Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[CH:5]=[C:6](OC1C=CC(OC(C)C)=CC=1)[O:7]2.[OH:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH:15]([CH3:16])[CH3:17])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[CH:5]=[C:6]([S:37][C:34]1[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=1)[O:7]2
Reactant: Oc1ccc(S)cc1
Reactant: COc1c(OC(C)C)cc2oc(Oc3ccc(OC(C)C)cc3)cc(=O)c2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(OC(C)C)cc2oc(Sc3ccc(O)cc3)cc(=O)c2c1O
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 89.6 %

Procedure:
A mixture consisting of 9.49 g of 5-hydroxy-7-isopropoxy-2-(4-isopropoxyphenoxy)-6-methoxychromone obtained in Example 4, 4.49 g of 4-hydroxythiophenol, 4.91 g of potassium carbonate, and 200 ml of acetone was stirred over 1.2 hours at room temperature. The solution thus reacted was made weakly acidic by addition of dilute hydrochloric acid. The product was extracted twice with chloroform. The organic layer was washed with saturated salt water and was then dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was recrystallized from hexane:ethyl acetate, so that 7.95 g of 5-hydroxy-2-(4-hydroxyphenylthio)-7-isopropoxy-6-methoxychromone with the following physicochemical properties was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I.O>[N:30]1([C:2]2[N:7]=[CH:6][C:5]([CH2:8][N:9]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]4=[N:19][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[CH3:29])[C:21](=[O:22])[C:11]4=[N:10]3)=[CH:4][CH:3]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)nc3)nc-2c1=O
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4ccnc4)nc3)nc-2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[(6-Bromopyridin-3-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 22) 80 mg, 0.18 mmol] was dissolved in dimethyl sulfoxide (1 mL) and treated with imidazole (49 mg, 0.72 mmol, 4 equiv), copper(I)iodide (14 mg, 0.072 mmol, 0.4 equiv), and (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (20 mg, 0.14 mmol, 0.8 equiv). An aqueous solution (0.2 mL) of tribasic potassium phosphate (0.11 g, 0.54 mmol, 3 equiv) was added and the mixture was placed into a preheated oil bath at 75° C. for 2 hours. The mixture was cooled to ambient temperature, poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 94:6; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.58 (1H, s), 8.43 (1H, br s), 8.33 (1H, d, J=6.9 Hz), 7.85 (1H, d, J=9.7 Hz), 7.77 (1H, br s), 7.68-7.54 (3H, m), 7.45 (1H, m), 7.38-7.32 (5H, m), 5.88 (2H, s), 2.36 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 434.1736 [(M+H)+; calculated for C25H20N7O: 434.1724].
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:35][CH3:36])=[C:7]([O:33][CH3:34])[CH:8]=2)[N:3]=1.[NH:37]([CH2:41][CH2:42][OH:43])[CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][OH:43])[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:35][CH3:36])=[C:7]([O:33][CH3:34])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N3CCC(CCNC(=O)c4cc(C)ccc4[N+](=O)[O-])CC3)c2cc1OC
Reactant: OCCNCCO
Product: COc1cc2nc(N(CCO)CCO)nc(N3CCC(CCNC(=O)c4cc(C)ccc4[N+](=O)[O-])CC3)c2cc1OC
Yield: 71 %

