Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)OC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-isopropoxycyclopropyl)-phenylethynyl]-benzoate (Compound 71, 110.0 mg, 0.32 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 89.0 mg (88%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[CH2:16]=O.CO.[C:20]([O-:23])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:16][O:23][CH3:20])[CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CNCCc1ccc(Cl)cc1
Reactant: C=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCN(CCc1ccc(Cl)cc1)C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 307 %

Procedure:
The compound of formula (P14), in which n=2 and R″ is chloro, was prepared from 4-chloro-N-[(trimethylsilyl)methyl]benzeneethanamine (5.17 g, 21.38 mmol) (Preparation 11), added dropwise to ice-cooled aqueous formaldehyde (37% w/v, 2.3 g, 28.34 mmol). After 10 min., MeOH (3 mL, 74 mmol) was added and the mixture stirred at 0° C. for 3 h. Anhydrous K2CO3 (1 g) was then added and the mixture stirred for 30 min at 0° C. The layers were separated and the aqueous phase extracted with τ-Bu methyl ether. The combined organic layers were dried over MgSO4 and concentrated to yield the titled compound as a pale yellow oil (6.35 g). 1H NMR (CDCl3): 7.21 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz), 4.03 (2H, s), 3.21 (3H, s), 2.8-2.9 (2H, m), 2.65-2.8 (2H, m), 2.22 (2H, s), 0.03 (9H, s).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)(OC(C)(C)C)=O.[CH:23]([Sn](CCCC)(CCCC)CCCC)=[CH2:24]>C1(C)C=CC=CC=1>[ClH:22].[Cl:22][C:18]1[N:17]=[CH:16][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:20][C:19]=1[CH:23]=[CH2:24]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC[C@@H]2CCCN2)cnc1Cl
Product: Cl
Temperature: 90 °C
Yield: 170 %

Procedure:
3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloro-pyridine from Example 69a (0.95 g, 2.4 mmol) and tetrakis(triphenylphophino) palladium (0.14 g, 0.12 mmol) were dissolved in toluene (50 mL) and degassed with nitrogen gas for 5 min. Vinyl tributyltin (0.78 mL, 2.67 mmol) was added and the mixture was heated to 90° C. for 1 day. The reaction solvent was evaporated and the crude residue was chromatographed (silica gel; hexanes/EtOAc, 4:1) to provide the title compound (0.69 g, 2.04 mmol, 85%). TLC Rf 0.3 (4:1 hexanes/EtOAc). MS (CI/NH3) m/z 339 (M+H)+. Continued elution provided a minor amount of 5,6-diethenylpyridine (0.044 g, 0.13 mmol, 5.5%): TLC Rf 0.25 (4:1 hexanes/EtOAc); MS (CI/NH3) m/e 331 (M+H)+.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].[O-]CC.[Na+].CN([CH:12]=[C:13]1[CH2:17][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:15][C:14]1=O)C>C(O)C.C(OCC)(=O)C>[N:3]1[C:14]2[CH2:15][NH:16][CH2:17][C:13]=2[CH:12]=[N:4][CH:2]=1
Reactant: N=CN
Reactant: CN(C)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ncc2c(n1)CNC2
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of formamidine hydrochloride (190 mg) in anhydrous ethanol (25.0 mL) under nitrogen were added sodium ethoxide (21% wt in ethanol, 1.2 mL) and 4-[(dimethylamino)methylene]-1-tritylpyrrolidin-3-one (300 mg, prepared as described for Step B, Intermediate 4). The mixture was refluxed at 80° C. for 8 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic layer was washed sequentially with 5% aqueous citric acid solution and brine, dried over anhydrous sodium sulfate, filtered, concentrated. The crude residue was deprotected by treatment with 4N methanolic hydrogen chloride for 2.5 h. The mixture was concentrated and the residue purified by chromatography on a Biotage® system (silica, gradient 15% to 25% of 10% concentrated ammonium hydroxide in methanol/dichloromethane) to give the title compound. LC-MS=243.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]([NH2:23])=[O:22].[CH3:24][C:25]1[O:29][C:28]([CH2:30][NH2:31])=[CH:27][CH:26]=1>O1CCOCC1>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:31][CH2:30][C:28]4[O:29][C:25]([CH3:24])=[CH:26][CH:27]=4)=[C:3]([C:21]([NH2:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: Cc1ccc(CN)o1
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1-c1c(C)noc1C
Solvent: C1COCCO1
Product: COc1cc2c(NCc3ccc(C)o3)c(C(N)=O)cnc2cc1-c1c(C)noc1C

