Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.[Cl:20][C:21]1[CH:27]=[CH:26][C:24](N)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1>[Cu](F)F.N1C=CC=CC=1>[N+:28]([C:23]1[CH:22]=[C:21]([Cl:20])[CH:27]=[CH:26][C:24]=1[O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11])([O-:30])=[O:29]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CC(O)CC(C)(C)N1Oc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 52.1 %

Procedure:
The procedure of Example 1 is repeated using 4.31 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 7.73 g (75 mmol) of tert-butyl nitrite, 25 mg (0.25 mmol) of copper(II) flouride, 70 mL of pyridine and 5.61 g (32.5 mmol) of 4-chloro-2-nitroaniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (70:30/heptane:ethyl acetate) to give 4.28 g of the title compound in 84.8% yield as a light yellow solid melting at 124-125.5° C. The structure is confirmed by 1Hnmr and elemental analysis.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]([C:16]2[C:17]([S:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[CH:9]=[C:10]([CH3:12])[CH:11]=1.C(O)C>C(OCC)(=O)C>[CH:1]1([NH:4][C:26]2[N:25]=[C:24]([CH2:23][S:22][C:17]3[C:16]([C:14]([NH:13][C:8]4[CH:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH3:5])[CH:7]=4)=[O:15])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:29]=[CH:28][N:27]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(S(C)=O)n2)c1
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC3CC3)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Cyclopropylamine (6.0 mL) was added to N-(3,5-dimethylphenyl)-2-(2-methylsulfinylpyrimidin-4-ylmethylthio) pyridine-3-carboxamide (990 mg, 2.4 mmol, Compound No. 1-27), and the mixture was stirred for 30 minutes at 80° C. The reaction mixture was diluted with ethyl acetate (80 mL), washed twice with water (50 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the residue was purified by silica gel column chromatography to give 650 mg (recrystallized from ethanol) of the target compound as a colorless solid (Yield: 67%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1.C(N(CC)CC)C.[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38])([O-:30])=[O:29].[Cl-].[NH4+]>C(Cl)Cl>[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1)(=[O:39])=[O:38])([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H](N)C1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
tert-Butyl (3R,4R)-3-amino-4-phenylpiperidine-1-carboxylate (124 mg) was dissolved in methylene chloride (2 ml), and thereto were added triethylamine (125 μl) and 2-nitrobenzene sulfonyl chloride (109 mg) at 0° C., and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=1/1) to give the title compound (202 mg).
Reaction SMILES: Br[CH:2]([CH:4]1[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:20])[NH:12][C:11](=[O:17])[C:10]([CH3:18])=[CH:9]3)[CH3:3].[N-:21]=[N+:22]=[N-:23].[Na+].CN(C)C=O>O>[N:21]([CH:2]([CH:4]1[O:19][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH:5]1[CH3:20])[NH:12][C:11](=[O:17])[C:10]([CH3:18])=[CH:9]3)[CH3:3])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)Br)O3
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)C(C)C(C(C)N=[N+]=[N-])O3
Yield: 72.1 %

Procedure:
A mixture of the compound obtained in Example 289 (3.30 g, 9.9 mmol), sodium azide (3.84 g, 59 mmol) and dimethylformamide (30 ml) was allowed to react at 120° C. for 4 hours. The reaction mixture was poured into water to obtain 2.13 g of the title compound as a pale brown solid (72.7%).
Reaction SMILES: CC([O:4][C:5]([CH3:7])=[O:6])=O.O[NH:9][C:10](=[NH:24])[CH2:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1.C(OCC)(=O)C>O>[C:5]([O:4][NH:24][C:10](=[NH:9])[CH2:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(Cc1ncccc1-c1ccccc1)NO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)ONC(=N)Cc1ncccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.94 %

