Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Cl[C:26]1[C:27]([C:35]#[N:36])=[N:28][CH:29]=[C:30](/[CH:32]=[CH:33]/[CH3:34])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:26]3[C:27](=[C:35]([NH2:36])[N:8]=[C:6]2[CH:7]=1)[N:28]=[CH:29][C:30](/[CH:32]=[CH:33]/[CH3:34])=[CH:31]3
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: C/C=C/c1cnc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: C/C=C/c1cnc2c(N)nc3cc(C)ccc3c2c1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.0 eq.) and (E)-3-chloro-5-(prop-1-enyl)picolinonitrile (from the previous step) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-8-methyl-2-(prop-1-enyl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH2:7][O:8][CH2:9][CH2:10]P(OCC)(OCC)=O)[CH3:4].[CH2:20]([O:22][CH:23]([O:34][CH2:35][CH3:36])[CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[CH3:21]>C1COCC1>[CH2:9]([O:8][C:7](=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([O:25][CH2:24][CH:23]([O:34][CH2:35][CH3:36])[O:22][CH2:20][CH3:21])=[CH:27][CH:28]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:19])[CH3:10]
Reactant: CCOC(COc1ccc(C=O)cc1)OCC
Reactant: CCOC(=O)COCCP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(OCC(OCC)OCC)cc1)OCC
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a stirred suspension of sodium hydride (756 mg, 32 mmol, 95%) in dry THF (60 mL) was added a solution of ethyl(diethylphosphono)ethoxyacetate (6.20 g, 23.1 mmol) in THF (20 mL) at 0-5° C. dropwise and stirred for 30 min at 5-25° C. To the reaction mixture was added a solution of 4-[(2,2-diethoxy)ethoxy]benzaldehyde (5.0 g, 21.0 mmol) in THF (10 mL) at 25° C. and stirred further for 30 min. After completion of the reaction (TLC monitored), THF was removed and the resultant residue was diluted with water (100 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield the title compound (6.5 g, 88%) as a mixture of E/Z isomers.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].C1COCC1.[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)[CH3:24]>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=C(C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.5 %

Procedure:
To a 50 mL volume two-necked flask, 3.0 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 20 ml of THF (anhydrous), 1.73 g of acetophenone and 780 mg of acetic acid were added under a nitrogen atmosphere, and the mixture was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure and hexane was added thereto. The precipitated crystals were collected by filtration and dried to give 3.77 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(1-phenyl-1-ethylidene)hydrazine ((40-a)-(14)-7).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([N:7]1[CH:11]=[CH:10][N:9]([C:12](=[O:14])[CH3:13])[C:8]1=[O:15])(=[O:6])[CH3:5]>CCOCC.C(OCCCC)CCC>[C:12]([N:9]1[CH:10]=[CH:11][N:7]([C:4](=[O:6])[CH3:5])[C:8]1=[O:15])(=[O:14])[CH3:13].[C:12]([N:9]1[C:8](=[O:15])[N:7]([C:4](=[O:6])[CH3:5])[CH:11]2[CH:10]1[CH2:3]2)(=[O:14])[CH3:13]
Reactant: C=[N+]=[N-]
Agent: CC(=O)n1ccn(C(C)=O)c1=O
Solvent: CCOCC
Solvent: CCCCOCCCC
Product: CC(=O)N1C(=O)N(C(C)=O)C2CC21
Yield: 20 %

Procedure:
A solution of diazomethane in ether(prepared from 200 g of N-nitrosomethylurea) is introduced in portions over the course of 3 days into a solution of 25.0 g (0.15 mol) of 1,3-diacetyl-4-imidazolin-2-one and 5.0 g of copper-I chloride in 250 ml of di-n-butyl ether at 80°-90°. The solution is then filtered, the residue is repeatedly eluted with benzene and the combined filtrates are concentrated in vacuo. Chromatography of the crude product on silica gel gives 10.3 g of unconverted 1,3-diacetyl-4-imidazolin-2-one and 3.6 g (about 20%) of 2,4-diacetyl-2,4-diaza-bicyclo[3,1,0]hexan-3-one as colourless crystals of melting point 134°-136° C. (from ether).
Reaction SMILES: O1CCCCC1OC1CCCCO1.[CH3:14][C:15]1([CH3:52])[S:20][CH2:19][CH2:18][N:17]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38]C3CCCCO3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C@H:16]1[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>>[OH:38][CH2:37][CH2:36][CH2:35][CH2:34][C:33]#[C:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:17]2[CH2:18][CH2:19][S:20][C:15]([CH3:52])([CH3:14])[C@@H:16]2[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCOC3CCCCO3)cc2)CCSC1(C)C
Agent: C1CCC(OC2CCCCO2)OC1
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCO)cc2)CCSC1(C)C
Yield: 83.9 %

