Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1([SH:32])[C:29]2[C:30]3=[C:31]4[C:26](=[CH:27][CH:28]=2)[CH:25]=[CH:24][CH:23]=[C:22]4[CH:21]=[CH:20][C:19]3=[CH:18][CH:17]=1>CN(C=O)C>[CH:18]1[C:19]2[C:30]3=[C:31]4[C:22](=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[C:26]4[CH:27]=[CH:28][C:29]3=[C:16]([S:32][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:17]=1
Reactant: O=Cc1ccccc1F
Reactant: Sc1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1ccc2ccc3cccc4ccc1c2c34
Temperature: 130 °C
Yield: 46.2 %

Procedure:
2-fluoro-benzaldehyde (477 mg, 3.8 mmol), potassium carbonate (700 mg, 5.0 mmol) and pyrene-1-thiol (300 mg, 1.28 mmol) were dissolved in 15 mL of dry DMF under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 130° C. for 24 h. After cooling the mixture was added to 50 mL of saturated potassium carbonate solution, and the mixture was extracted with 3 portions of ether. The extracts were dried with magnesium sulfate and evaporated. The residue of the crude product was further purified by chromatography on silica gel using 10:1 petroleum ether (60-80) and EtOAc as eluent to afford a yellow solid (200 mg, 46%). 1H-NMR (500 MHz, CDCl3): δ 6.56 (dd, J=0.8, 7.9 Hz, 1H), 7.07-7.22 (m, 2H), 7.89 (dd, J=1.7, 7.2 Hz, 1H), 8.02-8.28 (m, 8H), 8.58 (d, J=9.2 Hz, 1H), 10.45 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ 124.7, 124.9, 125.3, 125.5, 125.9, 126.0, 126.4, 127.1, 128.0, 128.7, 129.0, 130.8, 131.0, 132.5, 133.3, 133.4, 133.8, 133.9, 137.0, 143.2, 191.6. EI-MS: m/z M+Calculated 338.1, found 338.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:20](OC(=O)C)(=[O:22])C>C(O)=O>[CH:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCCON=C(C(=O)OCC)c1csc(N)n1
Solvent: O=CO
Product: CCOCCON=C(C(=O)OCC)c1csc(NC=O)n1
Yield: 68.1 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetate (syn isomer, 11.5 g.), acetic anhydride (8.2 g.) and formic acid (3.7 g.) were treated in a similar manner to that of Example A-(4) to give ethyl 2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetate (syn isomer, 8.6 g.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:4][C:3]=1[O:25][CH3:26].C=O.[C:29]([BH3-])#N.[Na+].[BrH:33]>CC(O)C.CO>[BrH:33].[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH3:29])[CH:9]2[C:12]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13]2)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC(C)(C)C1)NCC2
Reactant: [BH3-]C#N
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC(C)(C)C1)N(C)CC2
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-hydroxy-6-methoxy-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline (3.7 g), methanol (50 ml) and 37-40% aqueous formaldehyde solution was cooled to 5° C. Sodium cyanoborohydride (1.4 g) was added and the mixture stirred for 1.5 hours. The solvents were removed by evaporation and the residue partitioned between water and dichloromethane. The organic layer was washed with aqueous ammonia solution and then brine, dried and the solvent removed by evaporation to give a gum which was dissolved in propan-2-ol. Addition of 48% aqueous hydrobromic acid gave 7-hydroxy-6-methoxy-2-methyl-1-[1-(2-chlorophenyl)-3,3-dimethylcyclobutyl]-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 202°-204° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](Cl)[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:17][NH2:18])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: NN
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(NN)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 2,6-dichloroisonicotinate (11.0 g, 44.3 mmol) in ethanol (222 mL) was added hydrazine hydrate (6.46 mL, 133 mmol). The mixture was heated 75° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was concentrate down to half of the volume. The solid crashed out was filtered off and the filtrate was concentrated to dryness: LC-MS [M+1]=244.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([N:22]3[CH:26]=[N:25][N:24]=[CH:23]3)[CH2:17]2)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:27]([O:31]C=C)[CH2:28]CC.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]([C:2]1[CH:3]=[C:4]([S:12]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([N:22]3[CH:26]=[N:25][N:24]=[CH:23]3)[CH2:17]2)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1)(=[O:31])[CH3:28]
Reactant: O=S(=O)(N[C@H]1CCC[C@@H](n2cnnc2)C1)c1cc(Br)cc(C(F)(F)F)c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@H]2CCC[C@@H](n3cnnc3)C2)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Palladium acetate (9.9 mg, 0.044 mmol) was added to a stirred solution of 3a (100 mg, 0.221 mmol), n-butylvinyl ether (221 mg, 2.206 mmol) and triethylamine (92.0 μL, 0.662 mmol) in DMF (2.00 mL), and the resulting mixture was degassed and heated to 80° C. After 6 h, the reaction mixture was cooled to 0° C., 1M HCl was added, and the resulting mixture was allowed to warm to rt and stirred overnight. The reaction mixture was quenched with satd. aq. NaHCO3 and extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by preparative thin layer chromatography on silica gel (10% MeOH/DCM as eluent) to afford the title compound, 9a. m/z (ES) 417 (MH)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:21][CH:22]=2)=[CH:11][C:10]=1[CH:29]=[O:30])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:21][CH:22]=2)=[CH:11][C:10]=1[CH2:29][OH:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(OCCc2coc(-c3ccccc3)n2)cc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottomed flask was charged with 3-{2-formyl-4-[2-(2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (1.82 g, 4.18 mmol) and absolute ethanol (20 mL). The stirring solution was cooled in an ice/ethanol bath and treated with sodium borohydride (0.31 g, 8.36 mmol). The cold bath was removed, and the mixture was stirred at ambient temperature under a nitrogen atmosphere for 2 h. The reaction mixture was poured into EtOAc (100 mL) and ice water (100 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated to a yellow oil (1.62 g, 88%). 1H NMR (400 MHz, CDCl3) δ 1.38 (s, 9H), 2.37 (s, 3H), 2.54 (t, J=7.6 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.97 (t, J=6.6 Hz, 2H), 4.23 (t, J=6.6 Hz, 2H), 4.66 (s, 2H), 6.78 (dd, J=8.3, 2.9 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.38-7.45 (m, 3H), 7.97 (dd, J=8.1, 1.7 Hz, 2H). MS (ES) m/e 438 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:10]=1[C:11](OC)=[O:12]>C(OCC)C>[CH3:7][O:8][C:9]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:10]=1[CH2:11][OH:12]
Reactant: COC(=O)c1c(F)c(F)cc(F)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1c(F)cc(F)c(F)c1CO
Yield: 92.5 %

