Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1>N.CO.[Ni]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][NH2:12])[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: Cc1nn(C2CCCCO2)c2cccc(C#N)c12
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1nn(C2CCCCO2)c2cccc(CN)c12
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (130 mg, 0.54 mmol) in NH3/MeOH (7N, 10 mL) was added Raney nickel (20 mg). The mixture was stirred under hydrogen overnight. The reaction mixture was filtered, and the filtrate was concentrated to afford (3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanamine (120 mg, 91.5%). MS (ESI): m/z=246 [M+1]+.
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1>>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[CH:18][C:19]([NH:22][N:23]=[C:2]([CH3:13])[CH2:3][O:4][C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:20][CH:21]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)COc1ccc(C#N)cc1
Product: CC(COc1ccc(C#N)cc1)=NNc1ccc(C(F)(F)F)cc1

Procedure:
The sub-title compound was prepared by the method of example 20 step (ii), using the product from step (i) (3.8 g) and 4-(trifluoromethyl)phenylhydrazine (3.7 g). Yield 2.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[C:15]([Br:22])[C:14]=2[CH3:23])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:24][CH2:25][C:26]([OH:28])=[O:27]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[C:15]([Br:22])[C:14]=2[CH3:23])=[O:12])=[CH:7][C:3]=1[C:4]([NH:24][CH2:25][C:26]([O:28][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:27])=[O:5]
Reactant: NCC(=O)O
Reactant: Cc1c(Br)c2ccccn2c1C(=O)c1ccc(N)c(C(=O)O)c1
Product: Cc1c(Br)c2ccccn2c1C(=O)c1ccc(N)c(C(=O)NCC(=O)OC(C)(C)C)c1

Procedure:
Obtained according to the process described in Step 1.5, using 2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]benzoic acid and the tert-butyl ester of glycine, in the form of a yellow powder (74%).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]=1)[CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])C.C(OC(=O)C(C(OCC)=O)C(C1C=CC(OC)=C(OC)C=1)C(OCC)OCC)C>>[CH2:9]([O:8][CH:7]([O:11][CH2:12][CH3:13])[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:15]=1)[CH2:5][C:4]([OH:32])=[O:3])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OCC(C)C)c1)C(OCC)OCC
Agent: CCOC(=O)C(C(=O)OCC)C(c1ccc(OC)c(OC)c1)C(OCC)OCC
Product: CCOC(OCC)C(CC(=O)O)c1ccc(OC)c(OCC(C)C)c1
Yield: 48.6 %

Procedure:
Using the same procedure as in Example 1 (3), 4,4-diethoxy-2-ethoxycarbonyl-3-[4-methoxy-3-(2-methylpropoxy)phenyl]butyric acid ethyl ester, instead of 3-(3,4-dimethoxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutyric acid ethyl ester, was used to obtain a light yellow solid of the above-described compound via 4,4-diethoxy-3-[4-methoxy-3-(2-methylpropoxy)phenyl]butyric acid (yield 48.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(OCc2ccccc2)cc1)C1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCCC1

Procedure:
The title compound was prepared by hydrogenation of 3-(4-benzyloxy-phenyl)-l-cyclohexyl-prop-2-en-1-one (25.85 g, 84 mmol; prepared in Example C) as described in General Method 3 using 1.0 g of 5% Pd on BaSO4 in 600 mL of THF at room temperature. The crude product was flash chromatographed using CH2Cl2 :MeOH (99:1 to 98:2) to afford a gummy solid. 1H NMR (CDCl3) δ 1.1-1.9 (m, 10 H), 2.2-2.4 (m, 1 H), 2.68-2.74 (m, 2 H), 2.79-2.85 (m, 2 H), 5.04 (s, 2 H), 6.8-6.9 (d, 2 H), 7.1-7.2 (d, 2 H), 7.3-7.5 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccncc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 41.6 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.18 mmol), 4-(tributylstannyl)pyridine (99 mg, 0.27 mmol), and PdCl2(PPh3)2 (25 mg, 0.036 mmol) in DMF (4 mL) was heated at 120° C. under nitrogen atmosphere for 3 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (40 mL) were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes+2% AcOH) to give 29 mg of the title compound. MS: (+) m/z 388.33 (M+1).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.389 g, 4.16 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed toluene (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH2:23][F:24])[N:3]=1.[N+:25]([O-])([OH:27])=[O:26].OS(O)(=O)=O>>[Cl:1][C:2]1[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH2:23][F:24])[N:3]=1
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1OCCF
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCCF

