Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:11][S:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:22](OCC)(=[O:28])[C:23](OCC)=[O:24].Cl>C1COCC1>[C:7]([N:11]1[C:23](=[O:24])[C:22]([OH:28])=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12]1(=[O:14])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)(C)NS(=O)(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 150 °C
Yield: 471.3 %

Procedure:
Potassium tert-butoxide (0.845 g, 10.56 mmol) was added to a solution of N-(tert-butyl)-1-phenylmethanesulfonamide (1.2 g, 5.28 mmol) and diethyl oxalate (0.85 mL, 6.33 mmol) in THF (8 mL) and the mixture was heated at 150° C. for 15 mins in a microwave reactor. The reaction mixture was acidified with 1M HCl, the THF was evaporated and the residue was Example tracted with DCM. Evaporation and trituration of the residue with petroleum ether gave the title compound (7 g, 63%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.44-7.32 (m, 5H), 3.90 (br s, 1H), 1.36 (s, 9H); Mass Spectrum: M−H+ 280
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=S.CC(C)N=C=NC(C)C>C1COCC1>[C:8]1([NH:7][C:5]([C:4]2[CH:14]=[CH:15][C:16]3[NH:17][C:27]([NH:26][C:20]4[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:25])=[N:1][C:2]=3[CH:3]=2)=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1ccc(C(=O)Nc2ccccc2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of the product obtained at (1b) (250 mg, 0.99 mmol) in 5.0 mL of THF was combined with 1,3-dichloro-2-isothiocyanato-benzene (222 mg, 1.09 mmol) and stirred for 5 h at ambient temperature under nitrogen. DIC (166 μL, 1.04 mmol) was added and the stirred mixture was heated to 55° C. for 16 h. The mixture was filtrated and concentrated i.vac., the residue purified by HPLC (Symmetry C18, 7 μM, eluent gradient: (H2O+0.15% HCOOH)/acetonitrile=95:5->5:95).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:17][CH2:18][CH2:19][OH:20]>CN(C)C=O>[CH2:3]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:17][CH2:18][CH2:19][OH:20])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCOc1cccc(O)c1
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(OCCCO)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 0.80 g of 60% NaH in 28 ml of anhydrous dimethylformamide is cooled in an ice bath. To this is added 3.01 g of the above 3-pentyloxyphenol oil dissolved in 7 ml of anhydrous dimethylformamide. This mixture is then stirred at room temperature for 45 minutes; 1.81 ml of 3-Bromopropanol are added; and the resultant mixture is stirred at 60° C. for 17 hours. The solvent is removed under vacuum, and the residue worked up in same manner as above. The residue obtained is flash chromatographed on normal phase silica gel eluting with a 3:2 ratio of hexane:ether to yield 3-[3-(pentyloxy)phenoxy]propanol as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:25]([NH:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:24])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][CH2:16]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1NCc1ccccc1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
The obtained 4-(4-benzoylpiperazin-1-yl)-2-nitrobenzoic acid (0.40 g, 93%) was dissolved in 30 ml ethanol and 10 ml THF, followed by the addition of platinum oxide (20 mg, 5%) and stirred under hydrogen gas for 16 hours. The reaction was filtered with the aid of celite. 2-amino-4-(4-bezoylpiperazin-1-yl)benzoic acid (0.24 g, 70%) was obtained after removing of solvents. To a solution of 2-amino-4-(4-bezoylpiperazin-1-yl)benzoic acid (0.2 g, 0.6 mmol) and benzaldehyde (0.14 ml, 1.3 mmol) added sodium triacetoxyborohydride (0.4 g, 1.8 mmol) and stirred under argon atmosphere overnight. The reaction was quenched with 10 ml water and extracted with ethyl acetate (3×20 ml), followed by drying it over anhydrous sodium sulfate. 2-(benzylamino)-4-(4-benzoylpiperazin-1-yl)benzoic acid (0.11 g, 40%) was obtained after concentration. 1H NMR (500 MHz, CDCl3) δ (ppm) 3.25-3.88 (m, br, 8H), 4.48 (s, 2H), 6.20 (d, J=2.3 Hz, 1H), 6.22 (dd, J=2.3, 9.1 Hz, 1H), 7.30-7.45 (m, 10H), 7.48 (d, J=9.1 Hz, 1H), 8.25 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=2)[CH2:4][CH2:3]1.[O-:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H](NC(=O)c2cccc(Br)n2)CC1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](NC(=O)c2cccc(Oc3ccccc3)n2)CC1

Procedure:
A nitrogen purged mixture of N-(trans-4-methylcyclohexyl)-6-bromo picolinamide (446 mg, 1.5 mmol), sodium phenoxide (209 mg, 1.8 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalldium(II) (1:1 complex with dichloromethane; 83 mg, 0.1 mmol) in toluene-tetrahydrofuran (9:1, 5 mL) was treated with bis(dibenzylideneacetone)palladium(II) (86 mg, 0.15 mmol) and the mixture heated at reflux overnight. After this time the reaction mixture was diluted with ethyl acetate (25 mL) and filtered. The organic solution was washed with water (2×20 mL), brine, dried over anhydrous MgSO4, filtered and concentrated. Chromatography of the crude product on silica (2 mm, chromatotron) with ethyl acetate-hexane (1:3, containing 1% diethylamine) afforded 97 mg (21%) of 410:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42].[Cl-].[NH4+]>[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40]
Reactant: COC(=O)c1ccc(OC)cc1CBr
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC)cc1CC#C[Si](C)(C)C
Temperature: 55 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To the THF (16 ml) solution of 2-bromomethyl-4-methoxy-benzoic acid methyl ester (961 mg, 4.09 mmol), triphenylphosphine (107 mg, 0.1 eq.), cesium carbonate (1.87 g, 1.4 eq.), copper iodide (59 mg, 0.076 eq.) and tris(dibenzylideneacetone)dipalladium (86 mg, 0.023 eq.) were added, degassed, flushed with nitrogen gas, added with trimethylsilylacetylene (734 μl, 1.3 eq.), and then stirred overnight at 55° C. To the reaction solution, saturated aqueous solution of ammonium chloride was added followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (brown oily substance, 606 mg, 54%).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CCCCCC[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CN(C)CCO[C:38]1[CH:47]=[CH:46][C:45]2[CH2:44][CH2:43][CH2:42][CH2:41][C:40]=2[CH:39]=1.C(OCOCC)C.C1(C)C(C2C(C)=CC=CC=2)=CC=CC=1.CC1C=CC(O)=CC=1>>[CH3:32][C:31]1[CH:26]=[CH:27][C:28]([C:38]2[CH:39]=[C:40]3[C:45](=[CH:46][CH:47]=2)[CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:29][CH:30]=1
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2
Reactant: CCCCCCCCCCCCC
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1ccc(O)cc1
Agent: Cc1ccccc1-c1ccccc1C
Solvent: CCOCOCC
Product: Cc1ccc(-c2ccc3c(c2)CCCC3)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
In a reaction flask was placed NiCl2(PCy3)2 (69.0 mg, 0.0999 mmol), PCy3 (57.8 mg, 0.206 mmol), tridecane (328 mg, 1.778 mmol, as an internal standard), and N,N-dimethyl-N-[2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)ethyl]amine (409 mg, 1.867 mmol). The solvent in the Grignard reagent (1 M in ether, 6.0 mmol) was exchanged with diethoxymethane (6.0 mL) and this solution added to the above catalyst mixture under a nitrogen atmosphere at room temperature. The resulting solution was stirred for several minutes at room temperature and then warmed to 95° C. for 15 hours. A sample was withdrawn and quenched with an aqueous sodium citrate solution (1 M) and was extracted with ethyl acetate. GC analysis of the organic phase showed the presence of 6-(4-methylphenyl)-1,2,3,4-tetrahydronaphthalene (1.851 mmol, 99% yield) and bitoluene (0.654 mmol) and p-methylphenol (0.575 mmol) in the reaction mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([NH2:26])=[O:25])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[F:15])=[CH:11][C:10]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:9][CH:8]=3.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[F:15][C:14]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:11]=3)[NH:6][C:5]=2[C:4]([C:24]([NH2:26])=[O:25])=[CH:3][C:2]=1[C:32]1[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
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: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)N5CCOCC5)cc4c3c2F)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
3-Bromo-4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (25 mg, 0.059 mmol), 4-methoxyphenylboronic acid (13.56 mg, 0.089 mmol), Pd(Ph3P)4 (6.87 mg, 5.95 μmol) and Na2CO3(2M) (0.074 mL, 0.149 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was stirred at 105° C. for 3 hrs. The mixture was filtered through an ACRODISC® PTFE membrane (0.45 um) and purified using preparative HPLC to give 12.2 mg of titled product. MS (ESI) m/z 448.06 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.86 (bs, 1H), 8.31 (bs, 1H), 8.16 (d, 1H, J=9.1), 8.14 (s, 1H), 7.83 (d, 1H, J=8.6), 7.66 (d, 2H, J=8.2), 7.55(m, 2H), 7.11 (d, 2H, J=8.5), 3.84 (s, 3H), 3.7-3.5 (bm, 8H).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[N:15]=[C:14](F)[N:13]=2)=[CH:7][CH:6]=1>CS(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[N:15]=[C:14]([C:1]#[N:2])[N:13]=2)=[CH:7][CH:6]=1