Procedure:
Lithium aluminium hydride (1.5 g) was added in portions to a stirred mixture of methyl 2-methoxy-3,5,6-trifluorobenzoate (10.9 g) in dry diethyl ether (80 cm3) over a period of 30 minutes at the ambient temperature and the resultant mixture stirred for a further period of 30 minutes. The product, 2-methoxy-3,5,6-trifluorobenzyl alcohol (8.8 g), was isolated by a similar procedure to that illustrated in Example 6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:26]([O:28][C:29](=[O:33])[CH:30](Br)Br)[CH3:27]>CN(C=O)C>[CH2:26]([O:28][C:29]([CH:30]1[O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])[CH3:18])=[CH:11][C:12]=2[O:17]1)=[O:33])[CH3:27]
Reactant: CC(Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(CC(C)NC(=O)OC(C)(C)C)cc2O1
Temperature: 120 °C
Yield: 25.4 %

Procedure:
To 1.30 g (4.6 mmol) of 3C was added 40 ml of anhydrous DMF followed by 2.5 g (18 mmol) of anhydrous K2CO3, 2.5 g of 3 A° molecular sieves and 2.3 mL (17.7 mmol) of ethyldibromoacetate. The reaction mixture was heated at 120° C. for 3 hours under argon atmosphere and concentrated under reduced pressure. To the residue 100 mL of water and 75 mL of ethyl acetate were added and filtered. The filtrate was transferred to a separatory funnel and the organic layer was separated. The aqueous layer was extracted with 4×50 mL of ethyl acetate. All the organic layers were combined, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using 20% ethyl acetate in hexane to give 413 mg (1.17 mmol, 26%) of 3D as a colorless gum (M+Na, 374).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[CH:4][N:3]=1.[CH:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:10]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(OCC)c1ccc(Br)nc1
Yield: 92.2 %

