Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:14]([Si:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:18][CH2:19][CH2:20][CH:21]1[CH2:24][CH:23]([O:25][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)[CH2:22]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](OCCC1CC(O)C1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCC1CC(OC2CCCCO2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105 %

Procedure:
3-(2-{[Tert-butyl(diphenyl)silyl]oxy}ethyl)cyclobutanol (3.58 g, 10.1 mmol) was dissolved in dry tetrahydrofuran (50 mL) and 2,3-dihydro-4H-pyran and 4-toluenesulfonic acid pyridine salt were added and the reaction was stirred at room temperature for 48 hours. The reaction was concentrated in vacuo and purified on silica gel with a heptane-ethyl acetate gradient (5% ethyl acetate, then 20% ethyl acetate) to give crude tert-butyl(diphenyl){2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethoxy}silane (4.66 g, 105%) as a milky oil. Partial 1H NMR indicated a ˜4:1 mix of unknown cis-trans isomers. (CDCl3, δ ppm, key peaks are 4.05 (m, 0.80H), 4.30 (m, 0.20H), 4.52 (m, 0.20H), 4.56 (m, 0.80H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1cccs1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1cccs1
Yield: 82.6 %

Procedure:
2.8 g of ethyl 3-(4-chlorobenzoylamino)-3-(2-thienylcarbonyl)propionate, 10 ml of dimethylformamide and 1.4 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 2.2 g of ethyl 2-[2-(4-chlorophenyl)-5-(2-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([Cl:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19]I>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:19])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([Cl:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
N-(tert-Butoxycarbonyl)-3-chloro-4-methylaniline (60.0 g) was dissolved in N,N-dimethylformamide (300 ml) and 60% sodium hydride (10.4 g) was gradually added under ice-cooling over 10 min. The reaction mixture was stirred at room temperature for 30 min and methyl iodide (38.8 g) was added dropwise over 15 min under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure. Water (500 ml) was added and the mixture was extracted with ethyl acetate (500 ml). The organic layer was washed successively with water (500 ml), saturated aqueous sodium hydrogen carbonate solution (500 ml) and saturated brine (500 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate=9:1. The objective fraction was concentrated under reduced pressure to give N-(tert-butoxycarbonyl)-3-chloro-N,4-dimethylaniline as a pale-yellow oil (62.7 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].S(=O)(=O)(O)O.[CH3:21][C:22](=[CH2:24])[CH3:23].C(=O)=O>ClCCl.CC(C)=O>[C:22]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])([CH3:24])([CH3:23])[CH3:21]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: C=C(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 77 %

Procedure:
Dissolve 2-(3-hydroxypropyl)isoindole-1,3-dione (2 g, 9.74 mmol, 1 eq) in 40 mL of dichloromethane under N2. Add sulfuric acid (780 μL) and cool reaction mixture to −5° C. Condense isobutylene gas to a liquid using a −78° C. cold finger charged with dry ice and acetone. Add approximately 20 mL of the condensed liquid to the reaction mixture and slowly warm the solution to room temperature overnight while stirring. Add saturated, aqueous sodium hydrogencarbonate to the reaction mixture and extract product into the organics. Wash separated organic layer with water and dry over magnesium sulfate to give 1.969 g (77% yield) of 2-(3-tert-butoxypropyl)isoindole-1,3-dione as a colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:28])[CH:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:10])([CH3:9])[CH3:8].Cl[C:30]1[S:34][N:33]=[C:32]([CH3:35])[N:31]=1>O1CCCC1>[C:7]([O:11][C:12](=[O:28])[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])([C:30]1[S:34][N:33]=[C:32]([CH3:35])[N:31]=1)[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)C(CCCCCC#N)C(=O)OC(C)(C)C
Reactant: Cc1nsc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nsc(C(CCCCCC#N)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 42 %

