Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[CH2:15][N:16]([CH2:27][C:28]([F:31])([F:30])[F:29])[S:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:18].C(N(CC)C(C)C)(C)C.[N:41]([Si](C)(C)C)=[C:42]=[O:43].C([O-])(O)=O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[F:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:42]([NH2:41])=[O:43])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[CH2:15][N:16]([CH2:27][C:28]([F:31])([F:29])[F:30])[S:17]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:19])=[O:18]
Reactant: C[Si](C)(C)N=C=O
Reactant: O=S(=O)(Cc1ccccc1)N(Cc1ccc(C2CCNCC2)cc1F)CC(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC(=O)N1CCC(c2ccc(CN(CC(F)(F)F)S(=O)(=O)Cc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
To a solution of N-[[2-fluoro-4-(4-piperidyl)phenyl]methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)methanesulfonamide hydrochloride (Example 7, Step 2), (200 mg, 0.41 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.0 mmol) in dichloromethane (4 mL) was added 4-dimethylaminopyridine (5 mg, 0.041 mmol), followed by isocyanato(trimethyl)silane (0.30 mL, 2.1 mmol) and the reaction was stirred at ambient temperature for 2 hours. Saturated aqueous NaHCO3 was then added and the dichloromethane layer was isolated with a phase-separator cartridge. The organic layer was concentrated and purified by preparative reverse phase HPLC to yield 27 mg of 4-(3-fluoro-4-((1-phenyl-N-(2,2,2-trifluoroethyl)methylsulfonamido)methyl)phenyl)piperidine-1-carboxamide. 1H NMR (400 MHz, DMSO) δ 7.44-7.38 (m, 5H), 7.38-7.29 (m, 1H), 7.16-7.02 (m, 2H), 5.88 (s, 2H), 4.59 (s, 2H), 4.41 (s, 2H), 4.13-4.00 (m, 2H), 3.95 (q, J=9.3 Hz, 2H), 2.82-2.61 (m, 3H), 1.80-1.64 (m, 2H), 1.56-1.32 (m, 2H); LCMS (m/z) ES+ 488.1 [M+1]+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])(=O)C>[Zn].C1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:6]1([OH:16])[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: CC(=O)[O-]
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)c2ccccc2C=Cc2ccccc21

Procedure:
To a suspension of 8.35 g. of activated zinc in 120 ml. of absolute benzene is added at room temperature a solution of 10.3 g. of dibenzo[a,d]cyclohepten-5-one and 8.35 g. of ethyl bromoacetate in 50 ml. of absolute benzene. After about one quarter of said solution has been so added the mixture is heated at reflux until the resulting reaction subsides and then the remainder of the solution is added while maintaining reflux temperatures. After addition is completed the resulting mixture is refluxed for an additional 4 hours. The resulting mixture is then added to dilute acetate acid and extracted 2 times with ethyl acetate. The combined organic phases are washed with water, dried and evaporated in vacuo. The residue is crystallized from diethyl ether/pentane to obtain 5-hydroxy-dibenzo[a,d]cyclohepten-5-acetic acid ethyl ester, m.p. 93°-99° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([O:11][CH2:23][CH:22]=[CH2:21])=[O:10])([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrocinnamic acid (5.0, 25.9 mM) was dissolved in DMF (50 ml), and anhydrous K2CO3 (7.15 g, 51.8 mM) added with stirring. Allyl bromide (3.36 ml, 38.8 mM) was run in, and the mixture stirred for 18 hours at ambient temperature. After filtration, the solvent was evaporated, the residue treated with water, and product extracted into diethyl ether (2 ×100 ml). The organic solution was washed with an aqueous solution of NaHCO3, water, and brine, and dried (MgSO4). Evaporation of the solvent gave title compound (6 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([Cl:37])[N:36]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[C:30](=[O:31])[N:29]([O:32][CH3:33])[C:18]3[N:19]=[C:20]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[N:21]=[CH:22][C:17]=3[CH:16]=2)[CH:9]=1)=[O:6].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CS(C)=O>[Cl:37][C:35]1[CH:34]=[C:4]([CH:3]=[C:2]([N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[N:36]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[C:30](=[O:31])[N:29]([O:32][CH3:33])[C:18]3[N:19]=[C:20]([NH:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[N:21]=[CH:22][C:17]=3[CH:16]=2)[CH:9]=1)=[O:6]
Reactant: COn1c(=O)c(-c2cc(NC(=O)c3cc(Cl)nc(Cl)c3)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Reactant: CCNCC
Solvent: CS(C)=O
