Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC.CN([CH:23]=[O:24])C>>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([O:24][CH3:23])=[O:9]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc(C)ccc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To 5-methylsalicylic acid (3.04 g, 20 mmol) in DMF (100 ml) were added potassium carbonate (8.28 g, 60 mmol) and iodomethane (6.24 g, 44 mmol) under ice cooling and then the mixture was stirred at room temperature for 12 hours. The mixture were extracted by adding 5% sodium hydrogensulfite and ethyl acetate, and the extracted organic layer was washed with 5% citric acid and 5% brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (hexane-ethyl acetate) to give the captioned compound (3.43 g, 19.1 mmol, yield: 95%) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][CH2:35][C:36]1[CH:37]=[C:38]([S:42][C:43]2[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=2)[CH:39]=[CH:40][CH:41]=1.[OH:51][C:52]1[C:57]([CH3:58])=[C:56](O)[CH:55]=[CH:54][C:53]=1[C:60](=[O:62])[CH3:61]>C1COCC1.C(OCC)(=O)C>[C:60]([C:53]1[CH:54]=[CH:55][C:56]([O:34][CH2:35][C:36]2[CH:37]=[C:38]([S:42][C:43]3[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=3)[CH:39]=[CH:40][CH:41]=2)=[C:57]([CH3:58])[C:52]=1[OH:51])(=[O:62])[CH3:61]
Reactant: CC(=O)c1ccc(O)c(C)c1O
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OCc2cccc(Sc3ccc(C#N)nc3)c2)c(C)c1O
Reaction time: 8 h
Yield: 73 %

Procedure:
Add triphenylphosphine (1.84 g, 7.02 mmol) and diisopropylazodicarboxylate (1.42 g, 7.02 mmol) to a solution of 5-(3-(hydroxymethyl)phenylthio)picolinonitrile (1.70 g, 7.02 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.17 g, 7.02 mmol) in THF (35.1 mL). Stir overnight. Dilute with ethyl acetate. Wash the mixture with water and brine. Dry, filter and concentrate to afford the title compound (2.00 g, 73%). Use as is. MS (APCI-neg) m/z (rel intensity): 390 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.CC(O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1c(Br)cc2c(Cl)ncnc2c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1c(Br)cc2c(Nc3ccc(C#N)cc3)ncnc2c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 6-bromo-4-chloro-7-methyl-8-nitroquinazoline (211 mg, 0.70 mmol) and 4-aminobenzonitrile (208 mg, 1.76 mmol) in toluene (25 mL) was refluxed overnight. i-PrOH (25 mL) was added and the mixture was refluxed for 5 h. After cooling to rt the precipitate was filtered and washed with i-PrOH to give 4-(6-bromo-7-methyl-8-nitroquinazolin-4-ylamino)benzonitrile (195 mg, 72%). MS (ESI, pos. ion) m/z: 384 [M+H]+
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH:2]1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[N:13][C:14]([NH2:15])=[C:9]2[C:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][C:17]=2[F:29])=[N:7]1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[NH2:15][C:14]1[N:13]=[CH:12][N:11]=[C:10]2[N:6]([CH2:5][CH:2]3[CH2:3][CH2:4][N:1]3[C:33](=[O:34])[CH2:32][C:30]#[N:31])[N:7]=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:18][C:17]=3[F:29])[C:9]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CCN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a mixture of 1-(azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (236.4 mg, 0.610 mmol), 2-cyanoacetic acid (77.2 mg, 0.910 mmol) in DCM (8 mL) in ice bath, was added T3P (0.36 mL, 1.21 mmol) and TEA (0.34 mL, 2.42 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was loaded onto the silica gel column, purified with 0-3% gradient MeOH:CH2CL2, to get 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (201 mg) as yellow oil.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[CH:26]=1>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1
Reactant: O=Cc1cccnc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51 %

Procedure:
Tetrabromomethane (24.82 g, 0.747 mole) and triphenylphosphine (39.17 g, 0.149 mole) were stirred together in dry methylene chloride (100 mL) for 5 min. at 0° C. under a nitrogen atmosphere. To this mixture was added dropwise pyridine 3-carboxaldehyde (4 g, 0.0373 mole). The solution was then stirred for 45 min. at ambient temperature. The reaction mixture was extracted with aqueous 6N hydrochloric acid (3×25 mL), the aqueous layer basified with solid sodium bicarbonate to pH 8-9 and extracted with chloroform (4×25 mL). The combined organic liquours were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give a dark colored syrup. The crude product was chromatographed on silica gel (70-230 mesh) with chloroform:methanol (95:5) as eluant, to afford a light yellow solid (5.0 g, 70%) which rapidly turned dark on standing.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.ClC(O[CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=O>O1CCCC1>[Cl:35][C:34]([Cl:37])([Cl:36])[CH2:33][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C(=O)N1
Reaction time: 0.5 h

