Cl)c1C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
158 g of vanadium trichloride are dissolved in 800 ml of dichloromethane, and 500 ml of a solution of 1 mol of 2-methyl-3-chlorophenylmagnesium chloride in THF are added at 25° C. Stirring is carried out for 0.5 hour, after which 121 g of allyl bromide are added dropwise, stirring is effected for 10 hours at 25° C. and the mixture is then refluxed for 6 hours. The resulting reaction mixture is poured into 2 l of saturated, aqueous sodium bicarbonate solution and then extracted with methyl tertbutyl ether. 70.9 g of 1-chloro-2-methyl-3-prop-2-enylbenzene (bp. 78° C./1 mbar) are obtained by distillation.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]=[CH:9][N:8]=1>>[Cl:3][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][N:10]=[CH:9][N:8]=1
Reactant: Oc1ncncc1Oc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncncc1Oc1ccccc1
Reaction time: 1.5 h

Procedure:
To 500 ml. of phosphorus oxychloride was added 85.5 g. (0.455 mol) of 4-hydroxy-5-phenoxy pyrimidine and the suspension heated at 70° in an oil bath. After 1 hr the reaction mixture became homogeneous and after 1.5 hr total reduction time the bulk of the phosphorus oxychloride was removed by distillation at reduced pressure. The residue was slowly added to well stirred iced water and the residual acid was cautiously neutralized with ammonium hydroxide solution to pH 8 and was extracted with 3 × 700 ml. of chloroform. The chloroform extracts were dried over anhydrous sodium sulfate filtered and concentrated in vacuo to 85.7 g. (90%) of a black oil. A colorless oil could be obtained by evaporative distillation of this material at 130° (0.1 mm).
Reaction SMILES: O.C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]3[N:24]=[C:23]4[S:25][C:26]([C:28]5[CH:42]=[CH:41][C:31]([CH2:32][N:33]6[CH2:36][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:34]6)=[CH:30][C:29]=5[F:43])=[N:27][C:22]4=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.C(N(CC)CC)C>C1COCC1.CO.C(Cl)Cl.[Pd]>[F:43][C:29]1[CH:30]=[C:31]([CH2:32][N:33]2[CH2:34][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:36]2)[CH:41]=[CH:42][C:28]=1[C:26]1[S:25][C:23]2[C:22]([N:27]=1)=[CH:21][CH:20]=[C:19]([C:16]1([C:13]3[CH:12]=[CH:11][C:10]([OH:9])=[CH:15][CH:14]=3)[CH2:18][CH2:17]1)[N:24]=2
Reactant: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccc(OCc7ccccc7)cc6)CC5)nc4s3)c(F)c2)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccc(O)cc6)CC5)nc4s3)c(F)c2)C1

Procedure:
A slurry of palladium 10% on carbon, 50% water (0.26 g), methyl 1-(4-(5-(1-(4-(benzyloxy)phenyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate (0.144 g, 0.25 mmol), triethylamine (0.087 mL, 0.62 mmol) in 4 mL of 3:1 THF/MeOH was stirred rapidly under an atmosphere of hydrogen (balloon) for 36 h. The reaction mixture was diluted with DCM, and filtered through celite and concentrated in vacuo. The resulting solid was adsorbed onto 1.4 g silica gel and purified by silica gel chromatography 0-100% EA/hexanes, to give methyl 1-((3-fluoro-4-(5-(1-(4-hydroxyphenyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)-azetidine-3-carboxylate as a white solid. MS (ESI) m/z: calculated: 489.2; Observed: 490.1 (M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[Br:20][C:21]1[CH:22]=[C:23]2[NH:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:24]2=[N:25][CH:26]=1.[H-].[Na+]>CN(C=O)C>[Br:20][C:21]1[CH:22]=[C:23]2[N:29]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:3]=3[CH3:19])[CH2:28][C:27]([CH3:31])([CH3:30])[C:24]2=[N:25][CH:26]=1
Reactant: CC1(C)CNc2cc(Br)cnc21
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 60 °C

