Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=O)[CH3:3].Cl.[CH2:6]([O:9][C:10](=[O:15])[C@@H:11]([OH:14])[CH2:12][NH2:13])[CH:7]=[CH2:8].C(N(CC)CC)C.[BH4-].[Na+]>C(O)C.ClCCl.O>[CH2:6]([O:9][C:10](=[O:15])[C@@H:11]([OH:14])[CH2:12][NH:13][CH:2]([CH3:3])[CH3:1])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)[C@@H](O)CN
Reactant: CC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](O)CNC(C)C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
2-Propanone (0.22 g, 3.7 mmol) was added to a solution of (S)-3-amino-2-hydroxypropanoic acid 2-propenyl ester hydrochloride (0.45 g, 2.5 mmol) and triethylamine (0.25 g, 2.5 mmol) in ethanol (2.5 ml). After 2 h the solution was cooled to 0° and sodium borohydride (0.15 g, 3.9 mmol) was added. After 20 min, water (0.4 ml) and dichloromethane were added. The mixture was filtered and the filtrate evaporated. The residue was dissolved in ether/water, the organic layer dried (MgSO4) and the solvent evaporated to give the sub-title ester (0.15 g).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].CC(C)([O-])C.[K+].O>CN(C=O)C>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][CH2:10]1)=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 46.5 %

Procedure:
Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.50 g, 1.94 mmol) in DMF (5 mL) was mixed with ethyl acetate (0.38 mL, 3.88 mmol) and potassium tert-butoxide (0.33 g, 2.92 mmol). The mixture was heated to 50° C. for 20 hours. After cooling to room temperature, water was added (50 mL) and the product was extracted with diethyl ether. The ether extract was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluting with heptane-ethyl acetate to provide 4-(2-ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.27 g, 47% yield).
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18](=[O:32])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:12]([N+:33]([O-:35])=[O:34])[CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>CO>[N+:33]([C:12]1[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18](=[O:32])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([O-:35])=[O:34]
Reactant: CCCCCCCCCCCCNC(=O)COc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
In 1 liter of methanol were suspended 275 g of 1-benzoyloxy-3-nitro-4-(dodecylcarbamoylmethoxy)benzene and 50 g of sodium hydroxide were added to the suspension at room temperature under stirring. After stirring for 30 minutes, the reaction solution was poured into 3 liters of ice water to which 150 ml of concentrated hydrochloric acid had been added. Extraction with 3 liters of ethyl acetate was effected and the ethyl acetate layer was washed three times with 3 liters of 5% aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residual crystal was washed with acetonitrile. The yield was 203 g and the melting point was 150°-151° C. (acetonitrile).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([NH2:14])=[O:13])[C:6]1([CH3:16])[CH3:15])=[O:4].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([NH:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([NH2:14])=[O:13])[C:6]1([CH3:16])[CH3:15])=[O:4])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)N(CC(N)=O)C(=O)CN1C(=O)CN
Product: CC(=O)NCC(=O)N1CC(=O)N(CC(N)=O)C1(C)C

Procedure:
A solution of 3-(2-aminoacetyl)-2,2-dimethyl-5-oxo-1-imidazolidineacetamide (2 g) in acetic anhydride (10 ml) was stirred at 80° C. for 5 minutes. After cooling, the precipitate was collected and washed with acetone, affording the title compound as a white powder, m.p. 222° C. dec.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[F:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: Oc1ccc(F)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(F)cc2)CC1
Reaction time: 96 h
Yield: 50.1 %

Procedure:
A mixture of 2.00 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 0.95 g of p-fluorophenol was suspended in 20 ml of dry pyridine. To the suspension was added with stirring and ice-cooling 1.74 g of dicyclohexylcarbodiimide and the resulting mixture was allowed to stand at room temperature for 4 days. After removal of any insoluble materials, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue to give crystals which were then recrystallized from methanol-ether to obtain 1.4 g (yield: 50.0%) of p-fluorophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 131° to 133° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)#[N:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:28]#[N:29])[CH:31]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C#N)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (417 mg, 1 mmol), 2-cyanophenylboronic acid (162 mg, 1.1 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg) and potassium phosphate (318 mg, 1.5 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-(3-cyano-phenyl)-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:27])[NH:15][CH2:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][C:20](=[O:26])[NH:21]3)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[O:26]=[C:20]1[CH2:19][C:18]2[C:22](=[CH:23][CH:24]=[CH:25][C:17]=2[CH2:16][NH:15][C:14]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([C:10]([F:13])([F:11])[F:12])[CH:8]=2)=[O:27])[NH:21]1
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3c2CC(=O)N3)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1Cc2c(CNC(=O)c3cc(C(F)(F)F)c(C(=O)O)s3)cccc2N1
Reaction time: 15 h