Procedure:
According to the procedure of Step 1 of Example 245 the tetrahydropyranyl ether of 0.659 g (1.13 mmol) of tert-butyl(3S)-2,2-dimethyl-4-[(4-{[7-(tetrahydro-2H-pyran-2-yloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-3-thiomorpholinecarboxylate was cleaved to provide 0.472 g (84%) of tert-butyl(3S)-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholinecarboxylate as a colorless oil. Electrospray Mass Spec: 498.3 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Br:38])=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].O1CCCC1.CO>[Pd].C(O)(=O)C>[CH:1]([NH:3][C:4]1[S:5][C:6]([Br:38])=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nc(NC=O)sc1Br
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(NC=O)sc1Br
Yield: 38.5 %

Procedure:
4-Nitrobenzyl 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.65 g.) was add to a mixture of tetrahydrofuran (110 ml.) and methanol (80 ml.). To the solution was added a suspension of 10% palladium on carbon (1.5 g.) in acetic acid (10 ml.) and the mixture was subjected to catalytic hydrolysis at room temperature under ordinal pressure. The reaction mixture was filtered and washed with tetrahydrofuran. The filtrate and washings were combined and evaporated in vacuo. Ethyl acetate was added to the residue, adjusted to pH 7.5 with saturated aqueous sodium bicarbonate and filtered. The aqueous layer was separated and washed with ethyl acetate. 100 ml. of 20% Isopropyl alcohol in ethyl acetate was added to the aqueous solution and adjusted to pH 2.0 with 6N-hydrochloric acid. The mixture was saturated with sodium chloride and the organic layer was separated. The remaining aqueous layer was extracted with a mixture (100 ml. and 50 ml.) of ethyl acetate and isopropyl alcohol (4:1). The organic layer and the extracts were combined, washed with a small amount of saturated aqueous sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then evaporated in vacuo. The residue was pulverized with diisopropyl ether and the precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17]O)[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:39]1[CH2:43][C:42](=[O:44])[NH:41][C:40]1=[O:45].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:41]3[C:42](=[O:44])[CH2:43][S:39][C:40]3=[O:45])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN1C(=O)CSC1=O
Temperature: 0 °C
Yield: 50.3 %

Procedure:
To a solution of 2-amino-7-hydroxymethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.13 g, 0.46 mmol) in tetrahydrofuran (3 ml) was added triphenylphosphine (0.13 g, 0.51 mmol), and 2,4-thiazolidinedione (60 mg, 0.51 mmol). The reaction mixture was cooled to 0° C. and diisopropylazodicarboxylate (99 μL, 0.51 mmol) was added via syringe. The resultant mixture was stirred for 18 hours, gradually warming to room temperature. The volatiles were evaporated in vacuo and the resulting oil was diluted in ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (3×50 ml), brine (3×50 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a mixture of dichloromethane/methanol (9:1) as eluant. Pure fractions were collected (Rf=0.70) and the solvent evaporated in vacuo which afforded 89 mg (51%) of 2-amino-7-(2,4-dioxo-thiazolidin-3-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:23])([CH:16](OS(C)(=O)=O)[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[N:12]1.[Na].[CH3:25][SH:26]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:23])([CH:16]([S:26][CH3:25])[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[N:12]1
Reactant: CC(OS(C)(=O)=O)C(O)(Cn1ccnn1)c1ccc(Cl)cc1Cl
Reactant: CS
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: CSC(C)C(O)(Cn1ccnn1)c1ccc(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-3-mesyloxy-1-(triazol-1-yl)butan-2-ol (100 mg; 0.263 mmol) in dimethylsulfoxide (1 ml) was added 15 % aqueous methanethiol sodium salt at room temperature, and the mixture was stirred at 50 to 60° C. for 8 hours. The reaction mixture was diluted with water and extracted with ether. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 2-(2,4-dichlorophenyl)-3-methylthio-1-(triazol-1-yl)butan-2-ol (71 mg, 81 %) as crystals. m.p., 122-123° C. This compound was identical with Compound 4A obtained in Example 4.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](O)=[O:29])[N:25]=1>>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:29])[N:25]=1
Reactant: Nc1nc(-c2ccccc2C(=O)O)cs1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1csc(N)n1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-(2-Amino-thiazol-4-yl)-benzoic acid. LC-MS (basic): tR=1.15 min; [M+H]+=479.2.
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)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[ClH:18]>>[Cl:18][CH:6]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[CH:10]=[CH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2
Reactant: Cl
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [BH4-]
Product: ClC1c2ccccc2C=Cc2ccccc21