Procedure:
In 50 ml of tetrahydrofuran was dissolved 6.2 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and, following addition of 1.2 ml of pyridine, a solution of 5.4 g of 2,2,2-trichloroethyl chloroformate in 30 ml of tetrahydrofuran was added dropwise under cooling at 0°-5° C. The reaction mixture was stirred at the same temperature as above for 30 minutes and under reflux for 5 minutes and then concentrated to dryness under reduced pressure. The residue was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-ethyl acetate (3:1). The eluate was concentrated under reduced pressure, and the residue was dissolved in a small amount of ethyl ether. After addition of petroleum ether to the solution, the mixture was allowed to stand in a refrigerator overnight to give crystals. Yield 1.1 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:9])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[O:17][CH3:18])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1nnc(Cl)cc1-c1ccc(F)cc1OC
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of [6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-yl]-methyl-amine (95 mg, 355 μmol) in dichloromethane (5 mL) was added 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (95.2 mg, 355 mmol) and 2-bromo-1-ethylpyridinium tetrafluoroborate (117 mg, 426 μmol, CAS RN 878-23-9) and N-ethyldiisopropyl-amine (91.7 mg, 124 μL, 710 μmol). The reaction mixture was stirred at room temperature for 72 hours and then poured on 30 mL 10% aqueous bicarbonate solution and 30 mL dichloromethane and the layers were separated. The aqueous layer was extracted a second time with 30 mL dichloromethane. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Colorless solid (63 mg, 34.3%). MS (ESI+): m/z=518.056 ([M+H]+).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(O[P:23]([O:28]CC)([O:25]CC)=[O:24])C.P(Cl)(Cl)(Cl)=O.[CH2:36]([NH2:39])[CH2:37][NH2:38].[OH-].[Na+].C([O-])(=O)C>O>[P:23]([O:17][CH2:16][C@H:14]1[O:15][C@@H:11]([N:10]2[C:3]3[N:2]=[CH:1][N:6]=[C:5]([NH:38][CH2:37][CH2:36][NH2:39])[C:4]=3[N:8]=[CH:9]2)[C@H:12]([OH:19])[C@@H:13]1[OH:18])([OH:25])([OH:28])=[O:24]
Reactant: NCCN
Reactant: CCOP(=O)(OCC)OCC
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: NCCNc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reaction time: 8 h
Yield: 65 %

