Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[NH:18][C:17]2[C:16](=[O:19])[N:14]([CH3:15])[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([CH:24]([C:28](Cl)=[O:29])[C:25](Cl)=[O:26])C>O1CCOCC1.C(#N)C>[CH2:1]([N:8]1[C:9]2=[N:10][C:11]3[N:12]([CH3:21])[C:13](=[O:20])[N:14]([CH3:15])[C:16](=[O:19])[C:17]=3[N:18]2[C:28]([OH:29])=[CH:24][C:25]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2[nH]c(NCc3ccccc3)nc2n(C)c1=O
Reactant: CCC(C(=O)Cl)C(=O)Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cn1c(=O)c2c(nc3n(Cc4ccccc4)c(=O)cc(O)n23)n(C)c1=O
Temperature: 25 °C

Procedure:
Add 8-benzylaminotheophylline (30 g) and ethyl malonyl chloride (35.1 gm) to 600 ml of 1:1 dioxan/acetonitrile. Heat the reaction mixture to reflux under a nitrogen atmosphere until the 8-benzylaminotheophylline is consumed (ca. 3.5 hrs.). Cool the reaction mixture to room temperature and pour the solution into 800 ml of ether. Filter off the precipitate. Wash the precipitate with ether and dry the product to obtain the title compound, mp. 205.5°-209° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH3:25])[CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=2)[CH2:28][CH3:29])=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(Br)ccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1ccc(C(=O)c2ccccc2C)c(Cl)c1)c1ccc(Br)cc1C

Procedure:
A solution of 4-(4-bromo-2-methyl-phenylamino)-2-chloro-2′-methylbenzophenone (Compound 136)(110 mg) in dry tetrahydrofurane (2.0 ml was added sodium hydride (19 mg) in one portion under stirring. After 10 min at room temperature ethyl iodide (124 mg ) was added and the reaction mixture was stirred for 18 hours under reflux, then poured into water and extracted with EtOAc. The organic phases were separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography using a mixture of EtOAc/pentane 1:8 as eluant to yield the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([CH3:38])[CH:32]=2)[O:28][C:29]=1[CH3:30]>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:27]2[O:28][C:29]([CH3:30])=[C:25]([CH2:24][N:11]3[C:12]4[C:8](=[CH:7][C:6]([CH2:5][CH:4]([O:15][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:3]([OH:2])=[O:22])=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[N:26]=2)=[CH:32][C:33]=1[CH3:38]
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)Oc1ccccc1
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Product: Cc1cc(-c2nc(Cn3ccc4cc(CC(Oc5ccccc5)C(=O)O)ccc43)c(C)o2)ccc1F

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-phenoxy-propionic acid methyl ester (preparation 7) was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole to give rac-3-{1-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-2-phenoxy-propionic acid off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:21]/[C:22]2[NH:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])/[C:11](=[O:20])[NH:12]3)=[CH:4][CH:3]=1.[Cl-].[NH4+]>O.CO.[Zn]>[NH2:17][C:16]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:20])/[C:10]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc(O)cc3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc(O)cc3)c21
Yield: 49.7 %

Procedure:
Using Method L above, (Z)-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (84 mg, 0.22 mmol) (from Example 37 supra) was reduced with zinc (130 mg, 2.0 mmol) and ammonium chloride (25.9 mg, 0.48 mmol) in 10% water in methanol (20 mL) at reflux for 18 h to give (Z)-5-amino-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 38 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=[CH2:28])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]([CH3:16])=[N:18][CH:19]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ncc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)c2ccccc12