Procedure:
In ethanol (60 mL) was dissolved 6-bromonicotinaldehyde (2.00 g, 10.8 mmol). Triethyl orthoformate (5.37 mL, 32.3 mmol) and p-toluenesulfonic acid monohydrate (102 mg, 0.538 mmol) were added and the mixture was refluxed for 2 hours. The solvent in the reaction mixture was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution and water were added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 2-bromo-5-(diethoxymethyl)pyridine (2.59 g, 92% yield).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7]1[C:12]([C@@H:13](O)[CH2:14]N)=[CH:11][C:10]([OH:17])=[C:9](O)[CH:8]=1.[C:19]([O:22][CH2:23][CH3:24])(=O)[CH3:20]>[Pt]>[CH2:23]([O:22][C:19]1[CH:20]=[CH:11][C:12]([CH2:7][CH2:8][CH2:9][CH:10]=[O:17])=[CH:13][CH:14]=1)[C:24]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: NC[C@H](O)c1ccc(O)c(O)c1
Reactant: CCOC(C)=O
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=CCCCc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 4-(4-benzyloxyphenyl)-butanal (52.4 g, 206 mmol) in 150 mL ethyl acetate (1.4M solution) was prepared and set aside. 10% platinum on carbon (3.40 g) was prewetted with ethyl acetate and transferred to the reactor. To this was added magnesium sulfate (60.0 g, 500 mmol), followed by the ethyl acetate solution of (trimethylsilyl)-protected norepinephrine prepared as described in Example 1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:25][CH2:24][C:14]2([O:18][C:17](=[O:19])[NH:16][CH:15]2[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:28]1([CH2:34]Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2([O:18][C:17](=[O:19])[N:16]([CH2:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:15]2[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC1NC(=O)OC12CCN(C(=O)OCc1ccccc1)CC2
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC1N(CC2CCCCC2)C(=O)OC12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
To a solution of 5.0 g 4-butyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzyl ester (14.4 mmol) in 50 mL DMF was added 994 mg of sodium hydride (21.6 mmol, 60% dispersion in mineral oil). The reaction mixture stirred for five minutes and 2.2 mL of cyclohexylmethyl bromide (15.8 mmol) was then added. The reaction mixture stirred under nitrogen for 18 h. The reaction mixture was heated to 70° C. for three h. The reaction mixture cooled to room temperature and was diluted with 500 mL EtOAc and washed twice with water, once with brine. The organics were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel utilizing a gradient elution (10% to 15% EtOAc/DCM) to provide 4.1 g (65%) of 4-butyl-3-cyclohexylmethyl-2-oxo-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylic acid benzyl ester: ms [M]+=443.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]3[CH2:25][CH2:24][CH2:23]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:30][C:28]1[CH:27]=[CH:26][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:29]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCN(CCN2CCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2cc(NC(=O)N3CCN(CCN4CCC4)CC3)ncn2)c(F)c1
Reaction time: 16.5 h
Yield: 31.6 %

Procedure:
4-[2-(Azetidin-1-yl)ethyl]piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (110 mg) was dissolved in tetrahydrofuran (3 ml) and methanol (3 ml), and then 10% palladium carbon (53 mg) was added, followed by stirring under a hydrogen atmosphere for 16.5 hrs. The catalyst was filtered off and washed with methanol. The filtrate and washings were concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, heptane: ethyl acetate:ethanol=95:5 to 90:10). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (32.4 mg) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH:10]([NH:12][CH:13]([C:19]([O-])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:20])[CH:13]([NH:12][CH:10]=[O:11])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(NC=O)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(NC=O)C(=O)Nc1cc(Cl)cc(Cl)c1

Procedure:
3,5-Dichloroaniline, mono-ethyl formamidomalonate and 1,3-dicyclohexylcarbodiimide were reacted in a manner similer to that described in Example XCI Part B to give ethyl 3-[(3,5-dichlorophenyl)amino]-2-formamido-3-oxopropanoate having a melting point of 147.0° C.-148.0° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][N:38]=1)CCC.[Cl-].C(N(CC)CC)C>CN(C)C=O.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:34]1[S:35][CH:36]=[CH:37][N:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1-c1nccs1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 13.3 %

