Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[C:14](=[CH:7]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)/[C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=Cc1ccccn1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccccn2)cc1OC
Yield: 70.9 %

Procedure:
2-Pyridinecarboxaldehyde (2.14 g) was condensed with 3,4-dimethoxybenzyl cyanide (3.54 g) through Method A (production step 2), to thereby yield the target product (yield: 3.77 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][C:10]1([CH3:13])[CH2:12][O:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:9][C:10]([OH:11])([CH3:13])[CH3:12])[CH:7]=1
Reactant: CC1(C)CO1
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(O)Cn1cc(Br)ccc1=O
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of 5-bromopyridin-2(1H)-one (600 mg, 3.5 mmol), 2,2-dimethyloxirane (750 mg, 10 mmol) and K2CO3 (960 mg, 6.9 mmol) in DMF (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (80 mL), washed with water, brine, and dried over MgSO4. The organic layer was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10 to 50% EtOAc/hexane) to give Compound B387a (650 mg, 76% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.50 (d, J=2.6 Hz, 1H), 7.40 (dd, J=9.6, 2.8 Hz, 1H), 6.54 (d, J=9.7 Hz, 1H), 3.99 (s, 2H), 3.57-3.39 (s, 1H), 1.27 (s, 6H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]1
Reactant: CC(=O)O[C@@H]1C=C[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a solution of trans-1-acetoxy-4-(tert-butoxycarbonylamino)-2-cyclohexene (6.70 g, 26.3 mmol) in methanol (130 mL) was added solid K2CO3 (7.50 g, 54.4 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was dissolved in CH2Cl2 (250 mL) and saturated aqueous NaHCO3 (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH3OH) provided 3.38 g (60%) of trans-1-hydroxy-4-(tert-butoxycarbonylamino)-2-cyclohexene as a white solid. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.52-1.57 (m, 1H), 2.05-2.14 (m, 3H), 4.20-4.26 (br s, 2H), 4.45 (br s, 1H), 4.47-4.60 (m, 1H), 5.70 (d, 1H, J=10.2 Hz), 5.81 (d, 1H, J=10.2 Hz);
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[CH3:8][N:9]([CH3:17])[C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([O:4][CH2:5][CH2:6][O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N:9]([CH3:17])[CH3:8])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CN(C)c1cccc(O)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cccc(N(C)C)c1
Temperature: 80 °C

Procedure:
2-Bromoethyl acetate (1.34 g, 4.01 mmol) was added to a suspension of 3-(dimethylamino)phenol (0.50 g, 3.64 mmol) and K2CO3 (1.5 g, 10.8 mmol) in anhydrous DMF (3 mL). The reaction mixture was heated to 80° C. for 18 hours, cooled to rt, diluted with water, extracted with DCM. The organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 90:10-80:20, to provide the desired compound 2-(3-(dimethylamino)phenoxy)ethyl acetate (39A).
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Si](C)(C)C)=[CH:13][CH:12]=2)[N:7]=[C:6]([C:21]([O:23][CH3:24])=[O:22])[C:5]=1[Cl:25]>ClCCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:1])=[CH:13][CH:12]=2)[N:7]=[C:6]([C:21]([O:23][CH3:24])=[O:22])[C:5]=1[Cl:25]
Reactant: ClI
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(F)c(N)c1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(I)cc2)c(F)c(N)c1Cl
Temperature: 23 °C
Reaction time: 17 h
Yield: 72.3 %

Procedure:
Iodine monochloride (280 mg, 1.7 mmol, 2.0 equiv) was added to a stirred solution of methyl 4-amino-3-chloro-5-fluoro-6-(4-(trimethylsilyl)phenyl)picolinate (300 mg, 0.85 mmol, 1.0 equiv) in 1,2-dichloroethane (5.7 mL) at 23° C. The resulting brown solution was stirred at 23° C. for 17 h. The reaction mixture was diluted with saturated solution of sodium thiosulfate (100 mL) and extracted with dichloromethane (4×40 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (33% ethyl acetate in hexanes) to afford the title compound as a pale purple powder (250 mg, 71%).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[C@@H:18](/[CH:19]=[CH:20]/[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:17][CH2:16][C:15]1=[O:28]>C1COCC1>[CH2:1]([S:3][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]1[C@@H:18](/[CH:19]=[CH:20]/[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:17][CH2:16][C:15]1=[O:28])[CH3:2]
Reactant: O=C1CC[C@H](/C=C/CC2CCCCC2)[C@H]1CCCCCCCBr
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSCCCCCCC[C@H]1C(=O)CC[C@@H]1/C=C/CC1CCCCC1
Reaction time: 3 h