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 1-methyl-4-vinylisoquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:10][C:11]([C:13]1([C:43]([OH:45])=[O:44])[O:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][CH:23]([N:25](C(OC(C)(C)C)=O)[CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[OH:28])[CH3:24])=[CH:21][C:15]=2[O:14]1)=[O:12])[C:6]([O:8][CH3:9])=[O:7])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:9][O:8][C:6]([CH:5]([O:10][C:11]([C:13]1([C:43]([OH:45])=[O:44])[O:17][C:16]2[CH:18]=[CH:19][C:20]([CH2:22][CH:23]([NH:25][CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[OH:28])[CH3:24])=[CH:21][C:15]=2[O:14]1)=[O:12])[C:3]([O:2][CH3:1])=[O:4])=[O:7]
Reactant: COC(=O)C(OC(=O)C1(C(=O)O)Oc2ccc(CC(C)N(CC(O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2O1)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(OC(=O)C1(C(=O)O)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1)C(=O)OC
Temperature: 23 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To a stirred solution of 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-methoxycarbonyl-methyl ester (330 mg, 0.50 mmol) and CH2Cl2 (10 mL) was added trifluoroacetic acid (0.08 mL, 113 mg, 0.99 mmol). After stirring at 23° C. for 1 h, additional trifluoroacetic acid (0.08 mL, 113 mg, 0.99 mmol) was added. After a total of 22 h, the mixture was quenched with 5 mL of sat. aq. NaHCO3, and extracted with 3×30 mL of EtOAc. The combined organics were washed with 1×50 mL of brine, dried over MgSO4, filtered and concentrated to a yellow oil. Flash chromatography on silica gel, eluting with CHCl3 /MeOH (20/1 to 10/1) gave 145 mg (52%) of product as a white gum; 1H NMR (300 MHz, CDCl3): δ 1.33 (m, 3H), 1.70-2.40 (brm, 2H), 2.73-2.90 (brt, 1H), 3.04-3.30 (m, 2H), 3.37-3.53 (m, 2H), 3.75 (s, 3H), 3.76 (s, 3H), 4.80 (s, 2H), 4.81 (s, 2H), 5.40 (m, 1H), 6.73-6.93 (complexm, 4H), 7.15-7.32 (m, 2HO, 7.43 (s, 1H); MS (ES) m/z (relative intensity): 566 (M+, 80), 508 (M+ -CO2CH3 +H, 100), 450 (M+ -2CO2CH3 +2H, 30).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=[CH:40]1>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:47][CH2:46][CH2:45][CH2:44][N:39]2[CH:43]=[CH:42][N:41]=[CH:40]2)=[O:34])[C:15]1=[O:38]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: O=C(NCCCn1ccnc1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 3-(1H-imidazol-1-yl)-1-propanamine (0.0072 mL, 0.061 mmol) for 30 min.@150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional equivalent (0.0072 mL) of the amine, cooled to ambient temperature, and the resulting suspension was filtered, washed with EtOH and then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74-1.84 (m, 2 H), 3.18 (q, J=6.60 Hz, 2 H), 3.83 (t, J=6.95 Hz, 2 H), 3.91 (t, J=5.48 Hz, 2 H), 4.14 (s, 2 H), 4.57 (t, J=5.55 Hz, 2 H), 6.90 (t, J=1.05 Hz, 1 H) 7.09-7.18 (m, 3 H), 7.37 (td, J=6.00, 2.32 Hz, 2 H), 7.57 (t, J=1.12 Hz, 1 H), 7.70-7.75 (m, 2 H), 7.78-7.83 (m, 2 H), 8.19 (s, 1 H), 8.54 (s, 1 H), 9.93 (t, J=6.04 Hz, 1 H), 17.12 (bs, 1 H); ES+ MS: 595 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-])=O)=[C:4]([CH3:13])[CH:3]=1.[NH4+].[Cl-]>CCO.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: CNc1nc(Cl)cc(C)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CNc1nc(Cl)cc(C)c1N
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A flask was charged with 6-chloro-N,4-dimethyl-3-nitropyridin-2-amine (Step 109.2) (1 g, 4.96 mmol), Iron (1.385 g, 24.80 mmol) and 7N NH4Cl (21.26 mL, 149 mmol) in EtOH (40 mL) and the resulting mixture was heated up and stirred at 85° C. for 30 min. The reaction was filtered through a pad of Celite and volatils were removed under reduced pressure. The resulting aq. layer was extracted with CH2Cl2, the combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude paterial was purified by silica gel column chromatography (50% EtOAc/hexane) to afford the title product (660 mg, 3.85 mmol, 78% yield) as beige oil. tR: 0.74 min (LC-MS 2); ESI-MS: 172 [M+H]+ (LC-MS 2); Rf=0.39 (50% EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (s, 3H) 2.77 (d, J=4.7 Hz, 3H) 4.46 (s, 2H) 5.91 (d, J=4.3 Hz, 1H) 6.28 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([CH3:21])[NH:16]1>CN1CCCC1=O.C(OCC)(=O)C>[CH3:14][C@H:15]1[NH:16][C@@H:17]([CH3:21])[CH2:18][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=2)[CH2:20]1
Reactant: CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 1-(4-chloro-2-nitrophenyl)ethanone (WO 9322287) (700 mg, 3.5 mmol) and cis-2,6-dimethylpiperazine (1.2 g, 10.5 mmol) in 1-methyl-2-pyrrolidinone (12 ml) was heated at 160° C. in a microwave reactor for 40 min. The reaction mixture was cooled, diluted with ethyl acetate and washed with water (×3), brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting 1:1 mixture of the title compound (D5) MS (ES+) m/e [M+H]+278 and 1-[4-chloro-2-(cis-3,5-dimethyl-1-piperazinyl)phenyl]ethanone MS (ES+) m/e [M+H]+267/269 was used crude in the next reaction.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C@H:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]([CH3:15])([CH3:14])[C:12]#[N:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.O>C1COCC1>[CH3:14][C:11]([CH3:15])([C@H:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH3:22])[N:2]=[CH:3]2)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:12]#[N:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C#N)[C@@H](c1ccccc1)c1ccc2[nH]ncc2c1
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ncc2cc([C@H](c3ccccc3)C(C)(C)C#N)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a stirred solution of (S)-3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanenitrile (80 mg, 0.29 mmol) in anhydrous THF (5 mL) was added 1.0M NaHMDS in THF (0.30 mL, 0.30 mmol) at RT under nitrogen. After stirring at RT for 10 min, methyl iodide (0.03 mL, 0.48 mmol) was added, and the reaction was stirred overnight. The reaction mixture was poured into water, extracted with ethyl acetate (2×100 mL), dried (MgSO4) and concentrated. The resulting N1 and N2 adducts were separated by HPLC to give 54 mg (62% yield) of the desired N1 adduct (S)-2,2-dimethyl-3-(1-methyl-1H-indazol-5-yl)-3-phenylpropanenitrile. MS found: (M+H)+=290.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:27][CH3:28])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[F:30][C:31]([F:35])([F:34])[CH2:32][NH:33][C:24]([C@@H:16]1[CH2:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]1[C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:27][CH3:28])=[O:26]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1c2ccccc2C[C@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-Benzyloxycarbonyl-2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid (0.382 g, 1 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.207 g, 1.5 mmol) were dissolved in dried dichloromethane (10 ml), and triethylamine (5.5 mmol) was added, followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.508 g, 2.0 mmol) under nitrogen at 0° C. The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under reduced pressure to give a brown solid which was purified by column chromatography on silica gel using 7:3 petroleum spirit: ethyl acetate as eluent to afford a white solid.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[C:8]([C:11]#[N:12])[CH:7]=[CH:6][C:5]=1[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:2]=[CH2:3].CN(C=O)C.[Li+].[Cl-]>CC([O-])=O.CC([O-])=O.[Cu+2].Cl[Pd]Cl.O>[C:11]([C:8]1[C:9]2[O:10][C:2]([CH3:3])=[CH:1][C:4]=2[C:5]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:7]=1)#[N:12]
Reactant: C=CCc1c(NC(=O)C(C)(C)C)ccc(C#N)c1O
Agent: Cl[Pd]Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(NC(=O)C(C)(C)C)ccc(C#N)c2o1
Temperature: 100 °C
Yield: 60.3 %