Procedure:
Ac2O (30 mL) was added to N-hydroxy-2-(3-phenyl-pyridin-2-yl)-acetamidine (160) (5.3 g, 23.35 mmol) at room temperature. A purple colored solution was formed, after a few hours a dark brown solution was formed which was stirred for 6 h at room temperature. Silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.6). Cold water was added, the mixture was extracted with ethyl acetate (3×50 mL), the organic part was dried and concentrated, the crude product was purified by a CombiFlash column (eluted at 50% ethyl acetate in hexane) to get 2-(3-phenylpyridin-2-yl)ethanimidamido acetate (161) (2.7 g, 42.94% pure and 2 g mixture) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[F:5][CH:6]([C:11](OC)=[O:12])[C:7](OC)=[O:8].C[O-].[Na+]>CO>[F:5][C:6]1[C:7](=[O:8])[NH:1][C:2](=[O:3])[NH:4][C:11]=1[OH:12]
Reactant: COC(=O)C(F)C(=O)OC
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(O)c(F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A mechanically stirred solution of urea (60.06 g, 1 mol) and dimethyl fluoromalonate (150.11 g, 1 mol) in methanol (1 L) was treated with 25 wt % NaOMe in methanol (˜4.6 M, 435 mL, 2 mol). The mixture was refluxed for 3 h and then allowed to cool to room temperature. The mixture was filtered, the wet cake was dissolved in warm water (˜1.2 L), and the resulting aqueous solution was acidified with concentrated aqueous HCl (˜160 mL) to pH=2 while stirring over 1 h. The mixture was allowed to cool to room temperature, and the product was filtered and washed thoroughly with water, then dried under vacuum to give 5-fluoro-6-hydroxy-2,4(1H,3H)-pyrimidinedione (80 g, 55%) as a white solid. LCMS: (M+H)+: 147.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:18])[CH:4]=[N:3]1.[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[O:17])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[C:5]([CH3:18])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCCc1sc(C(=O)O)cc1-c1c(C)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(C)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (180 mg, 0.68 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (262 mg, 0.68 mmol)[prepared in Preparation 6] and diisopropylethylamine (0.59 ml, 3.40 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (350 mg, 0.75 mmol) in one portion. The solution stirred at 25° C. for 2 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (243 mg, 0.41 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.O.[NH2:15][NH2:16].O>CCO>[N:11]1[C:10]2[C:5]([C:3]([NH:15][NH2:16])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:13][CH:12]=1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]cnc12
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc2[nH]cnc12
Temperature: 25 °C