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2-fluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (2.08 g, 5.64 mmol), HNO3 (5.5 mL) and conc. H2SO4 (16 mL) in analogy with method described in example 1c.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(CN2CC[C@H](N3CCOCC3)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a mixture of 1-benzyl-3-phenyl-piperidin-4-one (2.07 g, 7.78 mmol) and morpholine (678 mg, 7.78 mmol) was added tetraisopropyl-orthotitanate (2.97 mL, 9.73 mmol) at room temperature. After stirring at room temperature overnight the reaction mixture was diluted with ethanol (8.0 mL) and sodium cyanoborohydride (369 mg, 5.37 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (2.0 mL). The inorganic precipitate was filtered off and washed with ethanol. The filtrate was evaporated and purified by flash chromatography on silica gel with toluene/ethyl acetate 6:1 to give rac-cis-4-(1-benzyl-3-phenyl-piperidin-4-yl)-morpholine (1.42 g, 54%) as a yellow solid, MS: m/e=337.3 (M+H+).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].N1C=CC=CC=1.[S:15]([OH:35])([O:18][C:19]1[C:20]([CH3:34])=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[C:23]([C:29](OCC)=[O:30])=[CH:22]2)(=[O:17])=[O:16].O>CN(C)C=O>[S:15]([OH:35])([O:18][C:19]1[C:20]([CH3:34])=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[C:23]([C:29]([NH:7][C:6]([NH2:8])=[NH:5])=[O:30])=[CH:22]2)(=[O:16])=[O:17]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2c(C)c(OS(=O)(=O)O)ccc2n1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(OS(=O)(=O)O)ccc2c1cc(C(=O)NC(=N)N)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of sodium methoxide (4.28 g, 79.2 mmol), guanidine hydrochloride (7.58 g, 79.3 mmol) and N,N-dimethylformamide (70 ml) was stirred at room temperature for 1 hour, and then the insoluble material was filtered off. A solution of 2-ethoxycarbonyl-1,4-dimethyl-1H-indole-5-yl hydrogen sulfate pyridine salt (3.11 g, 7.92 mmol) in N,N-dimethylformamide (10 ml) was added to the filtrate, and the resulting mixture was stirred at room temperature for 7.5 hours. Water was added to the reaction mixture, followed by washing with chloroform. Subsequently, chloroform and then 2N hydrochloric acid were added and the solid thus precipitated was collected by filtration and washed with methanol to obtain 2.12 g of 2-[[[amino(imino)-methyl]amino]carbonyl]-1,4-dimethyl-1H-indol-5-yl hydrogen sulfate.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=2[F:21])[CH2:8][CH2:7]1)=[O:5].[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:21][C:13]1[CH:14]=[C:15]([C:18](=[O:20])[CH3:19])[CH:16]=[CH:17][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([C:4]([C:3]2[C:2]([C:33]3[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:25][CH:24]=[C:23]([N+:26]([O-:28])=[O:27])[CH:22]=2)=[O:5])[CH2:11][CH2:10]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3Br)CC2)c(F)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3-c3ccc(C)cc3)CC2)c(F)c1

Procedure:
In analogy to a procedure described by Leadbeater et al. [N.E. Leadbeater, M. Marco, Org. Lett. 4, 2973 (2002)] a stirred mixture of 1 eq. 1-{4-[4-(2-bromo-5-nitro-benzoyl)-piperazin-1-yl]-3-fluoro-phenyl}-ethanone (Example 4), 1.05 eq. 4-methylphenylboronic acid, 1 eq. tetrabutylammonium bromide. 2.5 eq. sodium carbonate and 0.01 eq Pd(OAc)2 in water (20 ml per mmol) were heated in a sealed tube to 150° C. by microwave irradiation for 1 minute. Then the reaction mixture is diluted with water, extracted with AcOEt, the pooled organic extracts dried over Na2SO4, filtered and evaporated. The crude product is purified by preparative HPLC on a YMC Combiprep ODS-AQ column with an acetonitrile/water+0.1% formic acid gradient to yield the title compound (table 2).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=1.Cl.[NH:18]1[CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[N:18]1([C:14]([C:10]2[S:9][C:8]([Br:7])=[N:12][C:11]=2[CH3:13])=[O:16])[CH2:21][CH2:20][CH2:19]1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: C1CNC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
Oxalyl chloride (0.47 mL; 5.41 mmol) was added to a solution of 2-bromo-4-methyl-1,3-thiazole-5-carboxylic acid (1.0 g; 4.5 mmol) in DCM (25 mL). The mixture was stirred at RT for 18 hours, the DCM was evaporated in vacuo, the residue azeotroped with toluene (2×5 mL) and added to a solution of azetidine hydrochloride (503 mg; 5.41 mmol) and triethylamine (2.3 mL; 16.2 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, and the residue partitioned between water (75 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in isohexane, to give a solid which was crystallised from ethyl acetate/isohexane to give the desired compound (490 mg). 1H NMR δ (CDCl3): 2.35 (m, 2H), 2.55 (s, 3H) and 4.1 (t, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:25]([CH3:26])[C:5]2[CH:6]=[C:7]([C:20](OCC)=[O:21])[C:8]3[CH2:9][CH2:10][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:12][C:13]=3[C:4]=2[N:3]=1.[NH2:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][NH:27][C:20]([C:7]1[C:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:12][C:13]=2[C:4]2[N:3]=[C:2]([CH3:1])[N:25]([CH3:26])[C:5]=2[CH:6]=1)=[O:21]
Reactant: CCOC(=O)c1cc2c(nc(C)n2C)c2c1CCC(c1ccccc1)N2
Reactant: NCCO
Product: Cc1nc2c3c(c(C(=O)NCCO)cc2n1C)CCC(c1ccccc1)N3
Temperature: 145 °C
Yield: 52 %