Product: CCN(CC)c1cc(C(=O)Nc2ccc(Cl)c(-c3cc4cnc(NCCN(C)C)nc4n(OC)c3=O)c2)cc(Cl)n1
Temperature: 100 °C

Procedure:
40 mg 2,6-dichloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-isonicotinamide and 50 μl diethylamine were dissolved in 5 ml DMSO and heated at 100° C. in the microwave for 10 min. Addition of further diethylamine and heating in the microwave was repeated multiple times until the reaction was complete. The reaction mixture was purified on HPLC-MS in MeCN/water (1% formic acid) to yield 23 mg.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9][CH2:10][NH:11][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(CCN)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(CCNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension under argon of 4-acetylphenethylamine hydrochloride (1 g) in dichloromethane (20 ml) was added triethylamine (0.94 ml) and stirring continued for 15 minutes. The mixture was cooled to 4° C., then 4-methylphenylsulphonyl chloride (1.29 g) in dichloromethane (5 ml) added dropwise over 30 minutes. The reaction mixture was stirred for 18 hours at ambient temperature, then diluted with further dichloromethane (50 ml), washed with water, dried (MgSO4) and evaporated. Trituration of the residue gave N-(2-[4-acetylphenyl]ethyl)4-methylphenylsulphonamide, 1.58 g, as a yellow crystalline solid: m.p. 124°-126° C.; NMR(d6DMSO) δ7.84(2H,d), 7.63(3H,m), 7.37(2H,d), 7.29(2H,d), 2.98(2H,q), 2.75(2H,t), 2.55(3H,s), 2.39(3H,s); m/e 318(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([N:38]=[C:39]=[S:40])(=O)C1C=CC=CC=1.O>CC(C)=O>[NH2:38][C:39]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:26][C:27](=[O:29])[CH3:28])[S:13][C:14]=2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:7]=1)=[S:40]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(NC(N)=S)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a ice-cold solution of N-{4-[2-(4-aminophenyl)ethyl]-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (247.6 mg) in acetone (4.8 ml) was added benzoyl isothiocyanate (94.1 mg), and the mixture was stirred at r.t. for 1 hour. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual amorphous substance was dissolved in EtOH (5 ml), and 6N-NaOH (0.288 ml) was added to the solution at 0° C. The reaction mixture was stirred at r.t. for 2 hours, and neutralized with 1N-HCl at 0° C. The mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was solidified with ethyl ether to give N-{4-(2-{4-[(aminocarbonothioyl)amino]phenyl}ethyl)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-2-yl}acetamide (290.7 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:3](OC2C=C(C#N)C=C(C#N)C=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([NH:27][C:28]([C:30]1[CH:31]=[C:32]([O-:43])[CH:33]=[C:34]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[Na+].FC1C(F)=C(F)C=CC=1[N+]([O-])=O>>[F:1][C:2]1[C:3]([O:43][C:32]2[CH:31]=[C:30]([C:28](=[O:29])[NH:27][C:23]([CH3:26])([CH3:24])[CH3:25])[CH:35]=[C:34]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)NC(=O)c1cc([O-])cc(C(=O)NC(C)(C)C)c1
Reactant: N#Cc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Agent: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Na+]
Product: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1

Procedure:
In another embodiment of the present invention there is provided a process for the preparation of a compound according to formula III wherein R2 is 3,5-dicyano-phenyl which process further comprises (i) contacting sodium 3,5-bis-tert-butylcarbamoyl-phenolate with 2,3,4-trifluoronitrobenzene in an appropriate solvent at temperatures from about −30° C. up to about 40° C. to afford a 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene; and (ii) contacting 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobezene with phosphorus oxychloride or a similar dehydrating agent to afford 3,4-difluoro-2-(3,5-dicyano-phenoxy)nitrobenzene III (R2=3,5-dicyanophenyl). The ether can be convert to IV (R2=3,5-dicyanophenyl) as described below.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23](C(C)C)[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.Cl.[C:31]([O:35][C:36](N1CCC(OC2C=C3C(=CC=2)NC(C(O)=O)=C3)CC1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C1(N2CCC(OC3C=C4C(=CC=3)N(C3C=NC=NC=3)C(C(N3CCC(F)(F)CC3)=O)=C4)CC2)CCC1>>[C:31]([O:35][C:36]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]([C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:29])([F:1])[CH2:3][CH2:4]2)=[O:9])=[CH:18]3)[CH2:21][CH2:22]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: Cl