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-quinolinecarboxamide (for a preparation see Intermediate 56, 200 mg,) and [(5-methyl-2-furanyl)methyl]amine (200 mg) in 1,4-dioxane was heated to reflux overnight. The reaction mixture was evaporated to dryness and the residue was taken-up in DCM and washed with a saturated solution of sodium hydrogen carbonate. The organic was dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 7-(3,5-dimethyl-4-isoxazolyl)-4-{[(5-methyl-2-furanyl)methyl]amino}-6-(methyloxy)-3-quinolinecarboxamide (177 mg) as a beige powder.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3].[C:43]([NH:53][CH2:54][C:55](O)=[O:56])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[C:43]([NH:53][CH2:54][C:55]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3])=[O:56])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([F:11])=[CH:6][C:5]=1[F:12].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:12][C:5]1[CH:6]=[C:7]([F:11])[C:8]([CH3:10])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cc(C)c(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.8 %

Procedure:
To a solution of 2,4-difluoro-5-methyl-benzoic acid methyl ester from Step A (1.0 g, 5.37 mmol) in tetrahydrofuran (10 mL), cooled to −78° C. using a dry ice/acetone bath, was added lithium aluminum hydride, 1.0M in tetrahydrofuran (10 mL, 10 mmol), in a dropwise manner. The solution was stirred for two hours. The reaction was quenched by dropwise addition of ice-cold saturated sodium bicarbonate solution, allowed to warm to room temperature and was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the alcohol as a colorless liquid (1.0 g, quantitative yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[O:3]1.N1CCCCC1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O>C(O)C>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1/[CH:31]=[C:12]1/[C:13](=[O:18])[NH:14][C:15]2[C:11]/1=[CH:10][C:9]([B:4]1[O:3][C:2]([CH3:19])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1)=[CH:17][CH:16]=2
Reactant: O=Cc1ccco1
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1(C)OB(c2ccc3c(c2)/C(=C\c2ccco2)C(=O)N3)OC1(C)C
Temperature: 80 °C
Yield: 39.3 %

Procedure:
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (2.00 g, 7.7 mmol), ethyl alcohol (77 mL), piperidine (0.15 mL, 1.5 mmol), and 2-furaldehyde (0.77 mL, 9.3 mmol) were added to a 250 mL round-bottomed flask. The flask was sealed under a septum and heated to 80° C. for 5 hours. The mixture was cooled and filtered through a medium glass frit. The filtrate was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 70% EtOAc in hexane. The combined fractions were evaporated, and the product was crystallized out of EtOAc and hexanes at −20° C. to give (E)-3-(furan-2-ylmethylene)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (1.02 g, 39%) as an orange solid. LCMS (M+H) 338.1 calc. for C19H21BNO4338.1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[CH:12]=1>>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]=2)[CH2:4]1
Reactant: OCC1CCNC1
Reactant: COc1ccc2cc(CCBr)ccc2c1
Product: COc1ccc2cc(CCN3CCC(CO)C3)ccc2c1
Temperature: 120 °C

Procedure:
A mixture of 3.6 g (29.4 mmol) of 3-hydroxymethyl-pyrrolidine and 4.7 g (14.7 mmol) of 2-(2-bromoethyl)-6-methoxy-naphthalene is heated to 120° C. for 2 hours. The reaction mixture is purified over 200 g of silica gel (0.063-0.2 mm) with methylene chloride and then with increasing amounts of ethanol (up to 5%).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][C:10](=O)[N:11]([CH2:13][CH2:14][C@:15]1([OH:29])[CH2:20][C@H:19]2[CH2:21][CH2:22][C@@H:16]1[CH:17]=[C:18]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:12])(C)(C)C.COCCO[AlH2-]OCCOC.[Na+]>C1COCC1>[CH3:12][N:11]([CH2:10][CH2:9][CH2:8][NH:7][CH3:6])[CH2:13][CH2:14][C:15]1([OH:29])[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[C:18]2[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1)C(=O)CCNC(=O)OC(C)(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Product: CNCCCN(C)CCC1(O)CC2CCC1C=C2c1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 118.6 %

