Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][C@H:8]([CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19](OC(C)(C)C)=O)[CH2:15][CH2:14]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.C(N(CC)CC)C.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][C:45](C=O)=[CH:44][CH:43]=1.[B-]C#N.[Na+].C(O)(=O)C>>[N+:1]([C:4]1[N:5]=[C:6]2[N:10]([CH:11]=1)[CH2:9][C@H:8]([CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:45]3[CH:48]=[CH:49][C:42]([C:41]([F:51])([F:50])[F:40])=[CH:43][CH:44]=3)[CH2:17][CH2:18]1)[O:7]2)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@H]2Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](CN1CCN(Cc3ccc(C(F)(F)F)cc3)CC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A mixture of tert-butyl (S)-4-(6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate prepared in Example 394 (100 mg, 0.27 mmol) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and neutralized with triethylamine (1 ml, 7.17 mmol), and then the solution was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), and the solution was added 4-trifluoromethylbenzaldehyde (148 mg, 0.85 mmol), sodium cyanotrihydroborate (53 mg, 0.85 mmol), and acetic acid (49 μl, 0.85 mmol) in this order followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. To the residue, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=1/1) to afford (S)-6-nitro-2-[4-(4-trifluoromethylbenzyl)piperazin-1-ylmethyl]-2,3-dihydroimidazo[2,1-b]oxazole (53 mg, yield 46%) as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[NH2:10])[CH2:5][NH2:6].[C:12]([O-:15])([O-])=O.[K+].[K+].Cl.CNC.O.[CH3:23][N:24]([CH:26]=O)[CH3:25]>>[NH2:6][CH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:9]([NH:10][C:12](=[O:15])[CH2:23][N:24]([CH3:26])[CH3:25])=[C:8]([Cl:11])[CH:7]=1
Reactant: NCc1cc(Cl)c(N)c(Cl)c1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: CNC
Agent: Cl
Agent: [K+]
Solvent: O
Product: CN(C)CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Temperature: 0 °C
Yield: 72.9 %

Procedure:
Step F (3): To a solution of the compound of step F (2) (6 g 0.014 mol) in dry DMF (60 ml) under N2, anhydrous K2CO3 (6.03 g, 0.043 mol) was added with stirring. The reaction mixture was cooled to 0° C. and N,N-dimethylamine hydrochloride (2.37 g, 0.029 mol) was added at once. The reaction mixture was allowed stir for overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (2×150 ml). The organic layer was washed with water (25 ml), brine (25 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to remove the volatiles. The resulting crude product was purified by column chromatography using CHCl3: MeOH (9:1) as eluent to afford the product as an off-white solid (4 g, 72.9%)
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(NC(C)C)(C)C.[CH:48]1([C:51]#[CH:52])[CH2:50][CH2:49]1>[Cu]I.C(OCC)(=O)C>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9]([C:52]#[C:51][CH:48]4[CH2:50][CH2:49]4)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: C#CC1CC1
Reactant: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Agent: [Cu]I
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(Nc1nc2c(C#CC3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
9-bromo-4-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (5.03 g, 10.06 mmol), copper(I) iodide (0.230 g, 1.207 mmol), Pd(allyl)Cl dimer (0.221 g, 0.603 mmol) and tri(2-furyl)phosphine (0.280 g, 1.207 mmol) were combined in a 10-dram vial that was then flushed with nitrogen and kept under a nitrogen atmosphere. MeCN (101 ml) was then added followed by diisopropylamine (4.30 ml, 30.2 mmol) and cyclopropylacetylene (2.57 ml, 30.2 mmol). The resulting solution was then heated to 45° C. and stirred in the dark for 30 min. Then, the reaction was poured into ethyl acetate (350 mL) and washed with sat NaHCO3, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to afford the title compound as a pale yellow solid. LRMS (ESI) calc'd for (C23H25BrN3O) [M+H]+, 438.1; found 438.0.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:28][S:29]([OH:32])(=[O:31])=[O:30]>>[CH3:28][S:29]([O-:32])(=[O:31])=[O:30].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:25]2[CH:24]=[CH:23][C:22]([O:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:27][CH:26]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)O
Reactant: c1ccc(Oc2ccccc2)cc1
Product: CS(=O)(=O)[O-]
Product: c1ccc(Oc2ccc([S+](c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 100 °C
Yield: 54.6 %

Procedure:
A mixture of 40.45 g phenyl sulfoxide, 340.42 g of diphenyl ether and 192.20 g of methane sulfonic acid was heated at 100° C. for 68 hours. The disappearance of phenyl sulfoxide was monitored by gas chromatography. Workup substantially according to the method of Example 3 gave 49.24 g of diphenyl-4-phenoxyphenylsulfonium methane sulfonate (54.6 percent yield).