Procedure:
To a solution of compound 10D (0.5 g, 1.94 mmol) in a mixed solvent of DMF (2.5 mL) and water (1.9 mL) was added Cu(OAc)2 (1.057 g, 5.82 mmol), followed by a 10 M aqueous solution of LiCl (0.58 mL, 5.8 mmol) and PdCl2 (34.3 mg, 0.194 mmol). The resulting suspension was heated to 100° C. for 1 h. After cooling to rt, the reaction mixture was poured into ice/water, and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude product was chromatographed (silica gel) eluting with 10% to 50% EtOAc/hexane to furnish the title compound (0.3 g) as a white foam.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:31]=[CH:30][C:20]([O:21][CH2:22][C:23]3(O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:32][C@@H:33]([CH2:37][CH2:38][CH2:39][CH3:40])[C:34]([OH:36])=[O:35].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:32][C@@H:33]([CH2:37][CH2:38][CH2:39][CH3:40])[C:34]([O:36][C@H:26]1[CH2:27][CH2:28][C@H:23]([CH2:22][O:21][C:20]2[CH:30]=[CH:31][C:17]([C:14]3[N:13]=[CH:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1)=[O:35]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(OCC3(O)CCCCC3)cc2)nc1
Reactant: CCCC[C@H](F)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCc1cnc(-c2ccc(OC[C@H]3CC[C@H](OC(=O)[C@@H](F)CCCC)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
0.62 g of trans-4-[(p-(5-decyl-2-pyrimidinyl)phenoxymethyl]cyclohexanol, 0.196 g of (S)-2-fluorocaproic acid, 0.413 g of dicyclohexylcarbodiimide and 0.025 g of 4-(dimethylamino)pydidine were dissolved in 25 ml of methylene chloride and stirred at room temperature for 15 hours. The white suspension was subsequently filtered. The residue obtained after evaporation of the solvent from the filtrate was purified by chromatography on silica gel with ethyl acetate/petroleum ether (vol. 1:9). Subsequent crystallization from 10 ml of ethyl acetate and 50 ml of hexane gave 0.62 g of trans-4-[(p-(5-decyl-2-pyrimidinyl)phenoxy)methyl]cyclohexyl (S)-2-fluorohexanoate as colourless crystals, m.p. (C-S) 88.5° C., phase transitions (S-SC) 108.8° C., (SC -SA) 128° C., cl.p. (SA -I) 137.7° C.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20]O)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].C1C=CC(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.C1COCC1>C1(C)C=CC=CC=1>[N:36]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=2)[CH:9]=1)=[N+:37]=[N-:38]
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CO)cn12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(Sc3ccccc3CN=[N+]=[N-])cn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
To a suspension of [2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-phenyl]-methanol (254.0 mg, 0.85 mmol) and DPPA (220 μL, 1.02 mmol) in toluene (8.5 mL, 0.10 M) at 0° C. was added DBU (152.0 μL, 1.02 mmol), followed by the addition of THF (1 mL). The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was quenched with NaHCO3, and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 2% methanol/ethyl acetate) to give the title compound as an oil (228 mg, 83%). MS (M+1)=370.5.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:23])([F:22])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19](=S)[NH2:20])[CH:9]=[CH:10][CH:11]=1>CO>[F:4][C:5]([F:23])([F:22])[C:6]1[CH:7]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([NH:2][NH2:3])=[NH:20])[CH:9]=[CH:10][CH:11]=1
Reactant: NC(=S)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: N=C(NN)c1ccccc1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
Hydrazine hydrate (1.80 ml) is added dropwise to a room temperature solution of 2-[(3-trifluoromethylphenyl)amino]benzene thioamide (2.88 g, 9.73 mmoles) in 100 ml of methanol. The solution is stirred at room temperature under nitrogen for six hours. An additional 400 μl of hydrazine hydrate is added, and stirring is continued for one hour. The solution is concentrated in vacuo and purified by flash chromatography eluting with ethyl acetate to give 2.28 g (80%) of a gummy tan solid. This material is used immediately in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:37])([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]([F:37])([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(F)(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(F)(c4ccc(F)cc4)CC3)cnc12
Yield: 25.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-fluoro-4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo [1,5-a]pyrimidine-3-carboxylic acid (64 mg, 0.12 mmol) obtained in step 2 and ethanesulfonamide (51 mg, 0.48 mmol), the title compound (18 mg, 25%) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:22]4[CH:23]=[N:18][CH:19]=[N:20][CH:21]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1cncnc1
Product: N#Cc1cc(-c2cncnc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (16 mg, 22%), MS (ISN) m/z=290.5 [(M+H)+], mp 323.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].CC(C)=[O:12].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:1]([OH:12])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: CC(C)=O
Reactant: C=CCCCCCCO
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=CCCCCCC(=O)O
Reaction time: 0.17 h