Procedure:
Potassium tert-butoxide (14.6 g, 0.13 mol) followed by 2-(5-cyanopentyl)malonic acid di-tert-butyl ester (2021050) (32.3 g, 0.1 mol) was added portionwise to stirred tetrahydrofuran (150 mL). 5-Chloro-3-methyl-1,2,4-thiadiazole (2009380) (13.5 g, 0.10 mol) was then added to the slurry and the mixture was heated at reflux overnight before being quenched with water (150 mL) and extracted with dichloromethane (3×200 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (6:1 hexane/ethyl acetate) to afford 2-(5-cyanopentyl)-2-(3-methyl[1,2,4]thiadiazol-5-yl)malonic acid di-tert-butyl ester (2021051) (17.2 g, 42%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]#[N:10].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH2:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH:4]=1)[C:9]#[N:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromo-3-cyanophenol (1 g, 5.05 mmol) was dissolved in DMF (10 ml) and K2CO3 (1.40 g, 10.10 mmol) and benzyl bromide (0.66 ml, 5.56 mmol) added. The mixture was stirred under N2 for 1 hr at RT. The mixture was diluted with water (15 mL) and extracted with EtOAc (2×10 mL). The organic fractions were combined, washed with brine (saturated, 1×8 mL), dried over MgSO4, filtered and the volatiles removed in vacuo. The residue was purified by chromatography on silica gel Biotage 25M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 289 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:21][CH:20]=1)([C:12]1[CH:17]=CC=C[CH:13]=1)[C:6]1[CH:11]=CC=C[CH:7]=1)(C)([CH3:3])[CH3:2].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[O:42][N:41]=[C:40]([CH2:43][S:44]([C:47]3[CH:55]=[CH:54][C:50]([CH2:51][CH2:52][NH2:53])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[N:39]=2)=[CH:34][CH:33]=1>>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[O:42][N:41]=[C:40]([CH2:43][S:44]([C:47]3[CH:48]=[CH:49][C:50]([CH2:51][CH2:52][NH:53][CH2:29][C@H:27]([OH:28])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:19]([O:18][Si:5]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:11])[CH3:7])[CH:12]([CH3:13])[CH3:17])=[CH:20][CH:21]=4)=[CH:54][CH:55]=3)(=[O:45])=[O:46])[N:39]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCN)cc3)no2)cc1
Product: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCNC[C@H](O)COc4ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc4)cc3)no2)cc1
Yield: 72.9 %

Procedure:
This material was prepared as described in Example 11 from tert-butyl{4-[(2S)oxiranylmethoxy]phenoxy}diphenylsilane (0.45 g, 1.124 mmol) and 4-({[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}sulfonyl)phenethylamine (0.70 g, 1.875 mmol). This procedure afforded 0.570 g of the title compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>ClCCl>[C:13]([Si:10]([O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc(O)cc(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
To a solution of 3-fluoro-5-methylphenol (19.7 g, 156 mmol) and tert-butyldimethylsilyl chloride (25.9 g, 172 mmol) in dichloromethane (250 mL) was added imidazole (12.7 g, 187 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. The mixture was washed with water and brine and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (98:2 hexane/ethyl acetate) to give tert-butyl(3-fluoro-5-methylphenoxy)dimethylsilane (38.6 g, 100%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=2[OH:13])=[O:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][O:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=1[C:4]([CH:1]1[CH2:2][CH2:3]1)=[O:5])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1c(O)cccc1O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(O)c1C(=O)C1CC1