Procedure:
The same procedure as in Reference Example 11 was repeated, except that 4.0 g (7.80 mmol) of Compound m was used, and diethanolamine was used in place of morpholine, to give 3.24 g (yield: 71%) of Compound o as white crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20].CN(C1C=CC=CN=1)C>CCOC(C)=O.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To THF (15 mL) was added 3-tert-butylaniline (447 mg, 3 mmol), potassium carbonate (828 mg, 6 mmol), phenyl chloroformate (1.13 mL, 9 mmol), and dimethylaminopyridine (36 mg, 0.30 mmol) and the reaction stirred at room temperature overnight. The mixture was diluted with EtOAc, filtered, concentrated in vacuo, and purified by silica gel column chromatography (5-15% EtOAc/hexanes) to give phenyl 3-tert-butylphenylcarbamate (458 mg, 1.70 mmol, 57%). 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.59 (s, 1H), 7.49-7.10 (m, 7H), 7.08 (d, 1H), 1.25 (s, 9H); LC-MS (ESI) m/z 270 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].[C:21]12([CH2:31][CH2:32]I)[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:32][CH2:31][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)(=[O:3])[CH3:2]
Reactant: ICCC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](SCCC23CC4CC(CC(C4)C2)C3)[C@H]1OC(C)=O
Reaction time: 72 h
Yield: 54.9 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (2.14 g, 7 mmol) and 2-(1-adamantyl)ethyl iodide (2.03 g, 7 mmol) in dichloromethane (40 ml) containing triethylamine (0.71 g) is kept under nitrogen for 3 days. The reaction mixture is washed successively with N hydrochloric acid, aqueous sodium bicarbonate and water. The dried solution is concentrated to a residue which is taken up in ethanol to remove crystals (0.3 g, 2-(1-adamantyl)ethyl iodide). The mother liquor is put on a silica gel column and eluted with 1% methanol in chloroform. The desired fractions are pooled and evaporated to give 2-(1-adamantyl)ethyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside (1.8 g, 66%), [α]D +18° (c, 1.5, chloroform). Deblocking of this material with sodium methoxide in methanol affords the title compound, m.p. 130°-131°, [α]D +31° (c, 1.07, chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[CH3:44][N:45]1[CH:50]2[CH2:51][CH2:52][CH:46]1[CH2:47][CH:48](O)[CH2:49]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][CH:48]1[CH2:49][CH:50]2[N:45]([CH3:44])[CH:46]([CH2:52][CH2:51]2)[CH2:47]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C2CCC1CC(O)C2
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1C2CCC1CC(OC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (400 mg, 1.59 mmol) in THF (20 ml), were added N,N′-methanediylidenedicyclohexanamine (394 mg, 1.91 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (258 mg, 1.91 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-ol (270 mg, 1.91 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The residue was taken up with DCM, the insoluble was filtered off, and the clear solution was washed twice with aq. Na2CO3 and brine, dried over Na2SO4 and evaporated to give 8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-(tert-butoxycarbonylamino)-2-phenylacetate (460 mg; 77% yield). The product was used in the next step without any further purification.
Reaction SMILES: [H-].[Na+].[N:3]1([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]([CH3:28])[CH:21]=[C:20]2[C:29]1[N:43]([S:44]([C:47]2[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=2)(=[O:46])=[O:45])[C:32]2=[N:33][CH:34]=[CH:35][C:36]([CH2:37]OS(C)(=O)=O)=[C:31]2[CH:30]=1>C1COCC1.O.C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]([CH3:28])[CH:21]=[C:20]2[C:29]1[N:43]([S:44]([C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)(=[O:46])=[O:45])[C:32]2=[N:33][CH:34]=[CH:35][C:36]([CH2:37][N:12]3[CH2:13][CH2:14][CH:9]([N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH2:10][CH2:11]3)=[C:31]2[CH:30]=1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc2c(-c3cc4c(COS(C)(=O)=O)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(-c3cc4c(CN5CCC(N6CCCCC6)CC5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
0.003 g of sodium hydride is added to a solution of 0.008 g of 4-piperidinopiperidine in 0.5 cm3 of THF, at a temperature in the region of 20° C. The reaction medium is stirred at room temperature for 20 minutes. 0.04 g of methanesulfonic acid 2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl ester is added. The reaction medium is heated at 60° C. for 3 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 2 cm3 of water and 3 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 90/10 by volume as eluent), 0.026 g of 1′-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl][1,4′]bipiperidyl is obtained, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+].COCCOC>ClCCl.O.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>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 138 %

