Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)=[O:2].O[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[S:34](=[O:36])(=[O:35])[NH:33][C:32](=[O:37])[CH:31]=2)=[CH:26][CH:25]=1.C([SiH](CC)CC)C>Cl.O1CCOCC1>[O:35]=[S:34]1(=[O:36])[C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][O:2][CH2:1][C:3]3[CH:21]=[CH:20][C:6]([O:7][C:8]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:9]=4[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)=[CH:25][CH:26]=2)=[CH:31][C:32](=[O:37])[NH:33]1
Reactant: O=C1C=C(c2ccc(CO)cc2)S(=O)(=O)N1
Reactant: COC(=O)c1c(OC)cccc1Oc1ccc(C=O)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(OC)cccc1Oc1ccc(COCc2ccc(C3=CC(=O)NS3(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 5.6 %

Procedure:
Methyl 2-(4-formylphenoxy)-6-methoxybenzoate (0.071 g, 0.24 mmol) and 5-[4-(hydroxymethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide (0.050 g, 0.21 mmol) were dissolved in 4 M hydrogen chloride in 1,4-dioxane (2.1 m). The reaction was stirred at ambient temperature for 1.25 h. Triethylsilane (0.13 mL, 0.84 mmol) was added and stirred for 18 h. The reaction was quenched with acetone and evaporated. The product was purified on a 50 mm Luna C18 column using a 20–100% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 30 mL per minute over a 30 minute period. The product was lyophilized to give a white powder (6 mg, 6%). 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.32 (m, 2H), 6.71 (s, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.49 (d, J=8.3 Hz, 1H), 4.62 (m, 2H), 4.55 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H); LCMS found for C26H23NNaO8S (M+Na)+: m/z=532.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.[NH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[C:35]([NH:34][CH2:33][CH2:32][NH:31][C:27]([C:24]1[CH:25]=[CH:26][C:18]2[C:17]3[S:30][C:14]([C:9]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:12](=[O:13])[NH:11][N:10]=4)=[CH:15][C:16]=3[CH2:22][CH2:21][O:20][C:19]=2[CH:23]=1)=[O:28])(=[O:37])[CH3:36]
Reactant: CC(=O)NCCN
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with N-(2-aminoethyl)acetamide, HATU and DIPEA in THF to give 331 as a colorless solid after reverse phase HPLC. MS: (ESI+) 524.0
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].[C:8]([O:11]CC)(=[O:10])[CH3:9].C([O-])(=O)C.[Na+]>O>[C:8]([O-:11])(=[O:10])[CH3:9].[C:2]([NH2+:6][OH:7])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NO
Reactant: CCOC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[NH2+]O
Yield: 92.1 %

Procedure:
N-tert-Butylhydroxylamine hydrochloride (19.7 g, 98%, 0.15 mol) was dissolved in water (40 g) at +20° C. Ethyl acetate (118 g) and sodium acetate (19.3 g, 0.24 mol, 1.5 equiv.) were added. A slurry was formed initially but then dissolved. After 2 h the bluish organic phase was separated and concentrated giving an opaque, yellow oil (20.6 g, 88%) that solidified upon standing in the refrigerator. Chromatographic purity (GC): 97.0 area %.
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:13])=[O:6])[CH3:2].[C:53]1([C@@H:59]([N:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)[C:60](O)=[O:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[CH2:51]([N:3]([CH2:1][CH3:2])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:60](=[O:61])[C@@H:59]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:63]3[CH2:64][CH2:65][CH2:66][CH2:67]3)=[O:32])=[CH:26][CH:25]=2)=[CH:19][CH:20]=1)=[O:13])=[O:6])[CH3:52]
Reactant: O=C(O)[C@@H](c1ccccc1)N1CCCC1
Reactant: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCC3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Yield: 37.4 %