Procedure:
A mixture of 5-[(2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (270 mg, 0.68 mmol), lithium hydroxide monohydrate (280 mg, 6.77 mmol), THF (5 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 260 mg (99%). MS m/e 354.9 (M+H+).
Reaction SMILES: [CH2:1]([CH:17]1[CH2:22][C:21](=[O:23])[O:20][C:18]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][NH2:44])=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25].C1(C)C=CC=CC=1>O>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([NH:43][N:44]2[C:21](=[O:23])[CH2:22][CH:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]2=[O:20])=[O:42])[CH:29]=[C:28]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:33]=1[OH:34])([CH3:36])([CH3:37])[CH3:38]
Reactant: CCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
2-Hexadecylsuccinic anhydride (10.5 g, 31.3 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (9.2 g, 31.3 mmol) and 10 ml of toluene were combined and refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water. Solvent was then removed under vacuum as the mixture was warmed to about 130° C. After 20 minutes, the reaction mixture was cooled and the vacuum was removed. The resulting viscous yellow mass was further chilled in an acetone/dry ice bath causing the mass to harden for facile removal from the reaction vessel. About 19 g of a viscous yellow gum was obtained that solidified to a translucent white solid upon standing for several days at room temperature.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][Cl:26])[N:19]=[CH:18]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.O.C(OCC)(=O)C.CCOCC>[ClH:26].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:24][CH2:25][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:19]=[CH:18]3)[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCCl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c(cnn2CCN2CCNCC2)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of 4-(benzyloxy)-1-(1-(2-chloroethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (174 mg, 0.458 mmol) in DMF (2 mL) was treated with piperazine (788 mg, 9.15 mmol), Cs2CO3 (746 mg, 2.29 mmol) and KI (38 mg, 0.23 mmol). After stirring at 50° C. for 16 h, the reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (3×25 mL). The organics were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH/NH4OH, 30:1:0.1 to 20:1:0.2) provided the free base. This was dissolved in ethyl acetate (0.5 mL) and treated with 1 equivalent of 1 M HCl in Et2O. The resulting mixture was filtered to provide the title compound (157 mg, 74%) as a yellow solid: melting point (mp) 217-218° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.17 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.49-7.41 (m, 4H), 7.40-7.35 (m, 2H), 6.13-6.10 (m, 1H), δ 99 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.79-4.51 (m, 2H), 3.51-3.35 (m, 6H), 3.22-2.98 (m, 4H); ESI MS m/z 430 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:14][SiH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[CH3:14][Si:15]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[CH2:3][CH2:2][CH2:1][N:4]1[CH2:9][CH2:8][N:7]([Si:10]([CH3:11])([CH3:13])[CH3:12])[CH2:6][CH2:5]1
Reactant: C=CCN1CCN([Si](C)(C)C)CC1
Reactant: CCO[SiH](C)OCC
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCO[Si](C)(CCCN1CCN([Si](C)(C)C)CC1)OCC
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 99.2 g (0.5 mole) of 1-allyl-4-trimethylsilylpiperazine and 0.65 g of a toluene solution of platinum-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (platinum content 3 wt %) and heated at 70° C. Once the internal temperature became constant, 67.1 g (0.5 mole) of methyldiethoxysilane was added dropwise over 4 hours. Stirring was continued for a further one hour at the temperature. The reaction solution was distilled, collecting 130.8 g of a fraction having a boiling point of 105-106° C./30 Pa.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.S(Cl)(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1cccc(Cl)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A solution of 3-chloro-2-nitrobenzamide (step 1, 1.2 g, 4.9 mmol) in DMF (8 ml) was added thionyl chloride (2 ml, 24.8 mmol) in DMF (3 ml) dropwise at room temperature. The mixture was stirred at 120° C. for 2.5 h. The mixture was poured into ice-water and extracted with ethyl acetate (200 ml). The organic layer was washed with saturated aqueous NaHCO3 (100 ml), brine (100 ml), then dried (MgSO4), and concentrated. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3:1/1:2) to give 1 g (quant.) of the title compound as pale yellow solids.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>C(OCC)(=O)C>[OH:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6][CH2:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H](O)CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72 %