Agent: O=C(c1cc2cc(OC3CCN(C4CCC4)CC3)ccc2n1-c1cncnc1)N1CCC(F)(F)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 5-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride salt with 1 eq. lithium chloride (example 43, step 4). The title compound was obtained in 59% yield as white solid. MS (m/e): 464.3 (MH+, 75%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:21]=2)[CH:16]=[C:15]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[N:14]=1.O>CN(C=O)C>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:10][CH2:9][CH:7]3[CH2:6][O:5][C:4]([CH3:11])([CH3:3])[O:8]3)=[C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:21]=2)[CH:16]=[C:15]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)[N:14]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OCC1COC(C)(C)O1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
NaH (150 mg) was carefully added to the solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (0.3 ml) in DMF (2 ml) and the mixture was stirred for 1 hour. [1-Chloro-6-fluoro-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added under N2, and the mixture was heated at 90° C. for 1 hour. The mixture was poured into 50 ml of water. The mixture was extracted by ethyl acetate (50 ml×3). The organic layer was evaporated to give [1-Chloro-6-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine as oil (100 mg). LC-MS: m/e 463(MH+).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1>CN(C=O)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][CH2:11][CH2:10][O:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 60% NaH (2.66 g) in DMF (20 mL) was added methyl hydroxyacetate (5.00 g) under ice-water cooling, and the mixture was stirred at 0° C. for 0.5 hour. To this was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (12.8 g) under ice-water cooling, and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (10:1-3:1) to give methyl [2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate pale yellow oil (445 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([CH2:39][OH:40])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:57]([O:59][CH2:60][CH3:61])=[CH2:58])CCC>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>[CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([CH2:39][OH:40])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]2)[C:9]=1[C:57]([O:59][CH2:60][CH3:61])=[CH2:58]
Reactant: CCOC(=O)C1(CO)CCC(c2nc3c(-c4cnn(-c5ccccc5)c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1c(C2CCC(CO)(C(=O)OCC)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
A mixture of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (201 mg, 0.251 mmol), tributyl(1-ethoxyvinyl)stannane (0.255 mL, 0.754 mmol), Pd(PPh3)4 (29.0 g, 0.025 mmol) in dioxane was stirred at 100° C. under Ar2 for 16 h. The reaction mixture was passed through a short SiO2/KF (9:1) plug to remove majority of the Sn species, and then purified by a SiO2 column (0-30% EtOAc/Hexanes, Rf=0.7 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as a pale yellow oil (167 mg). HPLC-MS TR=3.18 min (UV 254 nm, 5 min method); mass calculated for formula C41H62N6O6Si2 790.4, observed LCMS m/z 791.2 (M+H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]4[CH2:20][O:21][C:22](=[O:23])[C:12]3=4)[CH:9]=2)[NH:4][N:3]=1.[O:24]1[C:29]2[CH:30]=[CH:31][C:32](B(O)O)=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>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>[O:24]1[C:29]2[CH:30]=[CH:31][C:32]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([CH:11]5[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]6[CH2:20][O:21][C:22](=[O:23])[C:12]5=6)[CH:9]=4)[NH:4][N:3]=3)=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(Br)c3c2)C2=C(COC2=O)N1
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: C1COCCO1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(-c4ccc5c(c4)OCCO5)c3c2)C2=C(COC2=O)N1
Temperature: 95 °C
Reaction time: 12 h
Yield: 18.9 %

Procedure:
To a degassed solution of 120 mg (0.323 mmol) 4-(3-bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile (Example 24) and 69.8 mg (0.388 mmol) 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid in anhydrous 1,4-dioxane (4.5 ml) were added under inert gas atmosphere 37.4 mg (0.032 mmol) tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonate solution (2 M, 0.77 ml). The resulting mixture was stirred at 95° C. for 12 h. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was subsequently washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 95:5 v/v) to yield the title compound as a white solid (26 mg, 19% of th.).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:6]=1)=[NH:4].[S:25]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=O)(=[O:28])(=[O:27])[NH2:26]>>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:32]([C:31]3[CH:30]=[C:29]([S:25]([NH2:26])(=[O:28])=[O:27])[CH:37]=[CH:36][CH:35]=3)[O:1][N:2]=2)[N:10]=1
Reactant: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Product: NS(=O)(=O)c1cccc(-c2nc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)no2)c1

Procedure:
The title compound was prepared from N-hydroxy-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carboxamidine (example C.2) (0.176 g, 0.5 mmol) and commercially available 3-sulfamoyl-benzoic acid (0.1 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.11 g, 42%). MS (ISN) 514.1 [(M−H)−]; mp 205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH:8]=2)[CH:3]=1.C(OC(=O)C)(=[O:20])C.[Br-].[NH4+]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:1]=[O:20])[CH:11]=[CH:10]2)(=[O:17])[CH:14]([CH3:15])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2cc(OC(=O)C(C)C)ccc2c1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(=O)Oc1ccc2cc(C=O)ccc2c1
Temperature: 150 °C
Reaction time: 2.4 h

Procedure:
The same reactor as used in the second half of Example 1 was charged with 30 parts of the 2-methyl-6-isobutyryloxynaphthalene, 80 parts of acetic acid, 20 parts of acetic anhydride, 1.87 parts (Co=4425 wt. ppm), of cobalt acetate tetrahydrate, and 1.08 parts (Br=8813 wt. ppm) of ammonium bromide, and pressurized to 10 kg/cm2 -G. The mixture was heated to 150° C., and air was introduced into the reactor at a rate of 10 Nl/hr. The reaction was terminated when the absorption of oxygen ceased. The reaction time was 2.4 hours. The reaction mixture was cooled, and the contents were withdrawn and analyzed. The conversion of 2-methyl-6-isobutyryloxynaphthalene was 100 mole %, and 65.0 mole % (selectivity 65.0 mole %) of 6-isobutyryloxy-2-naphthoic acid. At this time, 21.0 mole % of 6-isobutyryloxy-2-naphthaldehyde formed.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[N:50]=[CH:51][C:52]([CH2:55][NH2:56])=[N:53][CH:54]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:56][CH2:55][C:52]4[CH:51]=[N:50][C:49]([CH3:48])=[CH:54][N:53]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)cn1
Yield: 78 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-methylpyrazin-2-yl)methanamine, the title compound was obtained as a colorless solid in 78% yield: 1H NMR (300 MHz, CDCl3) δ 7.52 (s, 1H), 8.40 (s, 1H), 7.31-7.23 (m, 2H), 7.08-6.99 (m, 2H), 6.72 (t, J=4.6 Hz, 1H), 6.12 (s, 1H), 4.70 (d, J=4.6 Hz, 2H), 4.44 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.39 (m, 2H), 2.57 (s, 3H), 2.50 (s, 3H): MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH2:25]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][NH:22][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)[CH2:25][CH2:26]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a mixture of 4-hydroxybenzoic acid (2.5 g, 0.0182 mol), 1-hydroxybenzotriazole hydrate (3.33 g, 0.0218 mol), benzyl 4-(aminomethyl)piperidine-1-carboxylate (4.5 g, 0.0182 mol) and triethylamine (3.03 mL, 0.0218 mol) in DMF (30mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.2 g, 0.0218 mol) and the mixture allowed to stir at rt for 18 h. The mixture was quenched into water (200 mL) and extracted with ethyl acetate (200 nL). The ethyl acetate extract was washed with 10% aqueous sodium bicarbonate (100 mL), brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue chromatographed on silica using 10–20% acetone/dichloromethane to give 6.3 g of 4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester as a foam. The foam was dissolved in hot isopropyl acetate (125 mL), filtered, and allowed to cool and crystallize. The reaction volume was reduced in vacuo to 50 mL, allowed to stir overnight at rt and filtered. The resulting solid was dried in vacuo (50° C.) yielding the 4-[(4-hydroxy-benzoylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.