Procedure:
A mixture of 6-bromo-3-pyridinol (36 g, 207 mmol), [4-(methylsulfonyl)phenyl]boronic acid (50 g, 250 mmol), 2M Na2CO3 (315 mL) and DME (500 mL) was degassed with N2 for 30 min, and then Pd(PPh3)4 (12 g, 10 mmol) was added and the mixture was heated at 80° C. for 18 h. The reaction was allowed to cool to room temperature and was diluted with dichloromethane (500 mL) and water (500 mL) and stirred for 30 min. The reaction was filtered and the solids were rinsed with dichloromethane and the aqueous layer was extracted with dichloromethane. The combined organic extracts were extracted with 1 N NaOH (2×600 mL), and then cooled to 5° C. and the pH was adjusted to ˜8 with 6N HCl. The resulting precipitate was collected by filtration (water wash) and air-dried to afford a yellow solid. This procedure was repeated and the solids were combined to provide (71.2 g, 68%) of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol. 1H NMR (400 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.25 (d, 1H, J=2.7 Hz), 8.21 (d, 2H, J=8.5 Hz), 8.00-3H), 7.27 (dd, 1H, Ja=8.7 Hz, Jb=2.8 Hz), 3.21 (s, 3H); LRMS (ESI), m/z 250 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].C(OC(=O)C)(=O)C.[N:21]1[CH:26]=[CH:25][CH:24]=CC=1>>[N:21]1[CH:24]=[CH:25][C:26]=1[NH:13][S:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)(=[O:12])=[O:11]
Reactant: c1ccncc1
Reactant: NS(=O)(=O)c1nc2ccccc2s1
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)(NC1=NC=C1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Benzothiazolesulfonamide (1.0g., 0047 mol) was dissolved in 30 ml of pyridine and stirred at room temperature for 15 minutes. Freshly distilled acetic anhydride (2 ml) was added to this solution and the reaction stirred over night at room temperature. The reaction was poured into a 300 ml beaker containing 25 ml of concentrated HC1 and 250 of crushed ice. The reaction was allowed to stand at room temperature until the ice melted and then vacuum filtered to yield 0.2 g of product (quantitative yield). The product was purified by adding the crude product to 25 ml of 10% Ha2CO3.H2O solution, filtering the sodium salt of N-acetyl-2-benzothiazolesulfonamide and dissolving it into water followed by careful acidification and hydrochloric acid. m.p. 197° -199° C.; NMR(DMSO-D6) δ8.4-7.5 (m, 5H), 2.1 (2, 3H). Elemental Analyses: C9H8N2O3S2. Calculated: C 42.18%, H 3.15%, N 1-0.93%. Found: C 42.27%, H 3.14%, N 10.86%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13](F)[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:22][CH2:23][CH2:24][NH2:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([NH:25][CH2:24][CH2:23][OH:22])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1C
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(NCCO)c2)cc1C
Temperature: 120 °C

Procedure:
A mixture of N-(3,4-dimethyl-phenyl)-3-fluoro-4-nitrobenzamide (65 mg), 2-hydroxy-1-ethylamine (0.225 mL of 2M THF solution) in DMF (1 mL) was heated at 120° C. under microwave radiation for 5 min. Then saturated NaHCO3 aqueous solution was added. The aqueous layer was extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give N-(3,4-dimethyl-phenyl)-3-(2-hydroxy-ethylamino)-4-nitrobenzamide as a yellow oil: MS (m/z) 300 (M+1); 1H NMR (CDCl3, 400 MHz) δ 8.24 (d, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.42 (d, 2H), 7.35 (d, 1H), 7.13 (d, 1H), 6.95 (d, 1H), 3.09 (d, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 1.58 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:34]1[N:39]=[C:38]2[C:40]([C:62]([NH:64][C:65]([CH3:76])([CH3:75])[CH2:66][O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:70])[CH3:69])=[O:63])=[CH:41][N:42]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]2=[N:36][CH:35]=1>CN(C=O)C.[Cu]I.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>[Si:68]([O:67][CH2:66][C:65]([NH:64][C:62]([C:40]1[C:38]2=[N:39][C:34]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH:2]([F:1])[F:32])[CH:5]=4)[N:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:17])[CH3:18])[N:8]=3)=[CH:35][N:36]=[C:37]2[N:42]([C:43]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:41]=1)=[O:63])([CH3:75])[CH3:76])([C:71]([CH3:72])([CH3:73])[CH3:74])([CH3:70])[CH3:69]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCCN(C)C)c2ccc(OC(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN(C)CCCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Temperature: 80 °C
Yield: 46.6 %

Procedure:
To a solution of 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (120 mg, 0.22 mmol) and 2-bromo-N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (200 mg, 0.26 mmol) in DMF (10 mL) were added CuI (30 mg, 0.16 mmol) and Pd(PPh3)4 (47 mg, 0.041 mmol), Then the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen. After cooling to room temperature, water (50 mL) was added and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(5-(difluoromethoxy)-1-(3-(dimethylamino)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (88 mg, crude) as a yellow oil. LCMS: (M+H)+=858.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[NH2:11][CH2:12][CH2:13][SH:14]>CO.C[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][S:14][CH2:13][CH2:12][NH2:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: NCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CSCCN)cc1
Yield: 95.7 %