Procedure:
To a solution of (R)-3-hydroxytetradecanoic acid (36, see preparation below) (9.55 g, 39.1 mmol) and triethylamine (5.90 g, 58.6 mmol) in ethyl acetate (500 mL) was added 2-bromoacetophenone (7.90 g, 39.1 mmol) at room temperature. The mixture was stirred at room temperature for 14 h. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 50 min, 85 mL/min) to give the product 37 (10.2 g, 72% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (732 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (629 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 133–134° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[C:23]([O:27][C:28](=[O:40])[CH2:29][N:30]1[C:35](=[O:36])[CH:34]=[CH:33][C:32]([C:37](O)=[O:38])=[CH:31]1)([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([C@H:14]([NH:15][C:37]([C:32]2[CH:33]=[CH:34][C:35](=[O:36])[N:30]([CH2:29][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:40])[CH:31]=2)=[O:38])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)O)ccc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1=O
Temperature: 23 °C
Reaction time: 17 h

Procedure:
A solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (400 mg, 1.174 mmol, Intermediate 6), 1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (327 mg, 1.292 mmol) and HATU (491 mg, 1.292 mmol) in DMF (10 mL) was treated with TEA (0.490 mL, 3.52 mmol). The reaction was then stirred at 23° C. under nitrogen. After 17 h, the solution was diluted with EtOAc (100 mL) and washed with brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 5-30% EtOAc/DCM), affording the title compound as a colorless oil. The compound was taken forward to the next step. MS (ESI, positive ion) m/z: 540.2 (M+H).
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:5][N:4]([C:6]2[N:14]=[C:13]([N:15]3[C:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)[N:12]=[C:11]3[C:7]=2[NH:8][C:9](=[O:26])[NH:10]3)[CH2:3]1.[O:28]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29]1>C(Cl)(Cl)Cl>[F:27][C:2]1([F:1])[CH2:3][N:4]([C:6]2[N:14]=[C:13]([N:15]3[C:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=4[N:17]=[CH:16]3)[N:12]=[C:11]3[C:7]=2[NH:8][C:9](=[O:26])[N:10]3[CH2:33][CH:30]2[CH2:31][CH2:32][O:28][CH2:29]2)[CH2:5]1
Reactant: OCC1CCOC1
Reactant: N#Cc1ccc2ncn(-c3nc(N4CC(F)(F)C4)c4[nH]c(=O)[nH]c4n3)c2c1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2ncn(-c3nc(N4CC(F)(F)C4)c4[nH]c(=O)n(CC5CCOC5)c4n3)c2c1
Yield: 18 %

Procedure:
White solid. 18% yield. Synthesized from 3-(6-(3,3-difluoroazetidin-1-yl)-8-oxo-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (0.12 mmol) and tetrahydro-3-furan-methanol following the general procedure for diversifying at the N9 position of the purinones based on a Mitsunobu reaction. 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.22 (s, 1H), 8.99 (s, 1H), 7.89 (d, 1H), 7.67 (d, 1H), 4.76 (t, 4H), 4.10-3.97 (m, 3H), 3.90-3.77 (m, 3H), 3.06-2.93 (m, 1H), 2.22-2.07 (m, 1H), 1.90-1.83 (m, 1H); IR (CHCl3), cm−1: 2979 (w), 1703 (s), 1367 (m), 1167 (m); MS (EI) m/z 453.1 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)/C=C/C1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Solvent: CO
Product: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Reaction time: 5 h
Yield: 89 %

Procedure:
(E)-Ethyl 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)acrylate (1.28 mmol) was dissolved in methanol (20 ml), the mixture was degassed with argon and Pd(OH)2 (125 mg) was added. Hydrogenation was then carried out under normal pressure for 4-6 h. After thin layer chromatography control, the reaction mixture was filtered over Celite and the residue was rinsed with methanol. The filtrate was concentrated to dryness under reduced pressure. Yield: 89%
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[CH2:18]([NH:25][C:26]([N:4]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)[CH2:1][CH2:2][CH3:3])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C(=O)NCc1ccccc1)C1CCNCC1

Procedure:
The title compound was prepared by the reaction of 4-(N-(prop-1-yl)amino)-1-tert-butoxycarbonylpiperidine (from Example 17, Step A) with benzyl isocyanate, followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 276.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:14][CH:15]=1)=[O:20]
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)c(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2s1
Yield: 84 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-biphenylcarbonyl chloride (50 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave biphenyl-4-carboxylic acid (4-chloro-2-methyl-benzothiazol-5-yl)-amide (79 mg, 0.21 mmol, 84% yield) as a pale pink powder after crystallisation in hexane/DCM.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3ccno3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.