Procedure:
Ethyl mercaptan (0.1 ml) was injected dropwise into a slurry of 1.0 ml THF and 62.5 mg of sodium hydride (50% in oil). The resultant slurry was stirred for 1.0 hour at 25° whereupon a solution of 167 mg 1-Bromo-16,20-methanoprost-13E-en-9-one in 1.0 ml of THF was injected and the reaction mixture was stirred for 3.0 hours at 25°. The reaction mixture was quenched by the addition of 10% aqueous HCl and extracted twice with chloroform. The chloroform extracts were washed with saturated aqueous NaHCO3 and then brine. They were dried (Na2SO4), filtered and evaporated in vacuo to yield 135 mg of an orange oil. The oil was chromatographed (85:15 silicic acid-Celite, benzene-ethyl acetate gradient elution) to afford 70.1 mg of a clear oil having the following structure: ##STR58## The structure of this material was confirmed by nuclear magnetic resonance and mass spectral analysis.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:26]([C:38]1[S:42][C:41]([C:43](Cl)=[O:44])=[CH:40][CH:39]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>O>[CH2:26]([C:38]1[S:42][C:41]([C:43]([O:25][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[N:15]=[CH:14][C:13]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:18][N:17]=3)=[CH:24][CH:23]=2)=[O:44])=[CH:40][CH:39]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCc1ccc(C(=O)Cl)s1
Reactant: CCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(C(=O)Oc2ccc(-c3ncc(CCCCCC)cn3)cc2)s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 50.4 %

Procedure:
15 ml of pyridine was added to 0.49 g (1.93×10-3 mol) of 4-(5-hexyl-2-pyrimidinyl)phenol, followed by cooling on an iced water bath. To the mixture, 0.61 g (1.93×10-3 mol) of 5-dodecylthiophene-2-carboxylic chloride was added, followed by stirring for 4.5 hours at room temperature. After the reaction, the reaction mixture was poured into 100 ml of water and acidified with conc. hydrochloric acid, followed by three times of extraction with 50 ml of isopropyl ether. The organic layer was washed with water repeatedly until the washing liquid reached neutrality, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography with the use of a hexane/ethyl acetate (=10/1) mixture solvent and recrystallized from an ethanol/ethyl acetate mixture solvent to obtain 0.52 g of a pure product (yield: 50.5%). ##STR32##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([I:18])[CH:14]=[CH:13][CH:12]=2.C(O)C.NN>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:19][NH2:20])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([I:18])[CH:14]=[CH:13][CH:12]=2
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2cccc(I)c2nc1-c1ccccc1Cl
Agent: NN
Solvent: CCO
Product: NCc1nc2cccc(I)c2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-((3-(2-chlorophenyl)-5-iodoquinoxalin-2-yl)methyl)-isoindoline-1,3-dione (0.7028 g, 1.337 mmol) in ethanol (12.00 mL, 1.337 mmol) was added hydrazine, anhydrous (0.4196 mL, 13.37 mmol), and the mixture was stirred under reflux. After 30 min, the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a 80 g of Redi-Sep™ column using 0% to 50% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 25 min, and then 50% isocratic of CH2Cl2:MeOH:NR4OH (89:9:1) in CH2Cl2 for 5 min as eluent to give (3-(2-chlorophenyl)-5-iodoquinoxalin-2-yl)methanamine as a green syrupy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (1 H, dd, J=7.4, 1.0 Hz), 8.17 (1 H, dd, J=8.4, 1.2 Hz), 7.52-7.74 (5 H, m), 3.83 (2 H, br. s.), 1.97 (2 H, br. s.); LC-MS (ESI) m/z 396.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@H:21]([OH:23])[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a solution of 1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanone (2.31 g, 7.32 mmol) in THF (80 mL) at 0° C. were added portion wise LiAlH4 (0.245 g, 6.44 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (R)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-7) 0.98 g (42%) as a white solid ES-MS m/e: 318.1(M+H+) and (S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-A-7) 0.86 g (37%) as a white solid ES-MS m/e: 318.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15].[Cl:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20]>>[Cl:16][C:17]1[CH:25]=[N:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15])=[O:20]
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)cc21
Reactant: O=C(O)c1ccncc1Cl
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3ccncc3Cl)cc21

