Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:26])[CH2:23][CH:24]=C)=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[OH2:35].C(Cl)Cl>O1CCOCC1.O>[C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:26])[CH2:23][CH:24]=[O:35])=[N:18]3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: C=CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of compound 17 (330 mg, 0.760 mmol) in dioxane-water (3:1, 8 mL) were added 2,6-lutidine (0.177 mL, 1.73 mmol), K2OsO4·2 H2O (6 mg, 0.016 mmol), and NalO4 (655 mg, 3.06 mmol). The reaction was stirred at 25° C. and monitored by TLC. After the reaction was complete, water (10 mL) and CH2Cl2 (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted by DCM (10 mL) three times. The organic layers were pooled, washed with brine, and dried over Na2SO4. The solvent was removed, and the product was purified with SiO2 column chromatography (hexanes/EtOAc=2/3) to afford aldehyde 18 (250 mg, 0.573 mmol, 75%) as a colorless oil. MS-ESI (m/z): [M+H]+ calculated for C18H15BrNO5S, 435.99 (79Br) and 437.98 (81Br); found 436.04 (79Br) and 437.97 (81Br).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>CN(C)C=O>[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Fc1ccccc1CBr
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 120 h
Yield: 41.7 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 2-fluoro-benzyl bromide (58 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight and then allowed to stand at room temperature for five days. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(2-fluoro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (63 mg, 42%) as a white solid. APCI-MS (M+H) 315.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:26][C:25]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:25]2[N:26]=[C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccccc1

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester, shown below, were reacted, as described in Example 1, Step D, to provide 2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester, shown below, as a colorless oil (30%). 1H NMR (300 MHz, CDCl3): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13 (d, 2H), 7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H), 4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H), 1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)+, [EI−] 490 (M−H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:21].C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C1COCC1>[C:29]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([N:11]2[N:15]=[C:14]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:13]3=[N:12]2)[C:4]=1[OH:21])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(C)cc3n2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(C)cc3n2)c1O
Temperature: -10 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
In a 100 ml round bottom 3-neck flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 19.5 g (68.3 mmol) 2-(hydroxymethyl)-4-methoxy-6-(5-methyl-2H-benzo[d][1,2,3]triazol-2-yl)phenol in 200 ml anhydrous THF. Triethylamine (34 ml, 240 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (8.55 g, 81.8 mmol) was added dropwise and the mixture was stirred for 2 hr at 0° C. followed by 20 hours at ambient temperature. The solid was filtered and rinsed with diethyl ether and the filtrate was poured into 100 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude product was recrystallized in ethanol to give 7.2 g (30%) of a light yellow solid. 1H NMR (CDCl3) delta: 11.28 (s, 1H, Ar—OH), 7.89 (s, 1H, Ar—H benzotriazole 4-position), 7.79 (d, 1H, Ar—H benzotriazole 6-position), 7.66 (s, 1H, Ar—H phenol 6-position), 7.26 (d, 1H, Ar—H benzotriazole 7-position), 7.03 (s, 1H, Ar—H phenol 4-position), 6.21 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.39 (s, 2H, Ar—CH2), 3.89 (s, 3H, Ar—OCH3), 2.54 (s, 3H, Ar—CH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:41][O:42][C:43]([CH3:59])([CH3:58])[C:44]([NH:46][NH:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=1)=[O:45]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:41]/[O:42][C:43]([C:44](=[O:45])[NH:46][NH:47][C:48](=[O:57])[C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([OH:56])[CH:50]=2)([CH3:58])[CH3:59])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)n2n1