Procedure:
Certain of these prior art methods are described in U.S. Pat. No. 3,372,196 of Edward L. Engelhardt and in a publication of Engelhardt et al., J. Med. Chem., 11, 326-332 (1968). One such typical method begins with 5H-dibenzo[a,d]cycloheptene-5-one and first converts the ketone to the corresponding 5-hydroxy compound by reduction with borohydride followed by treatment with dry hydrogen chloride to produce the corresponding 5-chloro-5H-dibenzo[a,d]cycloheptene. This compound is then coupled with a Grignard reagent derived from dimethylaminopropyl chloride to produce the desired N,N-dimethyl-5H-dibenzo[a,d]cycloheptene-5-propylamine which is demethylated to the corresponding N-methyl derivative. Another method, disclosed in the above-mentioned patent, to prepare compounds of the type described involves the reaction of a 5H-dibenzo[a,d]cycloheptene-5-one with an alkoxypropyl magnesium halide to produce the corresponding 5-alkoxypropyl-5-hydroxy-5H-dibenzo[a,d]cycloheptene and reducing this compound using hydrogen iodide in acetic anhydride to produce a 5-(3-iodopropyl)-5H-dibenzo[a,d]cycloheptene in low yield. This compound is then reacted with ammonia or a lower alkyl or dialkyl amine to produce the corresponding 5-(3-aminopropyl, 3-alkylaminopropyl, or 3-dialkylaminopropyl)-5H-dibenzo[a,d]cycloheptene. Compounds of this type have tetrabenazine antagonist activity and are useful in the treatment of humans affected by depression as reported in the above-noted J. Med. Chem. article or as disclosed in the above-noted U.S. Pat. No. 3,372,196 of Engelhardt or are useful as intermediates in the preparation of such compounds.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][O:48]S(C)(=O)=O)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>>[CH:47]([OH:48])=[O:56].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:44]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCOS(C)(=O)=O)c2)n1
Reactant: C1COCCN1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCN3CCOCC3)c2)n1
Product: O=CO

