Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:23]1([C:29]2[N:30]=[C:31]([CH2:34][C:35](O)=[O:36])[S:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][C:35](=[O:36])[CH2:34][C:31]2[S:32][CH:33]=[C:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:30]=2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C(O)Cc1nc(-c2ccccc2)cs1
Product: CCCC(NC(=O)Cc1nc(-c2ccccc2)cs1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (4-phenyl-thiazol-2-yl)-acetic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.0, 24.2, 25.6, 26.6, 26.7, 35.2, 40.3, 53.6, 55.9, 59.1, 67.2, 105.3, 113.2, 126.5, 128.4, 129.0, 131.4, 134.2, 137.4, 155.5, 163.4, 167.3, 168.6; MS m/z 509.4 (M+1).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1>O.CC(C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)[N:17]=[CH:16][N:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 99.5 %

Procedure:
Dissolve NaOH (2.8 g, 71.9 mmol) in water (90 mL) at 0° C. Add para-nitrophenol (10 g, 71.9 mmol), and then a solution of 4,6-dichloropyrimidine (10.7 g, 71.9 mmol) in acetone (90 mL). Stir the reaction at 70° C. for 24 hrs. Cool the reaction, collect the solid, rinse the solid with the mixture of acetone-water (1:1, 20 mL), and dry the solid to afford the title compound (18 g, 77.8%). MS: (M+Na): 274.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH3:22][C:23]1[N:28]([C:29](O)=[O:30])[C:27](=[O:32])[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:8][C:7]1[C:2]([NH:1][C:29]([N:28]2[C:23]([CH3:22])=[CH:24][CH:25]=[CH:26][C:27]2=[O:32])=[O:30])=[CH:3][CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)[N:6]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: Cc1cccc(=O)n1C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(=O)n1C(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a vial were added (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (100 μmol), 6-methyl-2-oxopyridine-1(2H)-carboxylic acid and N,N-dimethylformamide (1.5 mL) followed by O-(7-Azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) (200 μmol) and triethylamine (250 μmol). The vial was shaken for 16 h at room temperature. The mixture was concentrated via Speedvac. The residue was partitioned between dichloromethane and water. The organics were evaporated under vacuum to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-methyl-2-oxopyridine-1(2H)-carboxamide which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:13])[CH2:7][CH2:6]1)=[O:20])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
A solution of ethyl-N-benzenesulfonyl-isonipecotate (5 g, 0.016 mole) in tetrahydrofuran (1 L) at -78° C. was treated with a solution of Lithium bis (trimethylsilyl)amide in tetrahydrofuran (18.5 mL of a 1M solution). The solution was stirred at -60° for 15 minutes at which time benzyl bromide (3.15 g, 0.016 moles) was added and the reaction warmed to room temperature over 1.5 hours. The reaction was concentrated at reduced pressure to @ one quarter volume and then poured into saturated aqueous sodium bicarbonate (1 L) and extracted with ethyl acetate (2×800 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel with 30% ethyl acetate/hexane as eluent to give 5.1 g.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]([F:29])([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[C:19](Cl)=[O:20]>ClCCl.Cl>[F:17][C:18]([F:29])([C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[C:19]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:20]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
A mixture of 4-aminobenzonitrile (1.58 g), triethylamine (1.36 g), and dichloromethane (20 mL) was cooled in ice under a nitrogen atmosphere. To this mixture was added perfluorobutyryl chloride (3.11 g) in dichloromethane (10 mL) and the resulting mixture was allowed to warm to room temperature and was then stirred for three hours. The reaction mixture was diluted with HCl solution (1N, 50 mL) and the layers were partitioned in a separatory funnel. The organic phase was washed with a saturated brine solution, dried over MgSO4, filtered and concentrated with a rotary evaporator. The residue was dissolved in dichloromethane. Upon dilution with hexane the product precipitated to give 1.55 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(cyano)phenyl]butanamide, m.p. 116°-118° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:57][C:58]1[CH:59]=[C:60]([N:64]2[CH2:68][CH2:67][CH:66]([C:69](O)=[O:70])[C:65]2=[O:72])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:69]([CH:66]1[CH2:67][CH2:68][N:64]([C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([F:57])[CH:59]=2)[C:65]1=[O:72])=[O:70]
Reactant: O=C(O)C1CCN(c2cccc(F)c2)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2cccc(F)c2)C1=O
Yield: 41.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.350 g; 0.672 mmol), N,N-diisopropylethylamine (0.232 mL; 1.34 mmol) and 1-(3-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (41%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1.O>CN(C=O)C>[CH:17]1([CH2:16][O:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(O)cn1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.9 %