Procedure:
Two g (7 mmol) 6-chloropurine riboside (available from Sigma Chemical Co., St. Louis, Mo.) was stirred with 17 ml triethylphosphate and was reacted with phosphoryl chloride in the presence of water as described in Chem. Scrip. 19: 165-70(1972). After hydrolysis of the phosphodichloridate, 9.5 ml ethylenediamine (140 mmol) was added and allowed to react at room temperature for 3 hr. The reaction mixture was diluted to 4 liters with water and adjusted to pH 12 with sodium hydroxide. This solution was passed through a 5×30 cm column of Dowex 1×8 (available from Bio-Rad Laboratories, Richmond, Calif.) in the acetate form. Then the column was washed with 3 liters 0.01M ammonium chloride and the chromatogram was developed with a linear gradient generated with 3 liters water and 3 liters 1M acetic acid. An isolated peak of uv absorbing material eluted between 1800 ml and 2050 ml of the gradient was concentrated to about 25 ml under vacuum. While this solution stood at 7° C. overnight, white crystals formed and these were collected and dried to give 65 percent yield of the product. A sample was recrystallized from hot water for analysis. Calculated for C12H19N6O7P.2H2O: C, 33.8; H, 5.45; N, 19.7. Found: C, 34.3; H, 5.22; N, 19.7. Separate thin-layer chromatograms developed with two solvent systems, the first consisting of 4 parts 0.5M ammonium acetate to 1 part ethanol and the second consisting of 3 parts isobutyric acid to 5 parts 1M ammonium hydroxide, each showed one component which quenched fluorescence and reacted with ninhydrin. The compound in 0.1N hydrochloric acid had an absorption maximum at 264 nm and the millimolar extinction coefficient was 17.7 which spectral properties are characteristic of N6 -alkylated adenosine derivatives.
Reaction SMILES: Cl.[C:2]([NH:5][C@:6]1([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH2:9][NH:8][CH2:7]1)(=[O:4])[CH3:3].CCN(CC)CC.[Cl:37][C:38]1[CH:47]=[C:46]2[C:41]([CH2:42][CH:43]([CH:55]=O)[N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]2)=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:2]([NH:5][C@:6]1([C:23](=[O:24])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15]2)[CH2:9][N:8]([CH2:55][CH:43]2[CH2:42][C:41]3[C:46](=[CH:47][C:38]([Cl:37])=[CH:39][CH:40]=3)[CH2:45][N:44]2[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C=O
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(CC2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
A stirred mixture of (3R,4S)-3-acetamido-N-tert-butyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxamide hydrochloride (226 mg, 0.524 mmol) and Et3N (0.110 mL, 0.786 mmol) in methylene chloride (2.5 mL) was treated with a solution of tert-butyl 7-chloro-3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (155 mg, 0.524 mmol) in methylene chloride (2.5 mL). After stirring for 20 min, sodium triacetoxyborohydride (233 mg, 1.10 mmol) was added and stirring was continued for 1 h. The resulting mixture was carefully quenched with saturated aqueous NaHCO3 (5 mL), diluted with saturated aqueous sodium chloride (15 mL) and extracted with methylene chloride (4×15 mL). The combined organic phase was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (40 g column, 2-4% MeOH in ethyl acetate) gave tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (296 mg, 84%, mixture of diastereomers) as a clear gum. LC-MS gives ESI+MS found for C35H56BClN4O6 m/z 675.4 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].[CH2:18]([C:20]1[NH:24][C:23]([C:25](O)=[O:26])=[N:22][C:21]=1[C:28]([F:31])([F:30])[F:29])[CH3:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:18]([C:20]1[NH:24][C:23]([C:25]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH3:17])=[O:26])=[N:22][C:21]=1[C:28]([F:30])([F:31])[F:29])[CH3:19]
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(C(F)(F)F)c(CC)[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained in Example (112d) (178 mg, 0.73 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained by the method described in Example (39e) (100 mg, 0.48 mmol), WSC hydrochloride (280 mg, 1.46 mmol) and HOBT (66 mg, 0.49 mmol), to obtain 173.5 mg of the title compound as a white foamy substance (91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][N:18]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ncc([N+](=O)[O-])cc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-chloro-3,5-dinitropyridine were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Direct filtration of the reaction mixture afforded a red solid which was recrystallized in ethanol to afford the title compound (7%) as a red solid: mp, 194.0°-195.0° C.; 13C NMR (DMSO-d6) δ152.2, 150.7, 134.7, 134.1, 131.2, 128.2, 127.1, 126.7, 123.9, 119.1, 114.8, 112.7, 111.4, 59.7, 44.9, 22.8; HRMS calculated for C17H18N6O4 370.1391, found 370.1358. Anal. calcd. for C17H18N6O4.1/2H2O: C, 53.82; H, 5.04; N, 22.15. Found: C, 53.55; H, 4.58; N, 21.98.
Reaction SMILES: [Cu][C:2]#[N:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2I)=[CH:7][CH:6]=1>C(O)CC.C(Cl)Cl.CCCCCCC>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[C:2]#[N:3])=[CH:7][CH:6]=1
Reactant: N#C[Cu]
Reactant: Fc1cc(I)c(N=Nc2ccc(Cl)cc2)cc1F
Solvent: CCCO
Solvent: ClCCl
Solvent: CCCCCCC
Product: N#Cc1cc(F)c(F)cc1N=Nc1ccc(Cl)cc1
Yield: 75 %

Procedure:
Copper (I) cyanide (9.76 g, 109 mmol) was added to a solution of (4-chloro-phenyl)-(4,5-difluoro-2-iodo-phenyl)-diazene (5.89 g, 16 mmol) in 1-propanol (95 ml) under an argon atmosphere. The reaction mixture was heated under reflux conditions for 14 h and diluted with CH2Cl2/heptane 1/1 (70 ml). The suspension was filtered and the filtrate was evaporated to dryness to give the title compound (3.3 g, 12 mmol; 77%) as brown solid which was used in the next step without further purification. MS: m/e=278.0 [M+H+].
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([OH:26])=O)[CH2:7]1)(=[O:4])=[O:3].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(#N)C>[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:24]([C@@H:8]2[CH2:7][C@@H:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][N:9]2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])=[O:26])[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
584 mg of N,N'-carbonyldiimidazole were added to a solution of 1.16 g of trans-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-L-proline in 10 ml of dry acetonitrile, and the resulting mixture was stirred at 40° C. for 1 hour. 586 mg of 1-(2-Hydroxyethyl)piperazine were then added to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 35 minutes. The solvent was then removed by distillation under reduced pressure, and the residue was purified in a similar manner so that described in step 54(a)(ii), to give 930 mg of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound obtained as described in step 54(a)(ii) above.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH2:27])[C:21]2=[CH:20][CH:19]=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>CN(C=O)C>[F:17][C:18]1[N:23]=[C:22]2[C:24]([CH3:28])=[CH:25][N:26]([NH:27][C:14]([C:10]3[C:11]([CH3:13])=[N:12][C:7]([C:2]4[N:1]=[CH:6][CH:5]=[CH:4][N:3]=4)=[N:8][CH:9]=3)=[O:16])[C:21]2=[CH:20][CH:19]=1
Reactant: Cc1cn(N)c2ccc(F)nc12
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
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: Cc1nc(-c2ncccn2)ncc1C(=O)Nn1cc(C)c2nc(F)ccc21
Yield: 24.4 %