Procedure:
Benzimidazole ester 3 (1.65 g, 9.36 mmol), hydrazine monohydrate (10 mL), and water (3 mL) were refluxed in EtOH (60 mL) for 24 hs. Reaction mixture was cooled to room temperature and solid formed was filtered, washed with EtOH and dried to give 1.13 g (68%) of pure 4: 1H NMR (DMSO-d6) δ 12.31 (br.s, 1H), 10.59 (s, 1H), 8.44 (s, 1H), 7.86 (d, 1H, J=6.5 Hz), 7.76 (d, 1H, J=8.0 Hz), 7.34 (t, 1H, J=8.0 Hz), 4.68 (s, 2H).
Reaction SMILES: [Br:1]Br.[F:3][CH:4]1[CH2:12][CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]1=[O:13].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[Br:1][C:4]1([F:3])[CH2:12][CH2:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]1=[O:13]
Reactant: O=C1c2ccsc2CCC1F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccsc2CCC1(F)Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Add a solution of bromine (10.08 g, 63.1 mmol, 1.1 equiv.) in dry carbon tetrachloride (60 mL) dropwise via addition funnel over 1 h20 min to a cold (0° C.) solution of 5-fluoro-6,7-dihydro-5H-benzo[b]thiophen-4-one (9.72 g, 57.1 mmol, 1 equiv.) in dry diethyl ether (300 mL). Once all the bromine is added warm to room temperature for 2 hours and add more bromine (0.7 M in CCl4, 7 mL, 4.9 mmol, 0.09 equiv.) and stir the reaction mixture at room temperature for 1 hr before adding saturated aqueous sodium thiosulfate. The layers are separated and the aqueous layer is extracted with diethyl ether (three times). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purify the resultant crude material by medium pressure liquid chromatography eluting with 0 to 20% ethyl acetate in hexanes to afford the title compound (6.976 g, 49%). δH (400 MHz, CDCl3) 2.67-2.78 (m, 1H), 2.93 (dddd, 1H, J=14, 4, 4, 4 Hz), 3.24-3.31 (m, 2H), 7.21 (d, 1H, J=6 Hz), 7.45 (d, 1H, J=6 Hz).
Reaction SMILES: OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[CH3:23][C:24]1[CH:33]=[CH:32][C:31]2[C:30]([C:34](O)=O)=[CH:29][CH:28]=[CH:27][C:26]=2[N:25]=1.[CH3:37][NH:38][C:39](=[S:42])[NH:40][NH2:41]>CN(C)C=O.C(N(CC)CC)C>[CH3:37][N:38]1[C:34]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:31]=2[CH:32]=[CH:33][C:24]([CH3:23])=[N:25]3)=[N:41][NH:40][C:39]1=[S:42]
Reactant: Cc1ccc2c(C(=O)O)cccc2n1
Reactant: CNC(=S)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Hydroxybenzotriazole (7.8 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11 g) and triethylamine were successively added to a stirred solution of 2-methyl-5-quinolinecarboxylic acid (10g) and 4-methyl-3-thiosemicarbazide (6.1 g) in dimethylformamide (200 ml), at 0° C. Following the addiction the reaction mixture was allowed to reach room temperature, the stirred continued over night and then the solvent was evaporated under reduced pressure. The residue was treated with an aqueous sodium hydroxide solution (500 ml, 0.5N) and the mixture was stirred at 80° C. for 3 h, after which time the mixture was cooled to room temperature and the pH adjusted to pH 6 using a aqueous hydrochloridric acid solution (2M) and the resulting precipitatye was filtered and dried in vacuo to give the title compound (11 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Brc1ccc2ccccc2c1
Product: COc1ccc(-c2ccc3ccccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 2-bromonaphthalene (0.31 g, 1.50 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.31 g, 1.80 mmol) according to method A to yield 0.30 g (79%) of a white solid: mp 108–110° C.; 1H NMR (CDCl3): δ (3.96, 3H, s), 7.04–7.10 (1H, m), 7.43–7.52 (4H, m), 7.68 (1H, dd, J=1.81 Hz, J=8.57 Hz), 7.84–7.92 (3H, m), 7.97 (1H, d, J=1.05 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[C:21]([NH:28][CH2:29][C:30]#[CH:31])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][C:30]#[C:31][C:13]1[CH:12]=[N:11][C:7]2[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=3[Cl:1])[C:6]=2[CH:14]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Product: CC(C)(C)OC(=O)NCC#Cc1cnc2c(c1)N(Cc1cc(Cl)ccc1Cl)CCN2
Yield: 63 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was coupled with N-boc propargylamine as in General Procedure 5 to give the title compound as a yellow solid (63% yield). LCMS: m/z=447.49 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.45 (9H, s), 3.41 (2H, t, J=4.8 Hz), 3.62 (2H, s), 4.05 (2H, m), 4.40 (2H, s), 4.81 (1H, m), 5.41 (1H, bs), 6.41 (1H, s), 7.21 (2H, m), 7.34 (1H, d, J=8.3 Hz), 7.61 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4](Cl)[N:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16][CH3:17])=[O:15])[C:5]([C:8]#[N:9])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C#N

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-cyanopyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave −20° C., 10 minutes) to afford 2-(2-chloro-5-cyano-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid. Mp: 228-32° C. (dec); MS: 288.26 (M+H); 1H NMR (chloroform-d): δ 12.49 (s, 1H), δ 8.69 (d, J=8 Hz, 1H), δ 8.50 (s, 1H), δ 7.57 (m, 2H), δ 7.22 (t, J=8 Hz, 1H), δ 6.31 (br s, 1H), δ 3.08 (d, J=5 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[CH:17]([O:20][CH3:21])[O:18][CH3:19])[NH:13][CH2:12][CH2:11][CH2:10]3)[CH2:3][CH2:2]1.[H][H]>C1COCC1.CO.[Pd]>[CH3:21][O:20][CH:17]([O:18][CH3:19])[C:16]1[N:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH2:12][NH:13]2)=[CH:8][C:7]=1[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: COC(OC)c1nc2c(cc1C1=CCOCC1)CCCN2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1C1CCOCC1)CCCN2
Temperature: 25 °C
Reaction time: 56 h