Procedure:
The product from Example 81A (0.032 g, 0.045 mmol) and (R)-2-phenyl-2-(pyrrolidin-1-yl)acetic acid (0.010 g, 0.05 mmol) were processed as in Example 81A to give 0.015 g (37%) of the title compound as an off-white solid. 1H NMR (500 MHz, DMSO-D6) δ ppm 0.89 (t, J=7.10 Hz, 6 H) 1.56-1.66 (m, 4 H) 1.74-1.88 (m, 4 H) 1.94-2.09 (m, 4 H) 2.29-2.34 (m, 2 H) 2.57-2.62 (m, 4 H) 3.36-3.50 (m, 4 H) 3.75-3.88 (m, 2 H) 4.21 (s, 1 H) 4.31 (dd, J=7.93, 4.27 Hz, 1 H) 4.38 (dd, J=8.16, 4.50 Hz, 1 H) 4.57 (s, 4 H) 4.68 (s, 1 H) 6.65 (dd, J=9.31, 4.43 Hz, 2 H) 6.92 (t, J=8.93 Hz, 2 H) 7.19 (d, J=8.24 Hz, 4 H) 7.26-7.30 (m, 2 H) 7.31-7.36 (m, 4 H) 7.40 (d, J=7.17 Hz, 2 H) 7.46 (d, J=6.87 Hz, 2 H) 7.53 (d, J=8.24 Hz, 4H) 9.96 (d, J=5.34 Hz, 2 H); MS ESI− m/z 890.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 4 (3.5 g, crude material), morpholine (0.99 g), potassium carbonate (2.89 g), and potassium iodide (1.66 g) in DMF (22 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated to a residue. The crude material was purified by flash chromatography (silica gel, 30-50% ethyl acetate/hexanes) to yield compound 5 as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])#[CH:9]>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>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: Brc1cccnc1
Reactant: C#Cc1ccc(C)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(C#Cc2cccnc2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-bromopyridine (608 mg, 3.85 mmol), PdCl2(PPh3)2 (246 mg, 0.35 mmol), and Cu(1)I (733 mg, 3.85 mmol) was added TEA (10 mL) followed by 1-ethynyl-4-methyl-2-nitro-benzene (564 mg, 3.5 mmol). After stirring at 60° C. for 4 h, the reaction was filtered, and diluted with EtOAc (150 mL) and 10% Na2CO3 (150 mL). The organic layer was washed with brine, dried over MgSO4; filtered, and dried under reduced pressure. The material was purified using a Biotage 40M cartridge eluting with hexanes/EtOAc (7/3) to yield a light brown oil.
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26][C:27](Cl)=O)=[CH:24][CH:23]=1.Cl>ClCCl>[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH2:27][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8])=[CH:30][CH:31]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(OCc2c(F)cccc2F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)CCc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Meldrum's acid (0.846 g, 5.8 mmol) in dichloromethane (5 ml) was added pyridine (2 ml) over a period of 10 minutes at 0° C. To this solution was added 4-(2,6-Difluorobenzyloxy)benzylcarbonyl chloride (Step D, 1.71 g, 5.7 mmol) in dichloromethane (5 ml), which resulted in an orange solution. The dark orange solution was stirred for 1 hour at 0° C., allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was diluted with dichloromethane and poured onto 2M HCl and ice. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 2M HCl and brine, dried over Na2SO4, filtered and concentrated to a solid. The solid was suspended in abs EtOH (15 ml) and refluxed for 2.5 hours. The solvent was removed in vacuo to give a dark oil. The residue was purified by flash chromatography on silica gel column (hex:ethyl acetate, 2:1) to provide the title compound as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:17])[CH2:15][CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2].C1C=C[NH+]=CC=1.[Br:24][Br-]Br.O>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:17])[CH:15]([Br:24])[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)CC2
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(Br)C2
Reaction time: 3.5 h

Procedure:
To a stirred mixture of 1-acetyl-8-chloro-3,4-dihydrobenz[cd]-indol-5(1H)-one (9.7 g, 0.04 mole) in acetic acid (80 ml.) is added in one portion pyridinium bromide perbromide (13.8 g., 0.042 mole). The stirring is continued for 3.5 hours and then water (150 ml.) is added to the reaction mixture. The dark solid that separates is recovered by filtration and dried. The crude yield is 10 g. (89%) of material that is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][C:11]#[N:12])=[C:5]([CH3:13])[CH:4]=1.[H][H]>N.[Ni]>[NH3:12].[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][CH2:11][NH2:12])=[C:5]([CH3:13])[CH:4]=1
Reactant: COc1cc(C)c(CC#N)cc1C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: COc1cc(C)c(CCN)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (4-methoxy-2,5-dimethyl-phenyl)-acetonitrile (200 mg, 1.14 mmol) and Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was stirred under 60 psi of hydrogen gas at room temperature for 18 hours. Tlc analysis showed that not all of the starting material had been consumed and so further Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was added. The reaction mixture was stirred under 60 psi of hydrogen gas for an additional 18 hours at room temperature and was then filtered through Arbocel®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1 to afford the title product as a pale brown solid in 38% yield, 98 mg. 1H NMR (400 MHz, CDCl3) δ: 6.87 (1H, s), 6.68 (1H, s), 3.77 (3H, s), 2.80 (2H, m), 2.69 (2H, m), 2.28 (3H, s), 2.10 (3H, s) ppm; LRMS APCI m/z 180 [M+H]+
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)=[O:7]>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)=[O:7]
Reactant: CNC
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Solvent: ClCCl
Product: CN(C)CC(=O)c1ccc(OC(F)F)cc1
Temperature: 20 °C
Yield: 44.4 %