Procedure:
A solution of 2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.41 mmol), 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.41 mmol), DIPEA (158 mg, 4.22 mmol) and HATU (1.69 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 16 hours. DMF is evaporated off in vacuo. The residue is dissolved in EtOAc (40 mL), washed with water (3×10 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 1-20% MeOH in DCM to afford 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (125 mg) as a solid. MS: 364 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.31 (s, 3H), 2.87 (s, 3H), 6.87 (d, H), 7.50 (s, H), 7.66 (t, H), 7.96 (t, H), 9.04 (d, 2H), 9.27 (s, H).
Reaction SMILES: O[C@@:2]12[CH2:22][CH2:21][CH:20]3[C:12]([C@@H:13]([C:28]4[CH:33]=[CH:32][C:31]([N:34](C)[C:35](=O)OC(C)(C)C)=[CH:30][CH:29]=4)[CH2:14][C@@:15]4([CH3:27])[CH:19]3[CH2:18][CH2:17][C@@:16]4([OH:26])[C:23]#[C:24][CH3:25])=[C:11]1[CH2:10][CH2:9][C:4]1(OCC[O:5]1)[CH2:3]2.CC1C=CC(S(O)(=O)=O)=CC=1.O.C(Cl)Cl.C1COCC1.C([O-])(O)=O.[Na+]>>[OH:26][C@:16]1([C:23]#[C:24][CH3:25])[CH2:17][CH2:18][C@H:19]2[C@H:20]3[C:12]([C@@H:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:34][CH3:35])=[CH:32][CH:33]=4)[CH2:14][C@:15]12[CH3:27])=[C:11]1[C:2](=[CH:3][C:4](=[O:5])[CH2:9][CH2:10]1)[CH2:22][CH2:21]3
Reactant: CC#C[C@]1(O)CCC2C3CC[C@@]4(O)CC5(CCC4=C3[C@@H](c3ccc(N(C)C(=O)OC(C)(C)C)cc3)C[C@@]21C)OCCO5
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(NC)cc3)C[C@@]21C
Yield: 77.2 %

Procedure:
The compound of Example 1G (36 mg) was dissolved in 0.3 mL of a solution of TsOH.H2O/CH2Cl2/THF (1.9 g/3 mL/3.8 mL); the resultant mixture was stirred at room temperature for 3 hour. The reaction mixture was added dropwise to NaHCO3 solution (2 mL, saturated) and then extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by preparative TLC to provide the titled compound (20 mg, 74% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=O)[CH:5]=[CH:4][C:3]1=2.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:43]2)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[S:43])[CH:5]=[CH:4][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(NC(=S)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 110.0 mg (0.25 mmol) ethyl 4-[[(5,6-dihydro-5,5-dimethyl-8-(4methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35) and 121.0 mg (0.30 mmol) of [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (Lawesson's Reagent) in 12.0 ml of benzene was refluxed overnight. Upon cooling to room temperature, the mixture was filtered and the filtrate concentrated under reduced pressure. The title compound was isolated by column chromatography (10 to 25% EtOAc/hexanes) as a yellow solid. 1H NMR (CDCl3): δ8.92 (1H, s), 8.06 (2H, t, J=8.5 Hz), 7.88-7.70 (3H, m), 7.42 (2H, d, J=8.1 Hz), 7.18 (4H, m), 6.03 (1H, t, J=4.7 Hz), 4.37 (2H, q, J=7.1 Hz), 2.38 (3H, s), 2,36 (2H, d, J=4.7 Hz), 1.56 (3H, t, J=7.1 Hz), 1.35 (6H, s).