Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24]([NH2:26])[CH3:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CO>O1CCCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:26][CH:24]([CH3:25])[CH3:23])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(C)N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(cc(NC(C)C)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a suspension of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20.0 mg, 0.0644 mmol, from Example 228, Step 7), 2-propanamine (51 μL, 0.60 mmol, Aldrich) and tBuXPhos Pd G1 (7.1 mg, 0.0096 mmol, Aldrich) in tetrahydrofuran (0.3 mL) was added 1.0 M LHMDS in THF (0.19 mL, 0.19 mmol, Aldrich). The reaction was stirred for 3 days, after which time additional amounts of tBuXPhos Pd G1 (6 mg, 0.008 mmol), 2-propanamine (51 uL, 0.60 mmol), THF (0.3 mL) and 1.0 M LHMDS in THF (0.2 mL, 0.2 mmol) were added and the mixture was heated at 100° C. for 2.5 hours. After cooling to room temperature, MeOH was added, and the mixture was filtered. The product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (0.2 mg, 1%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:36])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:36])[CH2:13][NH:14][C:15](=[O:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(N2CCNCC2)c1
Temperature: 27 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To a solution of tert-butyl 4-(3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy propylcarbamoyl)phenyl)piperazine-1-carboxylate (140 mg, 0.28 mmol) in DCM (2 mL) was added TFA (2 mL). The resulting solution was stirred at 27° C. for 4 h. The solution was concentrated and the residue was purified by prep-HPLC to give the title product (64.0 mg, Yield 57%). 1H NMR (CD3OD, 400 MHz): δ 7.47-7.38 (s, 1H), 7.31-7.21 (m, 2H), 7.19-7.08 (m, 4H), 7.08-7.01 (m, 1H), 4.13 (quin, J=6.0 Hz, 1H), 3.77 (s, 2H), 3.62-3.52 (m, 1H), 3.51-3.43 (m, 1H), 3.31-3.19 (m, 4H), 3.15-3.00 (m, 4H), 2.98-2.83 (m, 4H), 2.75-2.62 (m, 2H). LCMS (m/z): 395.2 (M+1).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][O:14][C:12](=[O:13])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]C(C)C)(C)C>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]([CH2:15][OH:14])[CH2:11][CH:12]=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](OC(=O)c2ccccc2)CO1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=CC[C@@H](CO)OC(=O)c1ccccc1
Temperature: -78 °C
Yield: 73.7 %

Procedure:
To a solution of 101 (0.780 g, 3.8 mmol) in 13 mL dry THF was slowly dropwise added 1.0 M diisopropyl aluminiumhydride (4.7 mL, 4.7 mmol) in toluene at −78° C. The reaction mixture was stirred at −78° C., and as soon as the material was completely consumed (TLC, 2 hours), methanol (2 mL) was slowly added in order to quench the reaction. The cooling bath was removed, 15 mL of a saturated ageous sodium potassium tartrate solution and 25 mL of EtOAc were added and the mixture stirred vigorously for 3 hours. The organic layer was washed with water and brine, and concentrated under vacuo. The residue was purified by chromatography on a silica gel column (n-hexane/EtOAc=8:2) to afford 102 (590 mg, 2.8 mmol) as a colorless oil, in 75% yield, which was characterized as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)cc(F)c3)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 3,5-difluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 46.1 mg (>100%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[C:15](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:16]1([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=2[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cl)ccc1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.1 %

Procedure:
4-Chloro-2-trifluoroacetylaniline (22.4 g, 100 mmol), trityl chloride (30.0 g, 107 mmol), triethylamine (11.6 g, 115 mmol) and DMAP (0.5 g, 4 mmol) were dissolved in DMF (50 mL) and held 14 h at 60° C. The resulting slurry was cooled to room temperature, diluted with 20 mL water and filtered to give 35.9 g (77%) of title compound. An analytical sample was obtained by recrystallization from acetonitrile: mp 165-167° C.; 1H NMR (CDCl3) δ 10.4 (brs, 1H), 7.71 (brt, J=2 Hz, 1H), 7.3 (brs, 15 H), 6.9 (dd, J=2, 8 Hz, 1H), 6.27 (d, J=8 Hz, 1H) 13C NMR (75 MHz, CDCl3) δ 180.5, 151.2, 144.1, 135.7, 130.7, 130.6, 129.2, 128.9, 128.7, 128.6, 128.5, 128.2, 128.0, 127.7, 127.5, 122.9, 120.3, 119.3, 119.1, 115.2, 112.3, 111.3, 71.9; 19F NMR (282 MHz, CDCL3) δ -69.5.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.O=[Pt]=O>[N:1]1([CH2:6][C@H:7]2[NH:12][CH2:11][C@@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CN2CCCC2)nc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@@H](CN2CCCC2)NC1
Yield: 118.7 %