Procedure:
The title compound was prepared starting from Intermediate 113f and morpholine using analogous procedures to those described in Example 113. LCMS (Method 5): Rt 3.36 min, m/z 722 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.54-1.60 (2H, m), 1.65-1.72 (4H, m), 1.80-1.96 (4H, m), 1.98-2.10 (4H, m) 2.22 (2H, t, J=7.0 Hz), 2.24-2.30 (4H, m), 3.10 (4H, t, J=5.2 Hz), 3.50 (4H, t, J=4.6 Hz), 4.09 (2H, t, J=7.0 Hz), 4.79 (1H, td, J=8.4, 5.5 Hz), 5.51 (1H, t, J=4.5 Hz), 6.21 (1H, s), 7.10-7.15 (2H, m), 7.22-7.36 (4H, m), 7.55-7.62 (3H, m), 7.97-8.01 (2H, m), 8.22 (0.3H, br s).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:25])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[CH3:23])[CH:17]=2)[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[F:28][C:29]([F:42])([F:41])[C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[CH:37]C(Cl)=O)=[CH:32][CH:31]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:25])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[CH3:23])[CH:17]=2)[O:13][CH:14]=1)[CH:37]=[CH:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:41])[F:42])=[CH:35][CH:34]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)c1cccc(Cc2nc(NC(=O)OC(C)(C)C)co2)c1
Reactant: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc(Cc2nc(N(C=Cc3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)co2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(3-acetyl-benzyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (15 mg, 0.05 mmol) in THF (1.0 mL) was added to a suspension of NaH (5 mg, 0.12 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 3-(4-trifluoromethyl-phenyl)-acryloyl chloride in THF (1.0 mL). The resulting suspension was stirred for 5 min at 0° C. followed by 30 min at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 02: tR=1.17 min, [M+H]+=515.82.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2)[CH2:15][CH3:16].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=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>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH:14]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH2:15][CH3:16])[CH:31]=[N:32][CH:33]=1
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
Reactant: OB(O)c1cncc(F)c1
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: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1cncc(F)c1
Temperature: 100 °C

Procedure:
To a mixture of 3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one (0.030 g, 0.065 mmol) and (5-fluoropyridin-3-yl)boronic acid (Combi-Blocks, 11.0 mg, 0.0780 mmol) in 1,4-dioxane (0.5 mL) was added a 1M solution of sodium carbonate (8.27 mg, 0.0780 mmol) in water (0.077 mL) and tetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on RP-HPLC at pH 10 conditions (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the desired product. LCMS calculated for C22H20FN8O (M+H)+: m/z=431.2. Found: 431.3.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1.C(N(CC)CC)C.[CH3:16][N:17]1[C:22](=[O:23])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:30])[C:19]([C:31](Cl)=[O:32])=[N:18]1.CC(C)(O)C#N>C(#N)C.ClCCl>[OH:8][C:7]1[N:3]([CH3:2])[N:4]=[CH:5][C:6]=1[C:31]([C:19]1[C:20](=[O:30])[N:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:22](=[O:23])[N:17]([CH3:16])[N:18]=1)=[O:32]
Reactant: Cn1nc(C(=O)Cl)c(=O)n(-c2ccccc2)c1=O
Reactant: Cn1nccc1O
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1ncc(C(=O)c2nn(C)c(=O)n(-c3ccccc3)c2=O)c1O
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Next, 1.22 g (9.10 mmol) of 1-methyl-5-hydroxypyrazole hydrochloride and 1.53 g (15.17 mmol) of triethylamine were added to dichloromethane (30 ml) under ice cooling. To the mixture, the dichloromethane solution (15 ml) of 2-methyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonyl chloride was slowly added dropwise, and stirred for 30 minutes. The reaction mixture was extracted with chloroform, and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residues obtained were dissolved in acetonitrile (30 ml), added with 0.92 g (9.10 mmol) of triethylamine and 0.05 g (0.61 mmol) of acetone cyanohydrin, and refluxed for 30 minutes under heating. The reaction mixture was concentrated under reduced pressure, and then the residues were dissolved in water and washed with ethyl acetate. The aqueous layer was acidified by using citric acid, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The crystals obtained were washed with methanol to obtain 0.40 g of the target compound (yield 20%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][N:35]5[CH2:3][CH2:2][CH2:41][CH2:36]5)[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN5CCCC5)c4)cc23)CC1
Yield: 41 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (20.4 mg, 0.42 mmol) for methanamine to afford 18 mg of the title compound (41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>[O-]CC.[Na+]>[C:9]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C(C#N)c1ccc(F)cc1

Procedure:
By employing the procedures described in Example 1, p-fluorophenylacetonitrile is reacted with diethyl oxalate in alcoholic sodium ethoxide to give ethyl 3-cyano-3-(p-fluoro-phenyl)pyruvate. The latter is reacted with phenylacetonitrile and subsequent synthetic steps yield 4-fluoropulvinic acid lactone. The lactone ring is opened with 2-aminothiazole as described above to give 4-fluoro-N-(2-thiazolyl)pulvinic acid amide.