Reactant: Fc1cc(Nc2ccc(Cl)cc2)nc(F)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1nc(F)cc(Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium cyanide (0.046 g) was added to a solution of the product from step (i) (0.113 g) in dimethylsulphoxide (3 ml) and stirred at room temperature for 1.5 h. The mixture was partitioned between ethyl acetate and water, the organics washed with water, dried (MgSO4), and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/ethyl acetate (4:1). Yield 0.036 g
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[NH:8][C:7](=[S:11])[NH:6][C:5]2=[O:12].[CH3:13]I>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[C:7]([S:11][CH3:13])[NH:6][C:5]2=[O:12]
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]n2cc(Br)cc12
Solvent: C1CCOC1
Product: CSc1nn2cc(Br)cc2c(=O)[nH]1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Into a round bottom flask, 6-Bromo-2-thioxo-2,3-dihydro-1H-pyrrolo[2,1-f][1,2,4]triazin-4-one (11.20 g, 0.04551 mol), Tetrahydrofuran (200 mL) and Methyl iodide (6.517 mL, 0.1047 mol) were added, respectively. The reaction was stirred at 45° C. for one hour. The solid was filtered. The solvent was removed under vacuum to give a solid. The combined solid was partitioned with water (500 mL) and saturated NaHCO3 (500 mL). The mixture was stirred for 30 minutes. The solid was filtered and washed with water to give 6-Bromo-2-methylsulfanyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as a white solid (5.80, 49%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.[Cl:37][C:38]1[C:39]([C:48](F)(F)F)=[N:40][N:41]([CH2:44][C:45](O)=[O:46])[C:42]=1[CH3:43]>>[Cl:37][C:38]1[C:39]([CH3:48])=[N:40][N:41]([CH2:44][C:45]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[CH2:36][CH2:35]2)=[O:46])[C:42]=1[CH3:43]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nn(CC(=O)N2CCN(c3ccncc3)CC2)c(C)c1Cl

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-pyridyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 8.28 (d, 2H), 7.18 (d, 2H), 5.41 (s, 2H), 3.83 (m, 2H), 3.72 (m, 4H), 3.63 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=388.1, found=388.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[C:5]([F:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:14])=[O:15])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cc(C(F)(F)F)c(F)cc1S(N)(=O)=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)c1cc(F)c(C(F)(F)F)cc1NC(=O)c1ccccc1
Reaction time: 8 h
Yield: 91 %

Procedure:
6.5 g 2-amino-4-trifluoromethyl-5-fluoro-benzene sulfonamide are suspended in 150 ml dry benzene. 2.6 g benzoyl chloride are added to the vigorously stirred suspension, after which the reaction mixture is gently refluxed during 4 hours. The reaction mixture is then left aside overnight. The resulting white solid is then suction filtered and recrystallized from aqueous ethanol, to give 6.1 g 2-benzoylamino-4-trifluoromethyl-5-fluoro-benzene sulfonamide, m.p.= 223° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:3]=1.[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>C1COCC1.CCOC(C)=O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CC(C)CN
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of Step C EXAMPLE 26 (300 mg) in THF (3.3 mL) was added isobutylamine (0.83 mL). The reaction stirred at room temperature overnight at which point LC/MS indicated incomplete reaction. The temperature was elevated to 50° C. for 6 hours at which point the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 0% to 15% EtOAc in hexane affording the title compound. HPLC/MS: 396.1 (M+1), 398.1 (M+3); Rt=4.77 min.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@@H:21]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[N:22]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](O)=[O:19])=[CH:13][C:12]=1[F:35].Cl.Cl.