Procedure:
A suspension of 1.0 g (2.9 mmol) ethyl 2,3-dimethyl-8-phenyl-6,7,8,9-tetrahydro-3H-imidazo[4,5h]-quinoline-5-carboxylate in 10 ml 2-aminoethanol was heated to 140-150° C. until no starting material was left. The mixture was partitioned between saturated aqueous ammonium chloride and dichloro-methane/methanol 9:1. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel (toluene/dioxane/methanol=6:3:1). Crystallization from diisopropyl ether yielded 0.55 g (52%) of the title compound as a colourless solid. m.p. 248-251° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:18]#[N:19])[CH:25]=1
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccc(C=O)cc2Cl)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Trifluoro-methanesulfonic acid 2-chloro-4-formyl-phenyl ester (I-6a: 10.0 g), 3-cyano-phenyl-boronic acid (5.26 g) and palladium tetrakis(triphenylphosphine) (3.00 g) were combined in 100 mL of dimethoxyethane, then treated with 10 mL of a 2M aqueous sodium carbonate solution before being heated in a 100° C. oil bath. After 24 hours, the reaction mixture was cooled to ambient temperature, the organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with 10% ethyl acetate in heptane to afford the title compound (I-6b).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C(N(CC)CC)C.Cl>CO>[F:13][C:14]([F:21])([F:20])[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)=[O:16]
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Yield: 94 %

Procedure:
A solution of 4-aminocinnamic acid (1.88 g), ethyl trifluoroacetate (6.8 ml) and triethylamine (4.8 ml) in 20 ml methanol was stirred at room temperature for 4 hours, and 0.3 mol/l hydrochloric acid was added thereto, on ice, to precipitate a solid, which was then filtered, washed with water, and then dried by heating under reduced pressure to give 4-(trifluoroacetylamino)cinnamic acid (2.81 g, 94%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[O:25](C(OC(C)(C)C)=O)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O.C(Cl)Cl>C1COCC1>[CH:1]1([C:4]2[N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Ic1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To the solution of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-iodo-2-phenylpyrimidin-4-amine (0.4 g, 0.99 mmol, 1.0 eq) in dry THF (50 mL), NaH (0.4 g, 60% dispersion in oil, 10.0 mmol, 10.0 eq) was added by portions. The reaction mixture was stirred at rt for 1 h. Then, BOC2O (0.26 mL, 1.19 mmol, 1.2 eq) was added to the reaction mixture and the resulting reaction was stirred at rt for 2 h. CH2Cl2 was added and organic layer was washed (water), dried and concentrated. The residue was purified by silica gel chromatography (hexane as eluant) to afford tert-butyl 5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (0.32 g, 60.3%). LC-MS (m/z): 504.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 0.81-0.85 (m, H), 1.09-1.15 (m, 2H), 1.67 (s, 1H), 2.49 (m, 1H), 6.86 (s, 2H), 7.50-7.60 (m, 3H), 8.41-8.44 (m, 2H), 9.40 (s, 1H), 10.46 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.S(Cl)(Cl)=O.C(Cl)(Cl)Cl.[NH3:22]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:22])=[O:13])=[CH:5]2
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cc1ccc2[nH]c(C(N)=O)cc2c1
Temperature: 25 °C