Procedure:
4-Methoxybenzyl chloride (15.6 g) was reacted with 2-aminoethanethiol (7.7 g) in methanol and sodium methoxide, to afford of 2-(4-methoxybezyl-sulfanyl)-ethylamine (1) (18.8 g). One half of this material was taken in dichloromethane (cooling bath 0° C.). Chloroacetyl chloride in the same solvent, was added slowly with stirring, followed by an equivalent of triethyl amine to produce 2-chloro N-[2-(4-methoxybenzyl-sulfanyl)-ethyl]acetamide (2) in a 94% yield. Compound 2 was reacted with an equivalent amount of 1 in refluxing acetonitrile for 6 hrs to provide N-[-2-(4-methoxy-benzylsulfanyl)-ethyl]-2-[2-(4-methoxy-benzylsulfanyl)-ethylamino]-acetamide (3) (40.4 g). Compound 3 was reduced with lithium aluminium hydride (LAH) to yield 4 in 85%.
Reaction SMILES: CN(C)C1C=CC=CC=1.[NH2:10][C:11]1[N:16]=[C:15](O)[C:14]([CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([NH2:27])=[C:21]([O:28][CH3:29])[CH:20]=2)=[C:13]([NH2:30])[N:12]=1.P(Cl)(Cl)([Cl:33])=O>>[NH2:10][C:11]1[N:12]=[C:13]([NH2:30])[C:14]([CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([NH2:27])=[C:21]([O:28][CH3:29])[CH:20]=2)=[C:15]([Cl:33])[N:16]=1
Reactant: COc1cc(Cc2c(N)nc(N)nc2O)cc(OC)c1N
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1cc(Cc2c(N)nc(N)nc2Cl)cc(OC)c1N
Reaction time: 1 h

Procedure:
2.5 G. of dimethylaniline were added dropwise to a suspension of 2.9 g. of 2,6-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-4-pyrimidinol in 15 ml. of phosphorus oxychloride with stirring. The mixture was brought to boil in 1 hour and then boiled under reflux for 4 hours. Thereafter, 8 to 9 ml. of phosphorus oxychloride were removed by distillation under reduced pressure and the residue was poured on to 80 g. of ice with stirring. The mixture was left to stand at room temperature for 6 days and then 35 ml. of concentrated ammonia were added portionwise. After standing for 2 hours, the solid material was removed by filtration under vacuum, dried, recrystallized from dimethylformamide/ether, whereby there was obtained 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-6-chloro-pyrimidine having a melting point of 222°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)=[N:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[N:6][CH:7]=1.[CH2:27]([Mg]Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:6][CH:7]=1
Reactant: Cn1nnnc1N=C(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: ClCCl
Product: Cn1nnnc1NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 15.6 %

Procedure:
At −78° C. to a solution of N-((5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methylene)-1-methyl-1H-tetrazol-5-amine (135 mg, 0.35 mmol) in CH2Cl2 (2 mL) was added BnMgCl (0.4 mL, 1 M in ether, 0.4 mol) drop wise. The reaction mixture was stirred at −78° C. for 5 min, then was allowed to slowly warm up to room temperature. After 30 min, the reaction mixture was quenched by saturated NH4Cl, extracted by CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-20%) over 16 min to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-1-methyl-1H-tetrazol-5-amine as a yellow solid (26 mg, 16% yield). LCMS RT=4.05 min [M+H] 477.26 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 8.34 ppm, 1H, d, J=2.02 Hz; 7.63 ppm, 2H, m; 7.39 ppm, 1H, d, J=9.85 Hz; 7.25 ppm, 1H, d, J=3.79 Hz; 7.21 ppm, 1H, d, J=8.08 Hz; 7.11 ppm, 2H, m; 7.02 ppm, 2H, t, J=7.33 Hz; 6.42 ppm, 2H, d, J=7.07 Hz; 4.40 ppm, 1H, d, J=13.14 Hz; 4.09 ppm, 3H, s; 3.68 ppm, 1H, d, J=13.14 Hz.