Procedure:
A solution of the product of stage (i) (4.1 g) in glacial acetic acid (80 ml) was hydrogenated at 22° and atmospheric pressure over Adams' catalyst (3 g). After 3 h the uptake of hydrogen was complete and the mixture was filtered. The filtrate was evaporated to leave an oil which was partitioned between 2N sodium carbonate solution (100 ml) and dichloromethane (100 ml). The aqueous phase was further extracted with dichloromethane (100 ml). The combined organic extracts were washed with saturated brine, dried and evaporated to leave an oil (5.0 g). The oil was purified by flash chromatography eluting with a mixture of dichloromethane, ethanol and ammonia (200:8:1) to give the title compound as an oil (2.6 g). N.m.r.-indicates mixture of cis:trans (3:1). T.l.c. Silica (Dichloromethane:ethanol: 0.88 ammonia 100:8:1) Rf 0.4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:15])=[C:5]([C:11]([Cl:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].CCN(CC)CC.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CCOC(C)=O>[Cl:14][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:15])[C:3]([CH2:2][NH:1][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CN)c1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (70 mg, 0.3 mmol) in THF (3 mL) were added Et3N (0.105 mL, 0.76 mmol) and pivaloyl chloride (38 μL, 0.31 mmol). The reaction mass was stirred at rt for 2 h, diluted with EtOAc and was washed with water, and brine. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.15 (br t, 1H), 7.43-7.35 (m, 2H), 4.38 (q, J=7.2 Hz, 2H), 4.26 (d, J=5.7 Hz, 2H), 1.30 (t, J=6.9 Hz, 3H), 1.11 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([Si:7]([O:10][C@H:11]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:17]3[CH2:18][CH2:19]/[C:20]/2=[CH:21]/[CH3:22])[CH2:12]1)([CH3:9])[CH3:8])([CH3:6])[CH:3]([CH3:5])[CH3:4].[CH3:32][C:33]([Si:36]([CH3:46])([CH3:45])[O:37][C:38]([CH3:44])([CH3:43])[C:39]#[C:40][CH:41]=[O:42])([CH3:35])[CH3:34].[Cl-].C[Al+]C.OP([O-])([O-])=O.[Na+].[Na+].Cl>CCCCCC>[CH3:35][C:33]([Si:36]([CH3:46])([CH3:45])[O:37][C:38]([C:39]#[C:40][CH:41]([OH:42])[C@H:21]([C:20]1[C@:23]2([CH3:31])[C@H:17]([C:16]3[C@H:26]([CH2:25][CH2:24]2)[C@:27]2([CH3:30])[C:13]([CH2:12][C@@H:11]([O:10][Si:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:6])[CH:3]([CH3:4])[CH3:5])[CH2:29][CH2:28]2)=[CH:14][CH:15]=3)[CH2:18][CH:19]=1)[CH3:22])([CH3:44])[CH3:43])([CH3:32])[CH3:34]
Reactant: C/C=C1/CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(C#CC=O)O[Si](C)(C)C(C)(C)C
Agent: C[Al+]C
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: CCCCCC
Product: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C([C@H](C)C(O)C#CC(C)(C)O[Si](C)(C)C(C)(C)C)=CC[C@@H]32)C1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A mixture of 57.65 g (131 mmol) (3β,17Z)-(1,1,2-trimethylpropyl)(pregna-5,7,17(20)-trien-3-yloxy)dimethylsilane, 34.11 g (151 mmol 4-[[(1,1-dimethylethyl)dimethylsilyl]oxy-4-methyl-2-pentynal, and 800 mL hexane was cooled to about -40° C. Then, 185 mL (185 mmol) 1M dimethylaluminum chloride in hexane was added dropwise within 30 min. After the dark brown solution was stirred at -40° C. for 30 min., 400 mL of 5% aqueous sodium phosphate dibasic (w/v) was added dropwise, and the mixture was allowed to warm to 5° C. Then, 300 mL of 3N HCl was added dropwise at a temperature of 0°-5° C. followed by 40 g of Celite. After 15 min, the solid was filtered and washed with 400 mL of hexane. The aqueous layer was extracted twice with hexane. The combined hexane solutions were washed successively with water, 10% aqueous NaHCO3, and brine. The hexane layer was dried and concentrated to give 90 g (overweight) of crude (3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy] cholesta-5,7,16-trien-23-yn-22-ol (5:1 mixture of epimers at C-22) as an orange oil. This crude material was used for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][N:22]([C:30]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:31])[CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(Nc2cc(N(C)C)nc(N3CCN(C(=O)c4cccs4)CC3)n2)c1
Yield: 79.8 %