Procedure:
Prepared in analogy to example 26 from 6-amino-5-fluoro-1,3,3-trimethylindolin-2-one (example 20 f) and 3-chloroisonicotinic acid. The title compound was obtained as white crystals.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:12]([N:14]([CH:22]3[CH2:24][CH2:23]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[CH:8][C:9]=2I)[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:3]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.[Pd]>[CH:22]1([N:14]([CH:12]([C:7]2[CH:6]=[C:5]3[C:10]([CH:2]=[N:3][N:4]3[CH2:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:9][CH:8]=2)[CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: COCCCn1nc(Br)c2c(I)cc(C(C)N(C(=O)OC(C)(C)C)C3CC3)cc21
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COCCCn1ncc2ccc(C(C)N(C(=O)OC(C)(C)C)C3CC3)cc21
Reaction time: 42 h
Yield: 25.9 %

Procedure:
To a solution of tert-butyl N-{1-[3-bromo-4-iodo-1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}cyclopropylcarbamate (1.0 g) in 1,4-dioxane (20 mL) were added diisopropylethylamine (0.90 mL) and 10% palladium on carbon catalyst (200 mg), and the mixture was stirred under hydrogen for 42 hours. An insoluble was filtered, and then the filtrate was sequentially washed with aqueous saturated sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1→4/1) to give tert-butyl cyclopropyl{1-[1-(3-methoxypropyl)-1H-indazol-6-yl]ethyl}carbamate [REx(30-1)] (167 mg) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH:9]([N:11]1[C:24]2[CH:23]=[C:22]([C:25](=S)[NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10].C(O)(=[O:35])C>>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH:9]([N:11]1[C:24]2[CH:23]=[C:22]([C:25]([NH:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:35])[CH:21]=[CH:20][C:19]=2[S:18][C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10]
Reactant: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCC[C@@H]1CO)c1ccccc1S2
Reactant: CC(=O)O
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCC[C@@H]1CO)c1ccccc1S2
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
Mercuric acetate (2.91 g) dissolved in glacial acetic acid (60 cc) is added in the course of 20 minutes to a solution of 10-{1-[(2R)-2-hydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarbothioamide, L series (4.29 g) in acetic acid (60 cc), and the mixture is stirred for 45 minutes at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with celite and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (250 cc) and distilled water (50 cc). The organic phase is washed successively with normal sodium hydroxide (2×100 cc) and distilled water (3×100 cc) and with saturated aqueous sodium chloride (100 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (4.6 g) is thereby obtained. This residue is purified by chromatography on a column (height: 25 cm; diameter: 3.0 cm) of silica gel (0.04-0.06 mm), eluting with pure ethyl acetate (3.6 liters) with a slight excess pressure of nitrogen (40 kPa) and collecting 150-cc fractions. Fractions 12 to 24 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-{1-[(2R)-2-h-ydroxymethyl-1-pyrrolidinyl]-2-propyl}-N-(3-methylbutyl)-2-phenothiazinecarboxamide, L series (0.89 g) in the form of an off-white solid, m.p. 140° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:16]
Reactant: Cc1cc(C)cc(C)c1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(C(=O)CCC(=O)O)c(C)c1
Yield: 54 %

Procedure:
Mesitylene 10i (99%, 4.8 eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 72 h according to the general procedure. Extractive purification of the crude product afforded white crystals of 11i in 54% yield. 1H-NMR (DMSO-d6): 6.63 (s, 2H, Ar--H); 2.84 (t, 2H, CH2CH2COOH); 2.22 (s, 3H, p-CH3); 2.18 (t, 2H, CH2CH2COOH); 2.13 (s, 6H, o-CH3).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(OCC)(=O)C(OCC)=[O:13]>>[O:13]=[C:2]([CH2:3][CH2:4][CH2:5][CH3:6])[C:1]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCCC(=O)OCC
Product: CCCCC(=O)C(=O)O

Procedure:
Ethyl n-hexanoate and diethyl oxalate were subjected to Claisen condensation, and then hydrolyzed to form 2-oxo-n-hexanoic acid. This product was then condensed with diaminomaleonitrile to form 9.1 g (0.042 mole) of 2,3-dicyano-5-hydroxy-6-n-pentylpyrazine (m.p. 61°-64° C.). The product was dissolved in 120 g of phosphorus oxychloride, and 3.32 g (0.042 mole) of pyridine was added. The mixture was refluxed for 5 hours, and then worked up in the same way as in Example 3 and the resulting oily product was concentrated under reduced pressure. The resulting product was chromatographed on a silica gel column with benzene as an eluent to afford 6.0 g (yield 61%) of 2,3-dicyano-5-chloro-6-n-pentyl-pyrazine as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][C:6](=[O:12])[C:5]2=[CH:13][N:14]([CH3:16])C.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH:19]1C1C=CC(N)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][C:6](=[O:12])/[C:5]/2=[CH:13]\[NH:14][C:16]1[CH:4]=[CH:3][C:2]([N:21]2[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]2)=[CH:11][CH:10]=1
Reactant: CN1CCNCC1c1ccc(N)cc1
Reactant: CN(C)C=C1C(=O)NCc2ccc(Br)cc21
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NCc4ccc(Br)cc43)cc2)CC1
Yield: 50.5 %