Procedure:
To 7.5 g (165 mmole) of anhydrous dimethylamine in 50 ml of methylene chloride and cooled to -30° C. was added a solution of 20 g (664 mmole) of 2-bromo-4'-difluoromethoxyacetophenone in 50 ml of methylene chloride. After the addition was complete the reaction was allowed to warm to 20° C. Concentration in vacuo, partitioning between diethyl ether and 1M aqueous sodium hydroxide, washing with brine, drying over anhydrous magnesium sulfate, and reconcentration in vacuo yielded 16.8 g of 2-dimethylamino-4'-difluoromethoxyacetophenone, an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[N+:17]([O-])=O)=[CH:4][CH:3]=1>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[NH2:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1NCc1ccc(Cl)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(F)ccc1NCc1ccc(Cl)cc1
Yield: 91.6 %

Procedure:
41.7 g of 2-(4-chlorophenylmethylamino)-5-fluoronitrobenzene, prepared in Example 1, re dissolved in 1 l of tetrahydrofuran and hydrogenated at ordinary temperature and pressure in the presence of 5 g of Raney nickel. When the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is evaporated off under vacuum to give 34.1 g of 2-(4-chlorophenylmethylamino)-5-fluoroaniline in the form of crystals melting at 99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)c2ccncc2)cn1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: Cc1ncc(C(CNC(=O)c2c(F)cccc2Cl)c2ccncc2)cn1

Procedure:
From 2-chloro-6-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(pyridin-4-yl)ethanamine. LCMS (MH+): m/z=371.1, tR (minutes, Method F)=1.65
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[C:15](=[O:16])[C:14]3[NH:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:7]2=[O:8])[CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][CH2:24][CH3:25]>>[CH:1]1([CH2:5][N:6]2[C:15](=[O:16])[C:14]3[N:13]([CH2:23][CH2:24][CH3:25])[CH:12]=[N:11][C:10]=3[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:7]2=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CCCCl
Reactant: O=c1c2[nH]cnc2n(CC2CCC2)c(=O)n1CC1CCC1
Product: CCCn1cnc2c1c(=O)n(CC1CCC1)c(=O)n2CC1CCC1

Procedure:
1,3-Di-cyclobutylmethyl-7-n-propyl xanthine was prepared from 1,3-di-cyclobutylmethyl xanthine and 1-chloropropane using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 91° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2Cl.[CH2:17]([N:19]([CH2:27][CH3:28])[CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:26][CH:23]1[CH2:22][CH2:21][CH:20]([N:19]([CH2:27][CH3:28])[CH2:17][CH3:18])[CH2:25][CH2:24]1
Reactant: CCN(CC)C1CCC(N)CC1
Reactant: CS(=O)(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCN(CC)C1CCC(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)CC1
Yield: 86.7 %

Procedure:
Following general procedure B, 6-bromo-4-chloro-3-(methylsulfonyl)quinoline (161 mg, 0.500 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (170 mg, 1.00 mmol) to afford the desired product (197 mg, 87%) as a white solid: ESI MS m/z 454 [C20H28BrN3O2S+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][N:8](C)[C:9](=O)OCC1C=CC=CC=1.[ClH:20]>C(O)C.[Pd]>[ClH:20].[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][NH:8][CH3:9]
Reactant: CN(CC1COCCO1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNCC1COCCO1
Reaction time: 12 h

Procedure:
Benzyl (1,4-dioxan-2-ylmethyl)methylcarbamate (Enantiomer A, 2.9 g, 10.9 mmol) was dissolved in 50 mL dry ethanol. 10% (w/w) palladium on carbon (0.29 g) and 1.0 mL 10 N HCl were added. The flask was sealed and flushed with hydrogen. Stirred solution under a hydrogen balloon. After 12 hours, the solution was filtered through celite and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, D6-DMSO) 8.64 (s, 2H); 3.82-3.75 (m, 2H); 3.69 (d, 1H); 3.64 (d, 1H); 3.59 (m, 1H); 3.44 (m, 1H); 3.22 (t, 1H); 2.94-2.84 (m, 2H); 2.51 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[S:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[C:19]1([C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=4)=[S:34])=[CH:7][CH:6]=3)[CH:18]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2cc(-c3ccccc3)c3ccccc3n2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3cc(-c4ccccc4)c4ccccc4n3)cc2)ccc1Cl
Yield: 55.1 %