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 36.9 mg (0.121 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride (55 mg) (0.093 mmol) are dissolved in 7 ml of absolute dimethylacetamide. After stirring at room temperature for 20 hours a further 18.4 mg (0.060 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are added. After a further 24 hours the solvent is removed at room temperature in a high vacuum and the residue is treated with water. The precipitated product is filtered off, washed well with water and dried at room temperature in a high vacuum. There are obtained 37 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[N:17]=[C:18]3[C:24]([C:25]([C:27]4([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][NH:22][C:19]3=[N:20][CH:21]=2)[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][S:12](=O)[CH2:11][CH2:10]2)[CH:8]=1.O=S1(=O)CCN(C2C=C(C3N=C4C(C(C5(C)CCCCC5)=O)=CNC4=NC=3)C=C(OC)C=2)CC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]2[N:17]=[C:18]3[C:24]([C:25]([C:27]4([CH3:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][NH:22][C:19]3=[N:20][CH:21]=2)[CH:6]=[C:7]([N:9]2[CH2:10][CH2:11][S:12][CH2:13][CH2:14]2)[CH:8]=1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc(N2CCS(=O)CC2)c1
Agent: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc(N2CCS(=O)(=O)CC2)c1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)cc(N2CCSCC2)c1

Procedure:
MP=212-214, (M+H)+=451; {2-[3-Methoxy-5-(1-oxo-1lambda*4*-thiomorpholin-4-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-(1-methyl-cyclohexyl)-methanone. MP=270-271, (M+H)+=467; {2-[3-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-yl)-5-methoxy-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-(1-methyl-cyclohexyl)-methanone. MP=245-247, (M+H)+=483.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=1.O>CS(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:15]=1
Reactant: CCOC(=O)/C=C/c1ccc(F)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.7 %

Procedure:
Trimethylsulfoxonium iodide (7.92 g, 36.0 mmol) in dimethyl sulfoxide (40 mL) was mixed with sodium hydride (55 wt % dispersion in mineral oil, 1.57 g, 36.0 mmol) under cooling with ice, stirred at room temperature for 1 hour and then stirred with (E)-ethyl 3-(4-fluorophenyl)acrylate (5.83 g, 30.0 mmol) for 18 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to give the title compound as a colorless oil (793 mg, yield 13%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].C([Sn](CCCC)(CCCC)[C:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1)CCC>C1(C)C=CC=CC=1>[C:29]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]3[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Reactant: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(Br)cc12
Solvent: Cc1ccccc1
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(C3=CCCCC3)cc12
Yield: 27.7 %

Procedure:
A solution of 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (Example 5a, 109.8 mg 0.30 mmol), 1-tributylstannylcyclohex-1-ene (111 mg, 0.30 mmol) and tetrakistriphenyphosphine palladium (80 mg, 0.07 mmol) in toluene (2 mL) was stirred at 100-110° C. overnight. After removal of the solvent in vacuo, flash chromatography on silica gel (2-10% 2M methanolic ammonia in dichloromethane) yielded 5-(cyclohex-1-en-1-yl)-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (31 mg, 28%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:27][CH2:26][C:13]2[N:14]([CH:22]([CH3:25])[CH:23]=[O:24])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1>C1COCC1.CCOC(C)=O.O>[CH3:9][N:10]1[CH2:27][CH2:26][C:13]2[N:14]([CH:22]([CH3:25])[CH:23]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:24])[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][C:20]=3[C:12]=2[CH2:11]1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccc2c(c1)c1c(n2C(C)C=O)CCN(C)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2C(C)C(O)c2ccccc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phenyl magnesium bromide (1M solution in THF) (6.24 mL, 6.24 mmol) was added dropwise at −70° C. to a stirred solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-propionaldehyde (400 mg, 1.56 mmol) in THF (40 mL), the reaction mixture stirred at RT for 16 h, diluted with EtOAc (75 mL) and water (60 mL). The two layers were separated, the aq. layer extracted with EtOAc (2×75 mL), and the combined organic layers dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude (500 mg) was purified by prep. HPLC to afford 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)1-phenyl-propan-1-ol yielded as the TFA salt (65 mg). 1H NMR (CDCl3, Free base) δ (ppm): 7.37 (d, 1H), 7.17 (t, 3H), 7.12 (s, 1H), 7.06 (m, 2H), 6.95 (d, 1H), 5.11 (t, 1H), 4.37 (t, 1H), 3.57 (dd, 1H), 3.46 (d, 1H), 2.67 (m, 2H), 2.51 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.68 (d, 3H). Separation by chiral HPLC provides diastereomers II-95a-d.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25].C(O)(=O)C.CC([O-])=O.[Na+]>CCOC(C)=O>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH:16]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:13]=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:25])([F:27])[F:26]
Reactant: COc1cc(C=O)ccc1-c1ccccc1C(F)(F)F
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C=C2SC(=S)NC2=O)ccc1-c1ccccc1C(F)(F)F
Temperature: 95 °C
Reaction time: 14 h