Procedure:
60 mg (0.07 mmol) of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one, 43 mg (0.11 mmol) of 2-(tributylstannyl)thiazole, 2.0 mg (0.01 mmol) of bis-triphenylphosphinepalladium(II) chloride, 4.4 mg (0.02 mmol) of copper (I) iodide and 32 μl (0.23 mmol) of triethylamine in dimethylformamide (1.5 mL) were heated to 120° C. for 20 minutes with microwave irradiation under nitrogen atmosphere. The reaction mixture was filtered through Celite® and washed with methanol. The solvent of the filtrates were evaporated in vacuum and the residue was dissolved in ethyl acetate and washed with brine, dried over magnesium sulphate, filtered and the solvent was removed. The product was purified first by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) and then by preparative HPLC (Waters XBridge C18 OBD column, mixture of eluents NB from 50% B to 65% B, in a 10 min. gradient) to give 4 mg (13% yield) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[K+]>CS(C)=O.O>[F:16][C:14]1[CH:15]=[C:10]([C:5]2([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:11]=[C:12]([F:17])[CH:13]=1
Reactant: COC(=O)C1(c2cc(F)cc(F)c2)CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)C1(c2cc(F)cc(F)c2)CCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)cyclopentanecarboxylic acid methyl ester (Step A, 2.0 g, 8.3 mmol) in dimethylsulfoxide (5 mL) was added potassium hydroxide (1.9 g, 33 mol) in 2 mL of water. After stirring at room temperature for 2.5 h, the reaction mixture was partitioned between ether (50 mL) and saturated aqueous hydrochloric acid (2 N, 50 mL). The organic layer was separated and the aqueous layer extracted with ether (2×50 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound. 1H NMR (400 MHz, CD3OD): δ 6.97 (m, 2H), 6.80 (m. 1H), 2.60 (m, 2H), 1.84 (m, 2H), 1.74 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][NH:26][CH2:27]3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:21][CH:22]=4)[CH2:27]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(cc1N1CCOCC1)CNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccc(N3CCOCC3)cc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18](O)=[O:19])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([NH2:31])[CH3:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:25])[CH3:26])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:31][CH2:29][CH3:30])=[O:19])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCN
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NCC)C1(C)C

Procedure:
The product from Example 173 and ethylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.48 (s, 3H), 0.90 (t, J=7.0 Hz, 3H), 1.00 (t, J=7.2 Hz, 3H), 1.23 (2, 3H), 1.19 (s, 3H), 1.26-1.44 (m, 3H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 1.96-2.09 (m, 1H), 2.59-2.67 (m, 3H), 2.72-2.82 (m, 1H), 2.94-3.19 (m, 2H), 7.53-7.57 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.03; H, 9.26; N, 9.86.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:32]([F:31])=[CH:39][C:38]([F:40])=[CH:37][C:36]=3[F:41])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1cc(F)c(CBr)c(F)c1
Product: Cc1nc2c(ccn2Cc2c(F)cc(F)cc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2,4,6-trifluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41 (s, 1 H), 7.20 (d, J=10.0 Hz, 1 H), 7.08 (t, J=4.0 Hz, 1 H), 6.91 (dd, J=5.6, 8.3 Hz, 1 H), 6.71 (t, J=8.1 Hz, 2 H), 6.23-6.16 (m, 1 H), 5.61-5.42 (m, 3 H), 4.31-4.24 (m, 2 H), 2.94-2.76 (m, 2 H), 2.72 (s, 3 H), 2.13-2.05 (m, 2 H), 0.96 (s, 9 H); LC/MS (m/z) ES+=539.33 (M+1).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]2=[N:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: OCc1ccn2c(I)cnc2c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.1 %

Procedure:
To a solution of (3-Iodo-imidazo[1,2-a]pyridin-7-yl)methanol (1.00 g, 3.65 mmol) and NMO (0.64 g, 5.47 mmol) in CH2Cl2 (30 ml) with sieves (3 g) at 0° C. was added TPAP (0.06 g, 0.18 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 h, before being filtered to remove the sieves. The organic layer was washed with H2O (×2), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography (0-60% MeOH in Et2O) to afford the product (0.15 g). MS: [M+H]+=273
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:27]3[CH:28]=[C:23]([CH:24]=[CH:25][CH:26]=3)[C:21]#[N:22])[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC1(C)CC(=O)c2ccc(-c3cccc(C#N)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-cyanophenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 262; HRMS: calcd for C18H15NO+H+, 262.12264; found (ESI, [M+H]+), 262.1219.