[CH3:38][C@H:39]1[C:47]2[C:46]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[N:45][CH:44]=[N:43][C:42]=2[C@H:41]([OH:54])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@H:21]2[N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]2)[C:18]([N:51]2[CH2:52][CH2:53][N:48]([C:46]3[C:47]4[C@H:39]([CH3:38])[CH2:40][C@@H:41]([OH:54])[C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:49][CH2:50]2)=[O:19])=[CH:13][C:12]=1[F:35]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)c(F)c2)CCC1(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)c(F)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (0.045 mL, 0.26 mmol) was added to a solution of (S)-2-(4-bromo-3-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.035 g, 0.081 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.025 g, 0.081 mmol; see Example 3, Step 12), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.031 g, 0.081 mmol) in DCM (5 mL). The reaction was stirred overnight at room temperature. The reaction was then quenched with H2O, washed with H2O (3×30 mL), dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography to give (S)-tert-butyl 5-((S)-1-(4-bromo-3-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (23% yield). LCMS (APCI+) 648.2 m/z [M+H]+; Retention time=4.28 minutes.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Si](C=[N+]=[N-])(C)C.CCOCC>C1COCC1.CO>[CH3:14][O:5][C:4](=[O:6])[C:3]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 2-fluoro-6-nitrobenzoic acid (10.3 g, 56 mmol) was dissolved in THF/MeOH (100 mL/40 mL) and the mixture was cooled to 0° C. 2M Trimethylsilyldiazomethane in ether (33.4 mL, 67 mmol) was then added dropwise. The reaction was allowed to stir overnight while gradually warming to room temperature. The reaction mixture was then reduced en vacuo to afford 11.1 grams of 2-fluoro-6-nitrobenzoic acid methyl ester as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H, J=7.32), 7.61 (m, 1H), 7.50 (m, 1H), 4.00 (s, 3H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[CH2:28]([O:30][CH2:31][CH2:32][C:33](=[NH:36])[NH:34]O)[CH3:29]>>[CH2:28]([O:30][CH2:31][CH2:32][C:33]1[N:36]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:34]=1)[CH3:29]
Reactant: CCOCCC(=N)NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Product: CCOCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 320 mg (approx.1.983 mmol) of 3-ethoxy-N-hydroxypropanimidamide were reacted Yield: 343 mg (46% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.OS(O)(=O)=O.[C:16]([O-])(O)=O.[Na+].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:16])=[O:9])=[CH:5][CH:4]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(C(=O)O)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(OC)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a 200 mL round-bottomed flask fitted with a condenser was added 5-(methyloxy)-2-thiophenecarboxylic acid (1.3 g, 8.22 mmol) in Methanol (40 mL). H2SO4 (5 mL, 94 mmol) was added slowly at room temperature and the reaction stirred at 50° C. overnight. The mixture was cooled to 0° C. and sat. NaHCO3 was added to neutral pH followed by 5N NaOH to pH 10. The mixture was partitioned between H2O/CHCl3 and the organic phase was separated and dried over Na2SO4. The solution was adsorbed onto silica and purified via column chromatography (5-50% EtOAc/Hexanes) affording the title compound (827 mg, 4.56 mmol, 56%): LC-MS (ES) m/z=173 (M+H)+.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:62])[C:51]4[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:53][CH:52]=4)=[CH:45][CH:44]=3)[CH:41]=2)[CH2:36][N:35]1[C:63]1([C:68]([O:70]C)=[O:69])[CH2:67][CH2:66][CH2:65][CH2:64]1>>[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:62])[C:51]4[CH:56]=[CH:55][C:54]([CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:53][CH:52]=4)=[CH:47][CH:48]=3)[CH:41]=2)[CH2:36][N:35]1[C:63]1([C:68]([OH:70])=[O:69])[CH2:64][CH2:65][CH2:66][CH2:67]1
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C3(C(=O)OC)CCCC3)C4)cc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C3(C(=O)O)CCCC3)C4)cc2)cc1
Yield: 84 %

Procedure:
The compound of example 537 was prepared analogous to compound of example 98 by hydrolysis of compound of example 536.
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH:19]([Mg]Br)=[CH2:20].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17])[CH:19]=[CH2:20]
Reactant: COCOCC(C)=CCCC(C)=CCCC(C)=O
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)COCOC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A solution of 6,10-dimethyl-11-(methoxymethyl)oxy-5,9-undecadien-2-one (60 mg, 0.24 mmol) in tetrahydrofuran (2 ml) was stirred on an ice bath under argon atmosphere. To the solution was added vinylmagnesium bromide in tetrahydrofuran (1.0 ml, 1.0 mmol, 1.0M), and the mixture was warmed to room temperature and stirred for 4 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(methoxymethyl)oxy-1,6,10-dodecatrien-3-ol (54 mg, 80%).