Procedure:
Prepared according to procedure M using 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (86 mg, 0.32 mmol) (described herein), 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (86 mg, 0.38 mmol) (described herein), and sodium hydride (25 mg, 0.63 mmol) in DMF (10 mL). Reaction was heated at 60° C. for 18 h, affording 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline as an orange solid. Mass Spectrum (ESI) m/e=463 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][CH3:12])=[O:10])[CH:5]=[C:4]([C:13]#[N:14])[CH:3]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([NH:8][C:9]([NH:11][CH3:12])=[O:10])[N:7]=1)[C:13]([NH:16][OH:17])=[NH:14]
Reactant: NO
Reactant: CNC(=O)Nc1cc(C#N)cc(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC(=O)Nc1cc(C(=N)NO)cc(N)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a solution of 0.200 g 1-(6-amino-4-cyano-pyridin-2-yl)-3-methyl-urea (example 23a) in 3.2 ml ethanol and 1.6 ml water was added 0.145 g hydroxylamine hydrochloride and 0.333 g sodium carbonate and the mixture was stirred at 85° C. for 2 h. The reaction mixture was purified by solid phase extraction with ethyl acetate to yield 0.154 g of the title compound as light yellow solid. MS (ISP) M+H+=225.1
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:24]=[CH:23][C:13]([CH2:14][P:15](=[O:22])([O:19]CC)[O:16]CC)=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>Cl>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][P:15](=[O:16])([OH:22])[OH:19])=[CH:23][CH:24]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOP(=O)(Cc1ccc(OCC2(C)CCCCC2)cc1)OCC
Agent: Cl
Product: CC1(COc2ccc(CP(=O)(O)O)cc2)CCCCC1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution 0.7 g (2.0 mmol) of diethyl 4-[((1methyl)cyclohexyl)methoxy]benzylphosphonate and 10 ml of concentrated hydrochloric acid was refluxed for 24 hours. The reaction was cooled to room temperature, filtered and the solids were washed with water. The solids were recrystallized from EtOAc/cyclohexane to give 0.4 g of the product; m.p. 170°-172° C.
Reaction SMILES: O[Li].O.[CH3:4][O:5][C:6]1[C:7]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][C:41]([O:43]C)=[O:42])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:10][CH:11]=1>C1COCC1.O.CO>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:9]3[N:8]=[C:7]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:40][C:41]([OH:43])=[O:42])[C:6]([O:5][CH3:4])=[CH:11][N:10]=3)=[CH:18][CH:17]=2)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.6 %

Procedure:
LiOH.H2O (0.025 g, 0.59 mmol) was added to a solution of tert-butyl 4-(4-((5-methoxy-4-(2-(2-methoxy-2-oxoethyl)phenethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A100) (0.11 g, 0.20 mmol) in THF (7 mL), water (1.5 mL) and MeOH (1 mL) and the resulting mixture stirred at room temperature for 17 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and the volatiles removed in vacuo to give the title compound A101 as a pale yellow oil (0.099 g, 92%); 1H NMR (400 MHz, d4-MeOH) δ 7.98 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.22-7.04 (m, 6H), 4.16 (d, J=13.1 Hz, 2H), 3.76 (s, 3H), 3.71 (s, 2H), 2.96-2.88 (m, 4H), 2.88-2.70 (m, 2H), 2.65-2.55 (m, 1H), 1.76 (d, J=12.3 Hz, 2H), 1.59-1.49 (m, 2H), 1.46 (s, 9H). LCMS-A: rt 6.35 min; m/z 547.3 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)([CH3:3])[CH3:2].CN1CCOCC1.[ClH:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH2:31][NH2:32])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:29][CH2:30][CH2:31][NH:32][C:6](=[O:8])[C@@H:5]([NH:4][CH:1]([CH3:2])[CH3:3])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:24][CH:23]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@H](NC(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
A suspension of (S)-2-isopropylamino-4-methyl-pentanoic acid (433 mg, 2.50 mmol), N-methylmorpholine (0.275 mL, 2.50 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (750 mg, 2.52 mmol) in dry DMF (12 mL) was treated with Triton® B (2.27 mL, 4.99 mmol, 40 wt percent solution in methanol, Aldrich, Milwaukee, Wis.), a clear solution was obtained and cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.940 g, 2.50 mmol) was then added. After stirring at 0° C. for 90 minutes the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 100 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (100 mL), brine (100 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (EtOAc:hexanes:MeOH 50:50:5). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 368 mg (35%) of the pure titled compound as a white foam: mp 100-103° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:22])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C2CCN(Cc3ccccc3)C2)cc1F
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1ccc(C2CCN(Cc3ccccc3)C2)cc1F
Yield: 80.9 %

Procedure:
1-Benzyl-3-(3-fluoro-4-nitro-phenyl)-pyrrolidine (550 mg, 1.83 mmol) was dissolved in methanol (30 ml), tin dichloride (3.125 g, 16.48 mmol) was added, and the reaction mixture stirred at reflux for 2 h. The methanol was evaporated, 1 N sodium hydroxide (60 ml) and ethyl acetate were added and stirring continued. The tin salts were filtered off, the organic phase was separated, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield an oil (400 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]([CH3:27])([CH3:26])[NH2:25].[ClH:28]>C(#N)C>[ClH:28].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]([NH:25][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[CH3:1])([CH3:26])[CH3:27]
Reactant: Cc1ccccc1OCC1CO1
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Br)cc12
Agent: Cl
Solvent: CC#N
Product: Cc1ccccc1OCC(O)CNC(C)(C)Cc1c[nH]c2ccc(Br)cc12

Procedure:
(2-Methylphenoxymethyl)oxirane, 4.1 g. (0.025 mole) and 6.65 g. (0.025 mole) of 5-bromo-α,α-dimethyl-1H-indol-3-yl-ethaneamine were mixed and heated at 140° for 1 hr. The mixture was then cooled and dissolved in 40 ml. of acetonitrile while still warm. The product was converted to the hydrochloride salt by treatment of the solution with 5 N ethanolic HCl. The solvent was removed by distillation and the residue dissolved in 30 ml. of acetonitrile. The product crystallized from this solution, yield 11.0 g., m.p. 197°-199°. This material was recrystallized from methanol/isopropanol, yield 8.0 g., m.p. 198.0°-200.0° dec. (corr.).