Procedure:
To a stirred solution of 152 g of oct-7-en-1-ol (prepared in Example 22 B-1) in 3.4 liters of acetone there was added 1.4 M of Jones Reagent (986 ml) while the mixture was maintained at less than 10° C. The mixture was stirred for 10 min and was quenched with 100 ml of isopropanol. The acetone volume was reduced in vacuo and the residue was diluted with water and extracted three times with equal volumes of ethyl acetate. The combined ethyl acetate extracts were washed two times with water, then with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to yield 164 g of the title compound having the following physical characteristics:
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([N:22]3[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[C:17]([F:29])[CH:16]=2)[CH2:10]1)(C)(C)C.[F:31][CH:32]([F:38])C(OCC)=O>>[F:21][C:19]1[CH:20]=[C:15]([N:11]2[CH2:10][CH:9]([CH2:8][NH:7][C:6](=[O:30])[CH:32]([F:38])[F:31])[O:13][C:12]2=[O:14])[CH:16]=[C:17]([F:29])[C:18]=1[N:22]1[CH:27]=[CH:26][C:25](=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(F)F
Reactant: CC(C)(C)OC(=O)NCC1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Product: O=C1C=CN(c2c(F)cc(N3CC(CNC(=O)C(F)F)OC3=O)cc2F)CC1

Procedure:
The compound is prepared from {3-[3,5-difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (402 mg, 0.92 mmol) and ethyl difluoroacetate (360 mg, 2.88 mmol) following the method described in example 9. The crude product is purified by silica gel column chromatography (eluent: EtOAc) to give a white solid. Yield 68 mg (18%). MS (m/z): 402 [M+1]+. 1H NMR (300 MHz, DMSO-d6): 9.16 (br. t, 1H), 7.46–7.38 (m, 3H), 6.24 (dd, J=11.0 and 14.8 Hz, 1H), 4.99 (d, J=7.4 Hz, 1H), 4.85–4.81 (m, 1H), 4.15 (t, J=9.3 Hz, 1H), 3.81–3.74 (m, 3H), 3.52 (t, J=5.5 Hz, 2H), 2.48 (m, 2H).