Procedure:
To a cold solution of 88 mg of rac-(2-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-carbamoyl}-ethyl)-carbamic acid tert.-butyl ester in 5 mL THF was added dropwise 0.5 mL Red-Al, 65% toluenel. The ice bath was removed and the reaction mixture was heated to 60° C. for 1.5 h. The reaction was cooled with an ice bath and quenched by careful addition of 1M NaOH. After stirring for 10 min, the 2 phases were separated and the organic phase was concentrated in vacuo to obtain 80 mg of crude rac-(1R*,2R*,4R*)-2-{2-[methyl-(3-methylamino-propyl)-amino]-ethyl}-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol as yellow oil.
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:21][C:22]([CH3:33])([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:17]([CH3:34])=[N:16]2)=[CH2:10])(C(C)(C)C)(C)C.[Br:35]N1C(=O)CCC1=O.O>C1COCC1.C(Cl)Cl>[Br:35][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:21][C:22]([CH3:33])([CH3:32])[CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:17]([CH3:34])=[N:16]2)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(NC(C)(C)CNC(=O)OC(C)(C)C)nc12
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of tert-butyl (2-((8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339b), 1-bromopyrrolidine-2,5-dione (0.41 g, 2.30 mmol), and water (0.60 mL, 33.5 mmol) in THF (21 mL) was stirred at 0° C. and warmed to RT and stir for 30 min when product was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 10-40% EtOAc in hexanes to give tert-butyl (2-((8-(2-bromoacetyl)-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339c) (0.49 g, 1.08 mmol, 52% yield) as a yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 1.57 (s, 6H) 2.55 (s, 3H) 3.32 (d, J=6.85 Hz, 2H) 5.00 (s, 2H) 5.11 (dd, J=7.63, 5.09 Hz, 1H) 6.73 (s, 1H) 7.36 (t, J=7.73 Hz, 1H) 7.85 (d, J=7.24 Hz, 1H) 7.93 (d, J=8.02 Hz, 1H). MS (ESI, pos. ion) m/z: 451.2/453.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH:26]1([C:29]2[C:34](OS(C(F)(F)F)(=O)=O)=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27]1>>[CH:26]1([C:29]2[C:34]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(Oc1cccnc1C1CC1)C(F)(F)F
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccnc4C4CC4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and trifluoro-methanesulfonic acid 2-cyclopropyl-pyridin-3-yl ester (Example B.10) (294 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 46%). MS (ISP) 473.3 [(M+H)+]; mp 202° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[N:9]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[CH:5]=[N:6][CH:7]=1.[F:27][C:28]([F:33])([F:32])[C@H:29]([NH2:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][OH:14])[N:9]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:31][C@H:29]([CH3:30])[C:28]([F:33])([F:32])[F:27])=[O:26])=[C:17]3[N:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12
Reactant: C[C@@H](N)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cnn2ccc(N3[C@H](CO)CC[C@@H]3c3cncc(F)c3)nc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.3 %

Procedure:
To a mixture of 5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (10.0 mg, 0.028 mmol), (R)-1,1,1-trifluoropropan-2-amine (6.33 mg, 0.056 mmol) and HATU (10.5 mg, 0.045 mmol) in dry DMF (0.2 mL) was added DIEA (15.0 μL, 0.084 mmol). The reaction vessel was flushed with nitrogen, sealed, and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was directly purified by reverse phase column chromatography (0-50% CH3CN/H2O) to provide the title compound (6.50 mg, 51% yield) as a white solid. MS (apci) m/z=453.0 (M+H).
Reaction SMILES: C=O.[CH2:3]([O:5][C:6](=[O:21])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:4].[CH:22]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34])(=[O:26])=[O:25])=[CH2:23].[C:37](O)(=O)C>C1(C)C=CC=CC=1>[CH2:3]([O:5][C:6]([CH:7]1[CH2:37][CH:22]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:34])([F:36])[F:35])(=[O:25])=[O:26])[CH2:23][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21])[CH3:4]
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CC(=O)O
Reactant: CCOC(=O)CNc1ccccc1-c1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
Paraformaldehyde (74 mg, 2.4 mmol) was added to a solution of (biphenyl-2-ylamino)-acetic acid ethyl ester (125 mg, 490 umol; CAS Reg. No. 39950-19-1) in toluene (9 ml) under an argon atmosphere. The mixture was stirred for 1 h at ambient temperature. A solution of 1-ethenesulfonyl-2-trifluoromethyl-benzene (231 mg, 979 umol) in toluene (1 ml) and acetic acid (10 ul, 98 umol) were added and the reaction mixture was heated under reflux conditions to 120° C. for 12 h. The solvent was removed under reduced pressure and purified by column chromatography (silica gel, EtOAc/heptane) to obtain the title compound (47 mg, 93 umol; 19%) as colorless oil. MS (ESI): m/z=504.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[N+:24]([O-])([O-:26])=[O:25].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:24]([O-:26])=[O:25])=[CH:14][C:13]=3[CH2:18][N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: Cn1nnc2ccc(Oc3ccccc3Cn3cncn3)cc21
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnc2ccc(Oc3ccc([N+](=O)[O-])cc3Cn3cncn3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.2 %