Procedure:
To a flask was added rhodanine (37 mg, 275 μmol), 2-Methoxy-2′-trifluoromethyl-biphenyl-4-carboxaldehyde (70 mg, 250 μmol), acetic acid (4 mL) and NaOAc (60 mg, 3 equiv). The reaction solution was allowed to stir at 95° C. under N2 for 14 h. Additional NaOAc (60 mg, 3 equiv) was added to the solution and stirred at 100° C. for an additional 24 h. The reaction solution was diluted with EtOAc (100 mL), washed with water (50 mL×3), washed with aq NaHCO3 (50 mL×3), dried and concentrated. The crude material was chromatographed (SiO2, Hex:EtOAc 100:0 to 70:30) to yield the intermediate compound. (79 mg, 80%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5])#[N:2].C([O-])(=O)C.[Na+].[Cl:24][C:25]([Cl:29])([Cl:28])[C:26]#[N:27]>C(O)C>[NH2:27][C:26]([C:25]([Cl:29])([Cl:28])[Cl:24])=[C:3]([C:1]#[N:2])[C:4]([NH:6][C:7]1[N:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: Cc1ncc(NC(=O)CC#N)n1-c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc(NC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-cyano-N-(2-methyl-3-phenyl-imidazol-4-yl)acetamide (100 mg, 0.4162 mmol) in Ethanol (1.5 mL) was sequentially added sodium acetate (68.28 mg, 0.8324 mmol), 2,2,2-trichloroacetonitrile (0.051 mL, 0.5016 mmol) and the reaction was stirred at room temperature for 4 h. A further 10 mg of sodium acetate and 10 uL 2,2,2-trichloroacetonitrile was sequentially added and the mixture was stirred for a further 2 h at RT. The reaction was concentrated in vacuo and the residue was partitioned between water and EtOAc. Combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo to give 3-amino-4,4,4-trichloro-2-cyano-N-(2-methyl-1-phenyl-1H-imidazol-5-yl)but-2-enamide as a redish oil. (153 mg, 79%). MS (ES+) 384.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(O)(=O)CCCCC(O)=O.[NH:27]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]([NH2:38])[CH3:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1.CCN(C(C)C)C(C)C.CCCCO>CCOC(C)=O>[NH:27]1[C:35]2[C:30](=[CH:31][C:32]([CH:36]([NH:38][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:10]=[C:11]([CH:14]5[CH2:16][CH2:15]5)[NH:12][N:13]=4)[CH:5]=[CH:4][N:3]=3)[CH3:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CC(N)c1ccc2[nH]ccc2c1
Agent: O=C(O)CCCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1ccc2[nH]ccc2c1
Temperature: 120 °C
Yield: 24.7 %