Procedure:
A solution of N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (33 mg, 0.1 mmol), 2-thiophenecarbonyl chloride (20 mg, 0.14 mmol), and triethylamine (40 mg, 0.4 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer was washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product as a pale red oil (35 mg, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([Sn](CCCC)(CCCC)C(C)=C)[CH2:19][CH2:20]C>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>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[C:19]([CH3:20])=[CH2:18])[CH2:12][CH2:13]1
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(C)c1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 105 °C

Procedure:
A mixture of 1-(2-bromo-4-nitrophenyl)-4-methylpiperazine (0.810 g, 2.70 mmol), tetrakis(triphenylphosphine)palladium(0) (0.094 g, 0.081 mmol), and tributyl(prop-1-en-2-yl)stannane (0.983 g, 2.97 mmol) in 1,4-dioxane (30 mL) was degassed and heated at 105° C. overnight. After cooling, the suspension was filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with methanol/ethyl acetate (5:95 to 10:90) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][N:11]3[CH:17]=[N:18][CH:19]=[C:10]23)=[CH:5][CH:4]=1.S(=O)(=O)(O)O>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][N:11]3[CH:17]=[N:18][CH:19]=[C:10]23)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(O)c3cncn3CCC2(C)C)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1ccc(C2c3cncn3CCC2(C)C)cc1
Reaction time: 6 h

Procedure:
A solution of 3.50 mmol of 8-(4-methoxyphenyl)-7,7-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-ol in 10 ml of ethanol is admixed with 3.5 mmol of concentrated sulphuric acid and 0.70 mmol of 10% Pd/C and the reaction mixture is hydrogenated in an autoclave at 4 bar and 60° C. for 4-8 hours. The reaction mixture is filtered over Hyflo and the filtrate is concentrated. The title compound is used without further purification for the next stage. Rt=5.89 (Gradient I).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH2:42]([O:49][C:50]1[CH:51]=[N:52][CH:53]=[C:54](Br)[CH:55]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:54]3[CH:53]=[N:52][CH:51]=[C:50]([O:49][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:55]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 6-bromo-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (800 mg, 2.6 mmol) in 1,4-dioxane (64 mL) is added bis(pinacolato)diboron (714 mg, 2.8 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (187 mg, 0.26 mmol) and potassium acetate (751 mg, 7.7 mmol) under nitrogen. The resultant mixture is heated to reflux for 2 h. After cooling to rt, 3-benzyloxy-5-bromo-pyridine (677 mg, 2.6 mmol), sodium carbonate (815 mg, 7.7 mmol) and additional 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (94 mg, 0.13 mmol) are added under nitrogen. The reaction is heated to reflux for 16 h. The crude product is purified by silica gel column to obtain 6-(5-benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (790 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].I[CH3:16]>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[N:7]2[CH3:16]
Reactant: CI
Reactant: O=C1CNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (415 mg, 2.5 mmol) in THF (10 ml) was added sodium hydride (60%, 100 mg, 2.5 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was cooled again in an ice/water bath and iodomethane (156 μl, 2.5 mmol) was added. The mixture was allowed to warm slowly to room temperature and stirred for 3 days. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and separated. The organic phase was washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 45:55) to give a white solid; yield 210 mg, 47%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Cl-].[Na+].O>[C:19]([NH:1][CH2:2][CH2:3][P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:21])[CH3:20]
Reactant: CCOP(=O)(CCN)OCC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CCNC(C)=O)OCC
Reaction time: 20 h
Yield: 93.5 %