Procedure:
To a solution of 6-methylpyridin-3-ol (5.0 g, 46 mmol) in DMF (45 mL) were added cesium carbonate (16.5 g, 53 mmol) and (bromomethyl)cyclopropane (7.1 g, 53 mmol) at room temperature. After being stirred at room temperature for 18 hours, the mixture was poured into H2O, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3:1 (v/v)) to give 3.9 g (52% yield) of the title compound as a yellow oil:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:33]#[N:34]>CN(C=O)C.N1C=CC=CC=1>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[NH:38][C:37]3[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=3[N:29]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(C3CCNCC3)nc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (15 g, 69.7 mmol) in DMF (50 mL) and pyridine (50 mL) was added CDI (11.3 g, 69.7 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 3,4-diamino-benzonitrile (9.27 g, 69.7 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (20 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 2-piperidin-4-yl-1H-benzoimidazole-5-carbonitrile (9 g, 70%) as pale solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH:1](=[N:17][NH:18][C:19]([NH2:21])=[NH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: N=C(N)NN
Reactant: CCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCC=NNC(=N)N

Procedure:
1 mol (170.3 g) of undecanol, 1.1 mol (150 g) of aminoguanidine hydrogen carbonate and 1 g of p-toluenesulphonic acid are mixed with 500 ml of toluene and refluxed with stirring. As soon as 2 mol of water have been separated using the water separator, the mixture is allowed to cool, concentrated by rotary evaporation and the dark red oil is taken up in 250 ml of petroleum ether 40/60°. The precipitate formed is suction filtered and washed again with petroleum ether. For recrystallisation the precipitate is dissolved in ethyl acetate and mixed with petroleum ether at boiling temperature (boiling range 40 to 60° C.) until beginning to turn cloudy. Fine crystals are obtained, m.p. 101° C. The structure and purity of the compound were confirmed by analytical and spectroscopic data.
Reaction SMILES: C1CCCCC=1.C([O:14][C:15]1[C:16]([CH3:36])=[C:17]([C:24]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[O:25])[N:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C1C=CC=CC=1>C(O)C.[Pd]>[OH:14][C:15]1[C:16]([CH3:36])=[C:17]([C:24]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=2)=[O:25])[N:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2
Reactant: COC(=O)c1ccc(C(=O)c2c(C)c(OCc3ccccc3)c3ccccn23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COC(=O)c1ccc(C(=O)c2c(C)c(O)c3ccccn23)cc1

Procedure:
8.75 ml (86.37 mmol) of cyclohexene are added to 3.45 g (8.64 mmol) of methyl 4-[(1-(benzyloxy)-2-methylindolizin-3-yl)carbonyl]benzoate in 40 ml of ethanol, in the presence of 690 mg of 10% Pd/C, and the medium is heated under reflux for one hour.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[CH2:20]([O:22][P:23]([O:27]CC)[O:24][CH2:25][CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][P:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])(=[O:27])[O:24][CH2:25][CH3:26])[CH3:21]
Reactant: CCOP(OCC)OCC
Reactant: O=C(Nc1ccc(CBr)c(C(F)(F)F)c1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(NC(=O)C(F)(F)F)cc1C(F)(F)F)OCC
Temperature: 120 °C