Procedure:
To a mixture of cyclopropyl-(2,6-dihydroxy-phenyl)-methanone (398 mg) and potassium carbonate (500 mg) in acetone (5 ml) was added bromoacetic acid ethyl ester (300 μl) at room temperature. The suspension was heated to reflux for 1.5 hours and diluted with ethyl acetate (10 ml), washed with diluted hydrochloric acid (5 ml) and brine (5 ml), dried over anhydrous sodium sulfate, then concentrated in vacuo. The mixture was purified by silica gel column chromatography developed by hexane-ethyl acetate to give (2-cyclopropanecarbonyl-3-hydroxy-phenoxy)-acetic acid ethyl ester as a pale yellow solid (382 mg). EI-MS: m/z 264 (M+); 1H-NMR (CDCl3): δ 1.04-1.09 (2H, m), 1.23-1.29 (2H, m), 1.28 (3H, t, J=7.26 Hz), 2.26-2.35 (1H, m), 4.29 (2H, q, J=7.26 Hz), 4.70 (2H, s), 6.27 (1H, dd J=0.99 Hz, 8.25 Hz), 6.62 (1H, dd, J=0.99 Hz, 8.25 Hz), 6.41 (2H, d, J=8.25 Hz), 7.31 (1H, dd, J=8.25 Hz, 8.25 Hz), 12.89 (1H, s).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH2:67])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)(=[O:46])[CH2:43][CH2:44][CH3:45]>CN(C=O)C>[C:42]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH:67][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:59][CH:60]=1)(=[O:46])[CH2:43][CH2:44][CH3:45]
Reactant: CCCC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 1.6 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid butyryloxymethyl ester (51 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (1 mg; purity 95%). MS m/z [M+H]+ calc'd for C27H32N4O6, 509.23. found 509.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14](OC(C)(C)C)=O)=[CH:8][CH:7]=2.[Cl:21][C:22]1[N:27]=[N:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:14]([CH2:13][C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12]4)=[N:29][N:28]=2)[N:27]=1
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Reactant: NNc1ccc(Cl)nn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cnc2ccc(Cc3nnc4ccc(Cl)nn34)cc2c1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a 5 ml CEM microwave tube was added tert-butyl 2-(3-methoxyquinolin-6-yl)acetate (0.05 g, 0.2 mmol), 1-(6-chloropyridazin-3-yl)hydrazine (0.04 g, 0.3 mmol), water (0.5 mL) and hydrochloric acid (0.05 ml, 0.5 mmol). The vial was sealed and first heated at 90° C. for 30 min then placed into CEM microwave for 10 min. at 100° C., with 100 Watts of power via Powermax. The reaction mixture was adjusted the pH to 7 by adding 5 N NaOH—brown ppt. was generated. The brown ppt. was dissolved in DCM. The organic was washed with water, dried over MgSO4, and removed solvent in vacuo. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-026, 12 g SiO2, DCM:EtOAc:MeOH=75%:20%:5%, Flow=30 mL/min). A peak at 25 min was collected. The solvent was removed in vacuo to afford the desired product as light yellowish solid. Wt: 20.0 mg. MS (ESI pos. ion) m/z: 326.53. Calc'd exact mass for C16H12ClN5O: 325.75.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.[CH3:47][N:48](C=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.[C-]#N.[Zn+2].[C-]#N>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[C:47]#[N:48])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH3:13])=[N:7]2
Reactant: CN(C)C=O
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#N)c3)c(=O)c12
Temperature: 120 °C
Yield: 66 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was charged with compound 138 (200 mg, 0.300 mmol), tetrakis(triphenylphosphine)palladium (34.0 mg, 0.029 mmol), zinc cyanide (70 mg, 0.60 mmol) and anhydrous DMF (1 mL). The vial was purged with nitrogen, heated to 120° C. for 3.5 h then cooled to ambient temperature and poured into a saturated aqueous sodium bicarbonate solution (25 mL). The resulting suspension was extracted with methylene chloride (3×20 mL), and the organic extracts were combined, dried over sodium sulfate and filtered. Concentration of the filtrate followed by purification by column chromatography gave a 66% yield of compound 141 as a white solid. 1H NMR (CDCl3) δ (ppm) 8.30 (d, 1H, J=6.9 Hz), 7.58-8.02 (m, 7H), 7.30 (d, 1H, J=7.0 Hz), 5.60 (s, 2H), 5.07 (bs, 1H), 3.65 (m, 2H), 2.84 (s, 3H), 1.58 (d, 3H, J=6.7 Hz), 0.96 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2.OS(O)(=O)=O.[N+:28]([O-])([O-:30])=[O:29].[K+]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:28]([O-:30])=[O:29])[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:20])([F:22])[F:21])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2c(c1)CCN(c1cnccc1C(F)(F)F)C2=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c(cc1[N+](=O)[O-])C(=O)N(c1cnccc1C(F)(F)F)CC2
Yield: 68 %

Procedure:
6-Methyl-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (71A: 450 mg, 1.465 mmol) was reacted with concentrated H2SO4 (4.4 mL) and KNO3 (163 mg, 1.6126 mmol) for 2 hours to afford 350 mg of the product (68% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1.[OH-].[Na+].CC(O)=O>O1CCOCC1>[C:15]1([CH:3]2[CH:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]2)[N:19]2[C:20]3[CH:26]=[CH:25][NH:24][C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc(C4CN(C(=O)OC(C)(C)C)CCC4C)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC1CCN(C(=O)OC(C)(C)C)CC1c1ncc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 92.8 %