Reaction SMILES: [CH3:1][CH:2]1[S:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19].C(N(CC)CC)C.C[C@H](N)[C@H](O)C1C=CC=CC=1>CO.O>[CH3:1][C@@H:2]1[S:8][C@@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19]
Reactant: CC1SC(C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: C[C@H](N)[C@H](O)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 500 mL of methanol-water (volume ratio 1:1) was suspended 50.6 g of a racemic mixture, 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (content 98.8%; trans compound 90.2%, cis compound 9.6%). To the suspension was added 25 mL of triethylamine, which was made into a solution by heating (50° C.). To the solution was added 13.6 g (0.5 equivalent) of (1R,2S)-norephedrine. The mixture was once made into a solution, which was crystallized in about 10 minutes, followed by cooling to 30° C. over about 60 minutes, and then to 5° C. The crystals were aged for 60 minutes at the same temperature. The resulting crystals were collected by filtration, washed with 200 mL of cold methanol-water (volume ratio 1:1) and dried at 35° C. under reduced pressure to afford 29.9 g of substantially pure (2R,4S)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid.(1R,2S)-norephedrine salt as colorless crystals [HPLC area percentage: (2R,4R):(2S,4S):(2S,4R):(2R,4S)=0.86%:0.46%:0.50%:97.9%].
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8].Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+]>CN(C)C=O.O>[F:18][CH:14]([F:19])[O:12][C:11]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[OH:3]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OC(F)F)c(O)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
Sodium hydroxide (4.8 g, 120 mmoles) is added to a solution of 3,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) and sodium chlorodifluoroacetate (18.3 g, 120 mmol) in dimethylformamide (150 mL) and water (3 mL). The mixture is heated to 120° C. and stirred at this temperature for 2 hours. The solvent is removed by vacuum distillation and aqueous hydrochloric acid (20 mL) is added to the residue. The mixture is extracted with diethyl ether (2×50 ml), the combined organic layers are washed with water and brine and the solvent removed under reduced pressure. The crude product is purified by chromatography on silica gel (hexane/ethyl acetate 8:2) to furnish 4-difluoromethoxy-3-hydroxybenzaldehyde as a colourless solid (10 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([O:8][CH3:9])=[N:6][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:4]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>O1CCCC1.O.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][O:8][C:7]1[C:3]([CH2:2][C:34]2[CH:33]=[CH:32][N:31]=[C:30]([C:29]([F:46])([F:45])[F:28])[CH:35]=2)=[N:4][N:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: CC1(C)OB(c2ccnc(C(F)(F)F)c2)OC1(C)C
Reactant: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nn(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccnc(C(F)(F)F)c1
Reaction time: 17 h

Procedure:
To a solution of 4-(bromomethyl)-5-methoxy-2-[4-(trifluoromethyl)phenyl]-2H-1,2,3-triazole (i.e. the product of Step D, 0.525 g, 66 weight %, 1.0 mmol) in tetrahydrofuran/water (3:1, 4 mL total), was added tetrakis(triphenylphosphine)palladium(0) (0.059 g, 0.05 mmol), potassium phosphate tribasic (0.43 g, 2.0 mmol) and 2-(trifluoromethyl)pyridine-4-boronic acid pinacol ester (0.42 g, 1.5 mmol). The mixture was heated to reflux and stirred for 17 h. The reaction mixture was diluted with water (20 mL) and extracted twice with ethyl acetate (25 mL, 15 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 10% ethyl acetate in hexanes to afford the title compound (0.12 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:36][CH2:35][CH2:34][C@H:29]1[C:30]([O:32]C)=[O:31].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:36][CH2:35][CH2:34][C@H:29]4[C:30]([OH:32])=[O:31])[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (90 mg, 0.224 mmol) (D15) in Dichloromethane (DCM) (20 mL) stirred at room temperature was added methyl L-prolinate (149 mg, 0.898 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. i-PrOH was added, followed by sodium hydroxide (8.98 mg, 0.224 mmol). The reaction mixture was stirred for another 2 hours. i-PrOH was evaporated in vacuo. The aqeuous layer was extracted by EA/THF for 3 times. The combined organic solution was washed by brine. The organic layers were concentrated, and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-L-proline (E52) (24 mg) as a off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>Cl.O1CCOCC1.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2Cl)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1ccc(N2CCNCC2)c(Cl)c1