Procedure:
2-(4-aminophenylthio)-4-phenylquinoline (3.0 moles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.3 mmoles, 0.79 g) were reacted according to procedure C to yield the title compound 1.03 g, 61%. Mass Spec (FD) 565. Calculated for C29H19ClF3N3S2 : C, 61.53; H, 3.38; N, 7.42. Found: C, 61.82; H, 3.63; N, 7.43.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:15](=[O:19])[C:16]([NH2:18])=[O:17])=[C:13]([CH2:20][CH3:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[OH-].[Na+]>CO>[NH2:18][C:16](=[O:17])[C:15]([C:14]1[C:7]2[C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[N:11][CH:10]=[N:9][C:8]=2[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:13]=1[CH2:20][CH3:21])=[O:19]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)ncnc2n1Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.8 %

Procedure:
A mixture of 70 mg (0.15 mmol) of [[5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 2 mL of methanol were treated with 0.15 mL of 2 M sodium hydroxide and stirred at ambient temperature for 3 days. The reaction was concentrated to an oil then diluted with 5 mL of water. The product precipitated upon the addition of 0.45 mL of 1 M HCl to provide 60 mg (90%) of [[5-(aminooxoacetyl)-6-ethyl-7-[[3-(trifluoromethyl)phenyl]-methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a white solid. nmr (500 MHz, dmso-d6) δ1.00 (t, J=7.4 Hz, 3H), 2.98 (q, J=7.4 Hz, 2H), 4.92 (s, 2H), 5.70 (s, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H) 7.58 (br s, 1H), 7.65 (m, 2H), 8.00 (br s, 1H), 8.46 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:8]=[N:9][N:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:11]=2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:12]1([C:11]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:20][CH:19]=3)[N:9]=[CH:8][C:7]=2[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[CH:30][CH:29]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CN(C)C=O
Reactant: FC(F)(F)Oc1ccc(-n2ncc(Cc3ccc(Br)cc3)c2C2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cnn(-c3ccc(OC(F)(F)F)cc3)c2C2CCCCC2)cc1
Temperature: 75 °C

Procedure:
A mixture of 782 mg 4-(4-bromobenzyl)-5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole from Step D above, 115 mg zinc cyanide, and 94 mg tetrakis(triphenylphosphine)palladium(0) in 5 mL DMF was heated under nitrogen in a 75° C. oil bath over night. Evaporate most of DMF. The residue was purified on silica gel using 10-40% EtOAc in hexanes to give the title compound as a yellowish solid. 1H NMR (CDCl3, 500 MHz) δ 7.61˜7.64 (m, 2H), 7.40˜7.44 (m, 2H), 7.33˜7.37 (m, 4), 7.31 (s, 1H), 4.06 (s, 2H), 2.70 (tt, J=3.1 & 12.5 Hz, 1H), 1.73˜1.79 (m, 4H), 1.66˜1.71 (m, 1H), 1.50˜1.58 (m, 2H), 1.09˜1.24 (m, 3H). LC-MS: 2.46 min. (M+H=426.2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:39][CH:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CN1CCC(N)CC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(NC2CCN(C)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 48, and 1-methylpiperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(1-methyl-piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ1.45 (m, 2H), 1.85 (m, 4H), 2.40 (s, 3H), 2.72 (m, 2H), 3.30 (m, 1H), 5.41 (m, 1H), 6.38 (d, 1H, J=9.7 Hz), 7.05 (m, 4H), 7.29 (m, 3H). LC MS (m/e)=480 (MH+). Rt=1.67 min
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12](Br)[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].O.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: COC(Cn1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(Cn1cc(-c2ccccc2)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (70 mg) obtained in Example 161, Step 2 in dimethoxyethane (1.4 ml)-water (0.7 ml) were successively added phenylboronic acid (32 mg), tetrakis(triphenylphosphine)palladium(0) (31 mg) and sodium carbonate (42 mg), and the mixture was stirred at 80° C. for 2 hr. After cooling to room temperature, the mixture was purified by silica gel column chromatography (ethyl acetate:hexane=1:3–1:1) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-4-oxo-5-phenyl-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (56 mg).