Procedure:
A mixture of 0.5 g of 5-methylindole-2-carboxylic acid, 0.25 mL of thionyl chloride, 5 mL of chloroform and small drop of DMF was refluxed for 2 hs. The reaction mixture was cooled to RT, poured into a mixture of 5 g of ice and 5 mL of 25% ammonia solution, and then stirred for 2 hs. The precipitated product was filtered off, washed with water and dried to yield 350 mg of 5-methylindole-2-carboxamide. 1H NMR (600 MHz, DMSO-d6): δ 11.37 (s, 1H), 7.89 (br, 1H), 7.36 (s, 1H), 7.30 (d, 1H, J=8.4 Hz), 7.28 (br, 1H), 7.02 (s, 1H), 6.99, (d, 1H, J=8.4 Hz), 2.36 (s, 3H). 13C NMR (150 MHz, CDCl3): δC 160.95, 132.95, 129.77, 126.15, 125.44, 123.10, 118.77, 110.02, 100.65, 19.20.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].[F:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH:16]=O)[CH:11]=[C:12]([F:14])[CH:13]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:16]=[C:15]([C:10]2[CH:9]=[C:8]([F:7])[CH:13]=[C:12]([F:14])[CH:11]=2)[N:4]=1
Reactant: O=CC(=O)c1cc(F)cc(F)c1
Reactant: CSC(=N)NN
Product: CSc1nncc(-c2cc(F)cc(F)c2)n1
Yield: 79.6 %

Procedure:
3-(methylsulfanyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (28 g, 80.0%) was prepared from methyl hydrazine carbimidothioate (20.68 g, 197.4 mmol) and 2-(3,5-difluorophenyl)-2-oxoacetaldehyde (25 g, 147.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]1([CH2:24][CH3:25])[CH2:23][O:22][CH2:21]1>CN(C)C=O>[CH2:24]([C:20]1([CH2:19][O:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH2:21][O:22][CH2:23]1)[CH3:25]
Reactant: CCC1(COCCCCBr)COC1
Reactant: CCOC(=O)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCC1(COCCCCOc2ccc(C(=O)O)cc2)COC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
In a 300 ml three neck flask, 5.2 g (31 mmol) of ethyl p-hydroxybenzoate, 4.7 g (34 mmol) of potassium carbonate anhydride, and 7.8 g (31 mmol) of the 3-[(4-bromobutoxy)methyl]-3-ethyloxetane were dissolved in 50 ml of dimethylformamide. After the solution remained turbid was heated to a temperature of 80° C. and stirred for 4 hours, the solvent was completely distilled out in a vacuum. To the resulting yellow oily substance were added 15 ml of a 7% sodium hydroxide aqueous solution and 15 ml of methanol. The mixture was refluxed for two and half hours. 1 N (normality) of hydrochloric acid was added to the mixture such that the pH is adjusted to about 3. The resulting white precipitate was filtered and dried in a vacuum thereby obtaining 8.6 g (28 mmol) of 4-[7-(3-ethyl-3-oxetanyl)-1,6-dioxaheptyl]benzoic acid (yield: 89%, identified with 1H-NMR). The resulting compound was no more purified and used in the following reaction.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([N:9]2C(=O)C3=CC=CC=C3C2=O)[CH2:7][S:6][CH2:5][C@@H:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:3]1[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CNN>>[NH2:9][C@H:8]1[CH2:7][S:6][CH2:5][C@@H:4]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[N:3]([CH2:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)CSC[C@H]1c1cccs1
Agent: CNN
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Yield: 90 %

Procedure:
1.18 g of t-butyl α-[5-oxo-6(R)-phthalimido-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] was subjected to de-phthaloylization with methylhydrazine in the manner described in Example 1(g), to give 0.77 g of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.CC[O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15].[OH-].[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:19]2[CH2:20][CH2:21][N:16]([C:14]([OH:15])=[O:13])[CH2:17][CH2:18]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: COc1cccc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1cccc(CN2CCN(C(=O)O)CC2)c1
Yield: 112.5 %

Procedure:
A mixture of 48.6 g (0.31 moles) of m-methoxybenzyl chloride, 49.0 g (0.31 moles) of ethyl N-piperazinocarboxylate, 250 ml of isopropyl alcohol and 35 ml of 10N sodium hydroxide was heated at reflux for 18 hours. The reaction mixture was evaporated in vacuo and gave an oil. The oil was Kugelrohr distilled bp 106° C./0.025 mm of mercury and gave 87.3 g of 4-[(3-methoxyphenyl)methyl]-1-piperazinecarboxylic acid, ethyl ether as an oil.