Reaction time: 0.5 h
Yield: 187.4 %

Procedure:
Tert-Butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (0.322 g, 1 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30 min. The thick white precipitate that formed was diluted with ethyl ether (10 mL) and stirred until a fine suspension resulted. The precipitate was filtered under nitrogen and dried in vacuum to afford 3-chloro-4-(piperazin-1-yl)benzonitrile hydrochloride (0.242 g, 0.937 mmol, 94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.14-3.29 (m, 4H) 3.27-3.38 (m, 4H) 7.33 (d, J=8.34 Hz, 1H) 7.80 (dd, J=8.46, 1.89 Hz, 1H) 8.02 (d, J=2.02 Hz, 1H) 9.37 (br. s., 2H); 4H) 7.25 (d, J=8.59 Hz, 1H) 7.77 (dd, J=8.34, 2.02 Hz, 1H) 7.97 (d, J=2.02 Hz, 1H); [M+H] calc'd for C11H12ClN3, 222. found, 222.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([CH3:19])[O:10]2)[C@H:6]1[O:20][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2].[CH2:24]([O:31][C:32](=[O:44])[CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][OH:43])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:24]([O:31][C:32](=[O:44])[CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][C@H:11]1[C@H:7]([NH:8][C:9](=[O:10])[CH3:19])[C@@H:6]([O:20][C:21](=[O:23])[CH3:22])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:13]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:12]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(COCCOCCOCCO)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H]2OC(C)=N[C@@H]2[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)OCc2ccccc2)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 96.2 %

Procedure:
The above prepared acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester (10.3 g, 26 mmol) and {2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethoxy}-acetic acid benzyl ester (8.62 g, 29 mmol) were mixed in 520 mL of CH2Cl2 and treated with 63 g of 4 Angstrom molecular sieves. After 1 h trimethylsilyl triflate (6.13 g, 28 mmol) was added. The reaction mixture was stirred over the weekend at ambient temperature. Triethylamine (5.21 ml, 37 mmol) was added, the molecular sieves filtered off, the filtrate diluted with CH2Cl2 and washed with NaHCO3-solution and water. Drying over Na2SO4 and evaporation of the solvent followed by flash chromatography (SiO2, ethyl acetate/AcOH/MeOH/water=60/3/3/2) afforded 15.7 g of the title compound as a brownish oil. MS (ISP): 626.6 [M−H]−.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([O:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[CH:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[C:34][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([O:16][CH:17]([CH3:19])[CH3:18])[CH:3]=3)=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CC(C)Oc1cc(I)ccc1OCCN1CCCC1
Product: CC(C)Oc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 1-[2-(4-iodo-2-isopropoxyphenoxy)ethyl]pyrrolidine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 7 mg (8% of theoretical); C28H29ClN2O2 (M=460.995); calc.: molpeak (M+H)+:461/463 (Cl); found: molpeak (M+H)+: 461/463 (Cl); HPLC-MS: 10.50 minutes (method A).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:50][CH3:51])[C:30]1[C:39]([CH2:40][N:41]([CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])[C:42](=[O:44])[CH3:43])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([CH2:40][N:41]([CH2:45][CH2:46][N:47]([CH3:48])[CH3:49])[C:42](=[O:44])[CH3:43])=[C:30]([CH:29]([O:28][CH3:27])[O:50][CH3:51])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: COCCNc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1CN(CCN(C)C)C(C)=O)CCCN2