Procedure:
A mixture of 1.75 g (5 mMol) N-(4-bromomethyl-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-acetamide (WO 2005/051366; Step 14.2) and 1.05 ml (6 mMol) triethylphosphite in 10 ml toluene is heated at 120° C. for 6 h. After cooling, the suspension is filtered and the crystalline solid washed with hexane to give the title compound as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccccc1-c1ccccc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 62.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), o-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.043 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-methylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:28])[CH:5]([CH:17]([OH:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[C:4](=[O:28])[CH:5]([CH:17]([OH:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1C(O)CCCCCC(=O)OC
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a solution of 35 mg of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 20 dissolved in 5 ml of dichloromethane was added 17 mg of 3-chloroperbenzoic acid, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. An organic layer was added, and the mixture was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel chromatography to give 7.3 mg (yield 21%) of 2-methylsulfinyl-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])(C)C)=[O:18]>O1CCOCC1>[CH2:3]([O:10][CH2:11][CH2:23][CH2:20][O:19][C:17](=[O:18])[CH2:16][O:14][CH2:13][CH2:12][CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(COCCCOCc1ccccc1)OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.24 g, 6 mmol) in dioxane (20 ml) is added 3-benzyloxypropan-1-ol (1.0, 6 mmol) and the mixture is allowed to stir at room temperature for 1 hour. t-Butyl bromoacetate (1.05 g, 6.5 mmol) is added slowly and the mixture is allowed to stir for 18 hours. The solvent is evaporated and saturated ammonium chloride (20 ml) is added. The mixture is extracted with methylene chloride (3×20 ml) and the combined organic extracts are dried, filtered and evaporated. Purification by flash column chromatography on silica gel using ethyl acetate/hexane (1:4) as eluent yields 3-benzyloxypropyl-2-[(3-benzyloxypropyl)oxy]-acetate; 1H NMR (CDCl3): δ7.3 (m, 10H), 4.48 (q,4H), 4.27 (t,8 Hz,2H), 4.0 (s,2H), 3.56 (m,6H), 1.92 (m,2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]1[C:33]([CH3:34])=[CH:32][C:31]([NH2:35])=[N:30]1.FC(F)(F)C(O)=O>O1CCOCC1>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:25][CH2:26]2)=[N:7][C:2]([NH:35][C:31]2[CH:32]=[C:33]([CH3:34])[N:29]([CH3:28])[N:30]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)nn1C
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)nn1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (1.52 g, 3.66 mmol) and 1,5-dimethyl-1H-pyrazol-3-amine (800.0 mg, 7.198 mmol in 1,4-dioxane (20 mL) was added trifluoroacetic acid (2.1 g, 18 mmol). The mixture was stirred at 100° C. overnight and concentrated in vacuo. The residue was dissolved in methanol (5 mL), and adjust to Ph=8˜9 with the saturated aqueous solution of NaHCO3. Then the mixture was exacted with DCM/MeOH (50 mL/10 mL) and the separated organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=50/1 to 10/1) to give the product as a yellow white solid (1.36 g, 95.3%).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([NH:9][NH2:10])=[O:8].[C:15](=S)=[S:16]>O.C(O)C>[SH:16][C:15]1[O:8][C:7]([C:6]2[CH:11]=[CH:12][C:13]([OH:14])=[C:4]([OH:3])[CH:5]=2)=[N:9][N:10]=1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc(O)c(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1ccc(-c2nnc(S)o2)cc1O
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
19.8 g (0.353 mol) of potassium hydroxide was dissolved in 5.1 ml of water and 830 ml of ethanol, and 39.6 g (0.236 mol) of 3,4-dihydroxybenzohydrazide and 99 ml (1.65 mol) of carbon disulfide was added thereto. The mixture was heated for 24 hours under reflux. The reaction solution was stirred for 1.5 hours under cooling with ice. The precipitated crystals were collected by filtration and washed with 200 ml of ethanol. The crystals were dissolved in 3 liter of water and adjusted to pH1.5 with 6N hydrochloric acid under cooling with ice. The solution was extracted with 1 liter of ethyl acetate and 400 ml of ethyl acetate. The organic layers were put together, washed twice with 300 ml of a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 42.8 g (yield: 86.5%) of 2-mercapto-5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazole.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C:22]4[N:23]([CH:26]=[CH:27][CH:28]=4)[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2.FC(F)(F)C(O)=O>ClCCl>[O:12]=[C:13]1[CH2:21][C@@H:20]2[C@@:15]3([C@H:22]4[CH:28]=[CH:27][C:26](=[O:9])[N:23]4[CH2:24][CH2:25][N:14]13)[CH2:16][CH2:17][CH2:18][CH2:19]2
Reactant: O=C1C[C@H]2CCCC[C@]23c2cccn2CCN13
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C[C@H]2N1CCN1C(=O)C[C@H]3CCCC[C@@]321
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.05 g (20 mmol) of m-chloroperbenzoic acid are added in portions at room temperature, with stirring, to a solution of 2.3 g (10 mmol) of (9bR*,13aR*)-2-oxo-1,4,5,10,11,12,13,13a-octahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole in 50 ml of dichloromethane (the exothermic reaction is maintained at room temperature using an ice-bath). 2.28 g (20 mmol) of trifluoroacetic acid are then added dropwise to the reaction mixture which is then stirred for 16 hours at room temperature. The reaction mixture is diluted with 100 ml of dichloromethane and then washed in succession with sodium hydrogen sulfite solution (5%) and sodium hydrogen carbonate solution (5%). The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product obtainable in that manner is chromatographed on 210 g of silica gel (0.040-0.063 mm) using trichloromethane as eluant. In this manner (9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,9a,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1' :3,4]pyrazino[2,1-i]indole is obtained in the form of an oil, which is crystallised from dichloromethane/diethyl ether and melts at 159°-162°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([C:12]#[C:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[N:10][CH:11]=1)[CH3:2].[H][H]>CN(C=O)C.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][C:6]1[C:7]([CH2:12][CH2:13][C:14]2[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[N:10][CH:11]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cncnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 22 h
Yield: 88.2 %

Procedure:
tert-Butyl 4-(4-((4-((5-(2-ethoxy-2-oxoethyl)pyrimidin-4-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I111) (0.108 g, 0.177 mmol) was dissolved in dry DMF (10 mL) under an atmosphere of nitrogen. Pd/C (10 wt. %; 0.040 g) in EtOAc (2 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with balloon and stirred at room temperature for 22 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×20 mL). The solvent was removed in vacuo to give a greyish semi-solid which was purified by silica gel chromatography (Isolera Biotage, 12 g Si Cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I112) (0.096 g, 88% yield) as a pale yellow foam; 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 9.00 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 4.11-4.04 (m, 4H), 3.83 (s, 2H), 3.28-3.21 (m, 4H), 2.79 (br s, 2H), 2.68-2.58 (m, 1H), 1.74 (d, J=13.1 Hz, 2H), 1.52-1.38 (m, 11H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: rt 6.65 min; m/z 615.1 [M+H]+.