Procedure:
A vessel was charged with 53 (665 mg, 2.82 mmol), 1-(1H-indol-5-yl)ethanamine adipic acid salt (1.45 g mg, 6.20 mmol, CASRN 1282097-87-3), DIPEA (7.4 mL) and n-BuOH (57 mL), sealed and heated at 120° C. for 12 d. The reaction mixture was cooled and diluted with EtOAc. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified by reverse-phase HPLC purification to afford 250.0 mg (24.7%) of racemic N2-(1-(1H-indol-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (180) as a white solid.
Reaction SMILES: C[C:2]([O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[K+].O.Cl>C(O)C>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][CH:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[CH:26][CH:27]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(Oc1ccc(OCc2ccccc2)cc1)(C(=O)O)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Oc1ccc(OCc2ccccc2)cc1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4.5 g of methyl(p-benzyloxyphenoxy){p-[3-(p-chlorophenoxy)propoxy]phenyl}acetic acid, 5.5 g of potassium hydroxide, 3 ml of water and 150 ml of ethanol is refluxed for 4 hours. The mixture is acidified with concentrated HCl and extracted with chloroform. The extract is dried (MgSO4) and the solvent removed under reduced pressure. The oil is dissolved in benzene and the solution diluted with hexane. On standing, crystals separate and are filtered off and recrystallized from benzene-hexane to give 2.15 g of light tan crystals, mp 105°-109° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58]Br)=[CH:54][CH:53]=1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([N:30]([CH2:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][CH3:50])=[CH:53][CH:54]=3)[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CNc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Reactant: COc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.6 %

Procedure:
At 0° C., to a solution of 6-chloro-N-(4-methoxybenzyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (2.0 g, 3.78 mmol) in anhydrous THF (30 mL) was added LiHMDS (1.0 M solution in Toluene, 7.56 mL, 7.56 mmol) and the contents were stirred at the same temperature. After 15 min, PMBBr (0.92 g, 4.53 mmol) was added at the same temperature and the contents were allowed to warm to ambient temperature. After 3 h, H2O (10 mL) was added and stirred for 5 min. The organic contents were extracted with EtOAc (3×40 mL) and the EtOAc layer washed with brine (1×20 mL), dried over anhydrous Na2SO4 and the solvents were removed under reduced pressure. The residue thus obtained was purified by a filter column to afford the title compound (1.0 g, 41% yield). MS ES calc'd. for C41H35ClN4O2 [M+H]+ 651. Found 651.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])[CH3:21].O[C:29]1[CH:38]=[C:37]2[C:32]([C:33]([O:39][C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH3:49])=[CH:43]4)=[N:34][CH:35]=[N:36]2)=[CH:31][C:30]=1[O:50][CH3:51].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH2:20]([N:22]([CH2:23][CH2:24][O:25][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([O:39][C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44]([CH3:49])=[CH:43]4)=[N:34][CH:35]=[N:36]2)=[CH:31][C:30]=1[O:50][CH3:51])[CH2:26][CH3:27])[CH3:21]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: CCN(CC)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Triphenylphosphine (262 mg, 1 mmol) and N,N-diethylethanolamine (88 mg, 0.75 mmol) were added to a suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (160 mg, 0.5 mmol), (prepared as described in Example 49), in methylene chloride (5 ml), followed by the addition, in portions, of diethyl azodicarboxylate (165 μl, 1 mmol). After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) followed by methylene chloride/3M ammonia in methanol (90/10) to give 7-(2-(N,N-diethylamino)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (147 mg, 70%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[CH3:22][Si:23]([C:26]#C)([CH3:25])[CH3:24]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:22][Si:23]([CH3:26])([CH3:25])[C:24]#[C:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:2]=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#COC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
25 g (0.08 mol) Methyl 4-iodo-3-nitrobenzoate (compound IV), 20 ml (0.14 mol) triethylamine and 200 ml tetrahydrofuran were added into a reaction flask, protected by nitrogen gas, and stirred to dissolve, then 2.4 g (0.0034 mol) bis(triphenylphosphine)palladium dichloride, 0.65 g (0.0034 mol) cuprous iodide and 13.7 ml (0.096 mol) trimethylsilylethyne were added, the mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure to evaporated most of the tetrahydrofuran. After extracting with 300 ml ethyl acetate, the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness and separated by column chromatography to obtain methyl 4-(2-(trimethylsilyl)ethynyl-3-nitrobenzoate (Compound III), 15.1 g (0.055 mol), yield 66.9%.