Procedure:
To a solution of tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (19.0 g, 37.3 mmol) in 1,4-dioxane (100 mL) was added aqueous NaOH (1N, 74.6 mL, 74.6 mmol). The reaction was heated at about 60° C. for about 30 min and allowed to cool to ambient temperature followed by the addition of 10% aqueous AcOH (250 mL). The mixture was extracted with EtOAc (2×250 mL) and the combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (330 g) eluting with a gradient of 10-70% EtOAc in heptane to provide tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (12.3 g, 93%) as a white foam: LC/MS (Table 2, Method a) Rt=1.96 min; MS m/z: 356 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([Cl:12])[CH:5]=1)[CH:2]=C.C[OH:14]>C(Cl)Cl>[Cl:12][C:6]1[CH:5]=[C:4]([CH2:1][CH:2]=[O:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: C=CCc1ccc(C#N)c(Cl)c1
Reactant: CO
Solvent: ClCCl
Product: N#Cc1ccc(CC=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4-Allyl-2-chlorobenzonitrile (265 mg, 1.5 mmol) in DCM (2 mL) and methanol (2 mL) was cooled to −78° C. Then O3 was bubbled into for 10 minutes. Then dimethylsulfide (1 mL) was added and the mixture was stirred at RT for 5 hours. The mixture was concentrated in vacuo to give the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]([N:6]([C:24](=[O:25])[CH2:23][Cl:22])[C:7]1[C:8]([CH3:14])=[CH:9][CH:10]=[CH:11][C:12]=1[CH3:13])[CH3:5])=[O:15]
Reactant: COC(=O)C(C)Nc1c(C)cccc1C
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C(C)N(C(=O)CCl)c1c(C)cccc1C
Temperature: 25 °C

Procedure:
990.3 g (= 4.76 g-moles) of α-(2,6-dimethylanilino)-propionic acid methyl ester is mixed with 605 g (= 5.7 g-moles) of sodium carbonate in 2.5 liters of benzene (absolute). An amount of 455 ml (= 5.7 g-moles) of monochloroacetyl chloride is then added dropwise and sufficiently slowly to ensure that a temperature of 30°-35° in the reaction mixture is not exceeded. After stirring has been maintained overnight at room temperature, the mixture is filtered off, and the filtrate concentrated in a rotary evaporator at ca. 50°. The resulting residue is recrystallised from ligroin (boiling range 65°-90° ). The yield obtained is 1132 g (= 83.8% of theory) of final product, M.P. 92°-94° (compound No. 3).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:21]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=3)=[O:22])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1nccc2c(N)cccc12
Product: Cc1nccc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cccc12

Procedure:
Prepared from 1-methylisoquinolin-5-amine (Description 68) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 360 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][C:37]1[C:38]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([F:36])[C:38]([CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(CCN2CCCCC2)c(F)cc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCN2CCCCC2)c(F)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 42.2 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]aniline (46 mg, 0.18 mmol), and p-toluenesulfonic acid (92 mg, 0.49 mmol) were weighed into a 10 mL microwave vial. 5 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and diluted with 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography, followed by MeOH re-crystallization to give the title compound (54 mg, 0.076 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.42 (d, J=6.96 Hz, 1H), 8.50 (s, 1H), 8.30-8.34 (m, 1H), 8.11 (s, 1H), 7.80-7.86 (m, 1H), 7.77 (d, J=8.06 Hz, 1H), 7.71 (d, J=9.16 Hz, 1H), 7.43-7.48 (m, 1H), 7.32-7.40 (m, 1H), 7.26 (d, J=8.61 Hz, 1H), 7.16 (t, J=8.06 Hz, 2H), 7.00 (t, J=6.23 Hz, 2H), 6.67 (d, J=4.94 Hz, 1H), 3.97 (s, 3H), 3.82 (s, 3H), 3.26-3.27 (m, 2H), 2.70 (t, J=7.33 Hz, 2H), 2.34-2.42 (m, 4H), 1.43-1.50 (m, J=4.76 Hz, 4H), 1.32-1.39 (m, 2H). MS (ESI): 708 [M+H]+.