Procedure:
To a solution of diethyl 2-aminoethylphosphonate (10.5 g), triethylamine (7.0 g) in dichloromethane (200 ml) at 0° C. was added dropwise acetic anhydride (7.1 g). After 20 hours at room temperature, the reaction mixture was diluted with brine, made basic with 5% aqueous potassium carbonate, and extracted twice with dichloromethane. The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (5% methanol in chloroform) to give (12.1 g) of diethyl 2-acetylaminoethylphosphonate as an oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:5][CH:4]=1
Reactant: OCCc1ccc(CBr)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: BrCc1ccc(CCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
A mixture of 16.9 g (78.5 mmoles) of 4-(bromomethyl)benzeneethanol (prepared according to Plaue S. and Heissler D. Tetrahedron Lett. (1987) 28, 1401-4), 10.6 g (125 mmoles) of 3,4-dihydro-2H-pyrane and 0.16 g of para-toluenesulfonic acid in 160 ml dry ethyl ether, is stirred 16 hours at room temperature. The reaction mixture is thereafter washed with a solution saturated with sodium bicarbonate, then water, dried over Na2SO4 and concentrated, to give 21.5 g (yield=91.5%) of a yellow oil used without other purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20][CH2:19]2)[C:14]1=[O:34]>C(O)C.Cl.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:34]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)c(F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Yield: 6.3 %

Procedure:
A solution of (S)-benzyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.3 g, 27 mmol) in ethanol (20 mL) and concentrated HCl (300 μL) was hydrogenated at 40 PSI with 10% Degussa type Pd/C (650 mg) for 18 hours. The mixture was filtered through celite and the solids were washed with MeOH (200 mL) and water (200 mL). The methanol in the filtrate was removed in vacuo. The water layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (600 mg, 1.7 mmol, 64%). Mass spectrum (apci) m/z=356.1 (M+H).
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(NC(=O)c4ccccc4)ccc3c2O)cc1
Reaction time: 16 h
Yield: 47.9 %

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 6, 200 mg, 0.48 mmol ) was dissolved in dichloromethane (3 mL) and diisopropylethylamine (160 μL, 114 mg, 0.96 mmol) was added. Benzoyl chloride (85 mg, 0.60 mmol ) was then added under nitrogen. The reaction mixture was allowed to stir for 16 h. The suspension was filtered to provide the title compound (120 mg, 0.23 mmol, 48%) as a red solid: NMR (DMSO-d6): δ 16.25 (s, 1H), 10.81 (s, 1H), 8.52 (m, 1H), 8.37 (d, J=9 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 8.02 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.64 (m, 3H), 7.18 (d, J=9 Hz, 2H), 4.82 (m, 1H), 3.83 (s, 3H), 1.25 (d, J=6 Hz, 6H); Analytical HPLC: 95% pure; MS (ES-NEG): [M−H] 518; Anal. Calc. for C27H24N3O6SNa: C, 62.42, H, 4.85, N, 8.09. Found: C, 60.61, H, 4.77, N, 7.70.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O1CCOCC1.O.C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C[C@@H](N)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(S(=O)(=O)N[C@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(D)-leucine (7.1 g, 53.9 mmol) is dissolved in dioxane (60.0 mL) and water (60.0 mL). To this solution is added triethylamine (11.3 mL, 80.9 mmol) and 4-methoxybenzenesulfonyl chloride (12.25 g, 59.3 mmol), and the reaction is stirred at room temperature overnight. The reaction is then diluted with methylene chloride and washed successively with 2.5N hydrochloric acid, water, and brine. The organic phase is dried (Na2SO4), and the solvent is evaporated to give N-[4-methoxybenzenesulfonyl]-(D)-leucine, which is used without further purification.