Procedure:
The suspension of 1-methyl-6-[2-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]-1H-benzotriazole (0.5 g) from Example 44, sodium nitrate (0.28 g) and trifluoroacetic acid (5 ml) was stirred at room temperature for 3 days. Stirring was done for another day after further addition of sodium nitrate (0.28 g), and the reaction solution was neutralized with sodium hydrogen carbonate solution, prior to extraction in ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate, prior to removal of the solvent under reduced pressure. The resulting crude crystal in pale yellow was washed with ethyl acetate to give white crystal, which was then recrystallized three times for methanol to give the title compound (0.15 g; 25%). The purity of the compound was 98.8% by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[CH2:23][CH2:22][CH2:21][C:20]=2[C:24]([O:26]CC)=O)=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Br:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:24](=[O:26])[C:20]3[CH2:21][CH2:22][CH2:23][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Br)cc2Cl)CCC1
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Cl)cc1Br

Procedure:
using isopropyl 2-bromo-4-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2-bromo-4-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 208°-210° C.,
Reaction SMILES: C([O:4][C:5](=O)[CH:6]([CH2:13][C:14]1[C:15]([O:27][C:28]2[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=2[CH3:36])=[N:16][C:17]([CH3:26])=[CH:18][C:19]=1[NH:20][CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])C(OC(C)C)=O)(C)C.P(=O)(O)(O)O>>[CH2:22]([CH:21]([N:20]1[C:19]2[C:14](=[C:15]([O:27][C:28]3[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[CH3:36])[N:16]=[C:17]([CH3:26])[CH:18]=2)[CH2:13][CH2:6][C:5]1=[O:4])[CH2:24][CH3:25])[CH3:23]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1CC(C(=O)OC(C)C)C(=O)OC(C)C
Agent: O=P(O)(O)O
Product: CCC(CC)N1C(=O)CCc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 73 °C
Yield: 97.9 %

Procedure:
A mixture of 2-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonic acid diisopropyl ester (40 mg, 0.078 mmol) and 85% phosphoric acid was heated at 73° C. overnight, and then heated at 133° C. for 1 hour. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give a brown oil. The oil residue was purified through silica gel column chromatography using 3% ethyl acetate in hexane as eluent to give 28 mg (98%) of the title compound. 1H NMR (CDCl3) δ 6.89(s,2H), 6.56(s,1H), 4.4(m,1H), 3.00(m,2H), 2.67(m,2H), 2.31(s,3H), 2.25(s,3H), 2.07(s,6H), 1.86(m,4H), 0.90(t,6H) ppm.
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[O-:14][CH2:15]C.[Na+]>O1CCCC1>[CH3:15][O:14][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1C=C(Cl)C(=O)c2ccccc21
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1=CC(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
A solution of 2-chloro-1,4-naphthoquinone (10.3 g) in tetrahydrofuran (100 mL) was treated with a suspension of sodium ethoxide (3.20 g) in tetrahydrofuran (25 mL) at room temperature. After stirring overnight, the mixture was evaporated, and the residue was taken up in ether. The organic layer was washed with brine, dried, filtered and evaporated. Chromatography over silica gel gave 2-methoxy-1,4-naphthoquinone, m.p. 182°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[CH2:23]([CH:25]([NH2:28])[CH2:26][CH3:27])[CH3:24]>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:28][CH:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester (500 mg, 1.56 mmol) and 1-ethyl-propyl-amine (0.8 ml) in 1 ml of DMSO was heated at reflux for 15 hours. The mixture was quenched with sat. ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to give 445.6 mg of yellow solid. The solid was purified through silica gel column chromatography using 1:1 ratio of chloroform:hexane as eluent to give (289 mg, 50%) of the title compound as white crystals, mp 98-102° C.; 1H NMR (CDCl3) δ 8.04 (d, 1H), 6.85 (s, 2H), 6.06 (s, 1H), 3.85 (s, 3H), 3.32 (m, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H), 1.62 (m, 4H), 0.95 (t, 6H) ppm.