Reactant: O=C(n1cncn1)n1cncn1
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN(CCN(C)C)C(C)=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 631 mg, 3.28 mmol) in anhydrous DMF (4 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (539 mg, 3.28 mmol) and DMF (4 ml) cooled at 0° C. After stirring for 30 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and stirred for approximately 2 h, after which a solution of N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)acetamide (intermediate 198, 460 mg, 1.313 mmol) in DMF (4 ml) was added. The reaction mixture was continued to stir for 48 h at room temperature and quenched by pouring it into aqueous NaHCO3. The reaction mixture was diluted with EtOAc, phases were separated and the water phase was extracted with EtOAc and DCM. The combined organic phases were dried using Na2SO4, filtered and evaporated. The crude product was purified by reversed phase preparative HPLC eluting with a gradient of MeCN and water (RP 5, H2O/MeCN 70:30 to 40:60 in 25 min). Fractions containing the product were collected, diluted with water and basified with NaHCO3. The mixture was concentrated and extracted with DCM, dried using Na2SO4, filtered, concentrated and dried to yield the title compound as a colorless foamy solid. (UPLC-MS 3) tR 0.73 min, ESI-MS 569.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.6:0.4) δ 13.55 (s, 0.6H), 13.52 (s, 0.4H), 8.28 (s, 1H), 7.53 (s, 1H), 7.51 (s, 0.4H), 7.40 (s, 0.6H), 6.98-6.91 (m, 1H), 5.41 (s, 0.6H), 5.40 (s, 0.4H), 4.70 (s, 0.8H), 4.65 (s, 1.2H), 3.96-3.90 (m, 2H), 3.53 (t, 2H), 3.42-3.24 (m, 13H), 2.86 (t, 0.8H), 2.81 (t, 1.2H), 2.36 (t, 1.2H), 2.30 (t, 0.8H), 2.17-2.08 (m, 7.8H), 1.96 (s, 1.2H), 1.94-1.86 (m, 2H).
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[O:6]1)[NH2:2].[Na+].[I-:28].FC(F)(F)C(O)=O>CC(=O)CC>[S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[I:28])[O:6]1)[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCC(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(I)ncnc21
Temperature: -10 °C
Reaction time: 4.5 h
Yield: 81.2 %

Procedure:
To a solution of ((3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl sulfamate (645 mg, 1.59 mmol) in 2-butanone (30.0 mL) was added NaI (4.77 g, 31.79 mmol). The reaction was cooled to −10° C. and trifluoroacetic acid (612 μL, 7.94 mmol) was added. The reaction was stirred for 4.5 hours, quenched with saturated aq NaHCO3 and extracted with DCM. The crude product was purified by flash chromatography (40% EtOAc/DCM) to isolate the title compound (0.642 g, 81%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 4-fluorobenzenesulfonyl chloride (564 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(4-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (937 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:14]=[N:13][C:12]=2[N:11](COCC[Si](C)(C)C)[CH:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+].C(N)CN>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:14]=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccccc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COc1ccccc1-c1c[nH]c2ncnc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2-methoxyphenyl)-4-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (60 mg, 0.13 mmol) in DCM (1.0 mL) was added TFA (0.964 mL, 12.5 mmol) and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was redissolved in MeOH (1.0 mL). 10 M aqueous NaOH (0.088 mL, 0.88 mmol) and ethylenediamine (17 μL, 0.25 mmol) were then added and the reaction was stirred for 30 minutes at room temperature. The reaction mixture was then acidified with TFA and purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained. The water layer was neutralized with 2 M aqueous potassium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure to give 5-(2-methoxyphenyl)-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C19H16N3O [M+H]+: 302, found 302. 1H NMR (600 MHz, DMSO-D6) δ 12.34 (s, 1H); 8.83 (s, 1H); 7.57 (d, 1H, J=2.3 Hz); 7.31 (m, 3H); 7.22 (m, 2H); 7.07 (t, 2H, J=7.6 Hz); 6.93 (t, 1H, J=7.6 Hz); 6.52 (d, 1H, J=8.2 Hz); 3.33 (s, 3H).