Procedure:
A toluene solution (0.75 mL) of 6-bromo-4-[(dimethylamino)methylene]-1,4-dihydroisoquinolin-3(2H)-one (60 mg, 0.213 mmol) and 4-(N-methylpiperazinyl)aniline (42.9 mg, 0.224 mmol) is heated at 110° C. for 3 h. It is dried up and triturated with ether and hexane to yield 23 mg (25%) of the title compound as a light-brown solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:33][N:34]([CH3:38])[C:35]([NH:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[CH:13][CH:12]=1)=[O:36]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4oc(C)nc4-c4ccc(N)cc4)ccnc32)cc1
Reactant: CN(C)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4oc(C)nc4-c4ccc(NC(=O)N(C)C)cc4)ccnc32)cc1

Procedure:
Following the procedure described for Intermediate 31 with 4-(2-methyl-5-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1,3-oxazol-4-yl)aniline and dimethylcarbamoyl chloride provided the title product. ESMS[M+H]+: 516.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.C(=N[OH:56])C>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][CH:34]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:56])[NH2:46])=[CH:41][C:40]=2[N:47]2[CH:51]=[CH:50][C:49]([CH3:52])=[N:48]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CC=NO
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C#N)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OC(c4ccc(C(N)=O)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 110 °C

Procedure:
To a solution of (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-cyano-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (150 mg, 0.2 mmol, see Ex. 14) in toluene (10 mL) was added acetaldehyde oxime (240 mg, 4 mmol) and InCl3 (44 mg, 0.2 mmol). The reaction was heated to 110° C. for 3 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/hepate) provided (3S)-2-benzyl 3-ethyl 8-(2-amino-6-(1-(4-carbamoyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: CO.[C:3]([O:7][C@H:8]([C:13]1[C:14]([CH3:40])=[N:15][C:16]2[N:17]([N:31]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:33]=2)[C:18]=1[C:19]1[C:20]([CH3:30])=[C:21]2[C:26](=[C:27]([F:29])[CH:28]=1)[O:25][CH2:24][CH2:23][CH2:22]2)[C:9]([O:11]C)=[O:10])([CH3:6])([CH3:5])[CH3:4]>C(=O)=O>[C:3]([O:7][C@H:8]([C:13]1[C:14]([CH3:40])=[N:15][C:16]2[N:17]([N:31]=[C:32]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:33]=2)[C:18]=1[C:19]1[C:20]([CH3:30])=[C:21]2[C:26](=[C:27]([F:29])[CH:28]=1)[O:25][CH2:24][CH2:23][CH2:22]2)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: O=C=O
Solvent: CO
Product: Cc1nc2cc(-c3ccccc3)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@@H](OC(C)(C)C)C(=O)O
Reaction time: 0.23 h

Procedure:
The title compound was synthesized using a two step method starting from the racemic ester precursor for Example 39. The racemic ester was separated into two enantiomers using a chiral column and (2R)-methyl 2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate was isolated. Chiral separation method: Chiralpak AD-H preparative column, 20×250 mm, 5 μm to give two enantiomers. Mobile Phase: 15% MeOH in CO2 @ 150 Bar. Temp: 35° C. Flow rate: 45.0 mL/min. for 14 min. UV was monitored @ 254 nm. Hydrolysis of (2R)-methyl 2-tert-butoxy-2-(7-(8-fluoro-5-methylchroman-6-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl)acetate as described in Example 1 provided the title compound with 100% enantiomeric excess. Retention time: 9.94 min. Chiral SFC method: Chiralpak AD-H analytical column, 4.6×250 mm, 5 μm. Mobile Phase: 15% MeOH in CO2. Temp: 35° C. Flow rate: 2.0 mL/min. for 14 min. UV monitored @ 254 nm.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+]>C1COCC1>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:13]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:12][CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2cc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCN1CCCc2cc(-c3ccccc3)c(-c3ccccc3)nc21

Procedure:
A solution of Ethyl 7-(6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoate (step 1) (100 mg, 0.226 mmol) and lithium hydroxide (37.9 mg, 0.904 mmol) in THF (2 ml) was heated at 75° C. for 6 h. The reaction was quenched with water and the pH was adjusted to pH 3-4 by addition of 1M HCl. The mixture was partitioned between EtOAc and water. The organic portion was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 3:2 iso-hexane/EtOAc afforded the title compound.