Procedure:
A suspension of 10% Pd on carbon (0.34 g) in a solution of 6-(3,6-dihydro-2H-pyran-4-yl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 313, 0.94 g, 3.24 mmol) in THF (60 ml) and MeOH (20 ml) was stirred under an atmosphere of hydrogen at room temperature for 56 h, at which point 1 equivalent of hydrogen had been consumed. The reaction mixture was flushed with argon, filtered and evaporated to give the title compound as a beige solid. (UPLC-MS 3) tR 0.54 min; ESI-MS 293.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1.[H-].[Na+].C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][C@@H:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:11])[N:15]=1
Reactant: C[C@@H](O)c1cccc([N+](=O)[O-])c1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](Oc1cncc(Cl)n1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a solution of (R)-1-(3-nitrophenyl)ethanol (167 mg, 1 mmol) and 2,6-dichloropyrazine (164 mg, 1.1 mmol) in dioxane was added sodium hydride (88 mg, 60% oil dispersion, 2.2 mmol) in one portion and the mixture was heated at reflux for 4 hours. After this time the mixture was allowed to cool to room temperature and was poured into saturated aqueous sodium hydrogen carbonate (25 mL) and ethyl acetate (25 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate (25 mL). The combined organic phases were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give (R)-2-chloro-6-(1-(3-nitrophenyl)ethoxy)pyrazine (250 mg, 89%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:23][CH:22]=3)=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:26]=3)[C@H:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(C)(C)C(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)OC(C)(C)[C@@H](c1ccccc1)[C@H]2c1ccc(OCCN2CCCC2)cc1

Procedure:
7-Methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-3-chromene (25 g) was dissolved in acetic acid (250 ml) at 60° C. Palladium on carbon (2.5 g, 10%, 50% wet) was added and the mixture hydrogenated at 1 atmosphere hydrogen pressure at 60° C. for 24 hours. The catalyst was filtered off and the filtrate evaporated to en oil. The oil was dissolved in toluene (100 ml) and washed with sodium hydroxide solution (4M) until alkaline. The aqueous phase was separated and extracted with another portion of toluene (20 ml). The combined organic phases was washed with water (2×50 ml) and evaporated to an oil. The oil was dissolved in methanol (100 ml) and crystallized by adding water (200 ml). The product was filtered off and dried.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[C:10]2=[O:17])=[C:5]1[C:27]([O:29]C)=[O:28])[CH:2]=[CH2:3].[OH2:31]>CC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[F:25])[CH2:18][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13](=[O:14])[N:4]3[CH2:1][CH:2]([CH2:3][OH:31])[O:29][C:27](=[O:28])[C:5]3=2)[C:10]1=[O:17]
Reactant: O
Reactant: C=CCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: COc1c2c(c3n(c1=O)CC(CO)OC3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.20 g, 0.46 mmol), N-methylmoroholine N-oxide (67 mg, 0.58 mmol), water (0.2 mL), and osmium tetroxide (0.75 mL, 0.08 M in t-butanol) in acetone (1 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: C([O:3][P:4]([CH2:16][C:17]([OH:19])=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1.CCCCCC>[OH:5][P:4]([CH2:16][C:17]([OH:19])=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:3]
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)CP(=O)(O)CCCCc1ccccc1

Procedure:
[Ethoxy(4-phenylbutyl)phosphinyl]acetic acid from Example 1(b), is further saponified by heating with excess sodium hydroxide, acidification and recrystallization of the product from tetrahydrofuran/hexane to obtain [hydroxy(4-phenylbutyl)phosphinyl]acetic acid; m.p. 109.5°-110°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2)=[O:2].C(=O)=O.CC(C)=O.[C:30]1([Mg]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[OH:2][CH:1]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]1[CH:4]=[C:5]([CH3:22])[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(C)cc(C=O)c2OC1C(F)(F)F
Reactant: Br[Mg]c1ccccc1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(C)cc(C(O)c3ccccc3)c2OC1C(F)(F)F
Reaction time: 4 h
Yield: 54 %

Procedure:
The ethyl 8-formyl-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 605a, Step 1 (0.45 g, 1.43 mmole) was dissolved in anhydrous THF (5 mL) and the solution was cooled to −78° C. (dry ice/acetone). Phenylmagnesium bromide (1.58 mL, 1.58 mmole) was added to the above solution dropwise, which was allowed to stir for 4 hours. The reaction was quenched with saturated ammonium chloride (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give an orange oil. The oil was purified by flash chromatography (silica gel) with 100% CH2Cl2 to give a light yellow oil (0.3g, 54%): GCMS m/z 392.0 (M+). 1H NMR (CDCl3/400 MHz) 7.62 (s, 1H), 7.32 (m, 6H), 6.95 (s, 1H), 6.10 (s, 1H), 5.68 (q, 1H, J=7.0 Hz), 4.28 (m, 2H), 2.28 (s, 3H), 1.32 (m, 3H).